Cleveland Clinic Journal of Medicine

A 69-year-old diabetic woman with stage 4 non–small-cell lung cancer presented with a 3-day history of abdominal pain and loss of appetite. She was being treated with corticosteroids for a brain metastasis.

Computed tomography (CT) (Figure 1) revealed air within the bladder wall and lumen; diffuse air in the intraperitoneum and retroperitoneum; air distributed from the left iliopsoas muscle to the left femur that spread around the obturator muscle; air in the left ureter; and an abscess in the psoas major muscle extending to the ala of the ilium. A diagnosis of emphysematous cystitis complicated by extensive abdominal emphysema and abscess was made.

Blood cultures were negative, but urine cultures grew extended-spectrum beta-lactamase-producing Escherichia coli, which was sensitive to meropenem. Meropenem was given intravenously for 24 days and was stopped when levels of inflammatory markers improved and urine cultures were negative. However, on day 29, the patient developed a fever. Follow-up CT showed that the abscess in the psoas muscle had enlarged (Figure 2). We chose not to surgically drain the abscess because the patient had terminal lung cancer. The patient expired 6 days later, 35 days after her hospital admission.

EMPHYSEMATOUS CYSTITIS ASSOCIATED WITH A PSOAS MUSCLE ABSCESS

Emphysematous cystitis is an uncommon urinary tract infection characterized by air within the bladder wall and lumen that is caused by gas-producing pathogens.^1,2 The disease is often found in elderly diabetic women. Treatment of emphysematous cystitis typically includes intravenous antibiotics, adequate bladder drainage, and, for diabetic patients, appropriate glycemic control.

Psoas muscle abscess is a collection of pus in the retroperitoneal space.³ It can be primary, caused by hematogenous spread from the site of an occult infection, or secondary, caused by contiguous spread from adjacent infected organs, including those of the urinary tract. Psoas muscle abscess associated with emphysematous cystitis, as in our patient, is rare. We have seen only one other report in the medical literature.⁴

TREATMENT

The treatment of psoas muscle abscess involves the use of broad-spectrum antibiotics and drainage.⁵ Small abscesses (less than 3.5 cm) can be controlled with antibiotics alone. Image-guided percutaneous drainage is a safe, minimally invasive option. Surgery is indicated for unsuccessful percutaneous drainage, loculated abscesses, and abscesses difficult to approach percutaneously, or when the underlying disease requires definitive surgical management.

As in our patient, the presence of additional comorbid immunosuppressive conditions² such as lung cancer and treatment with corticosteroids can allow the infection to become widespread and life-threatening.

A 69-year-old diabetic woman with stage 4 non–small-cell lung cancer presented with a 3-day history of abdominal pain and loss of appetite. She was being treated with corticosteroids for a brain metastasis.

Computed tomography (CT) (Figure 1) revealed air within the bladder wall and lumen; diffuse air in the intraperitoneum and retroperitoneum; air distributed from the left iliopsoas muscle to the left femur that spread around the obturator muscle; air in the left ureter; and an abscess in the psoas major muscle extending to the ala of the ilium. A diagnosis of emphysematous cystitis complicated by extensive abdominal emphysema and abscess was made.

Blood cultures were negative, but urine cultures grew extended-spectrum beta-lactamase-producing Escherichia coli, which was sensitive to meropenem. Meropenem was given intravenously for 24 days and was stopped when levels of inflammatory markers improved and urine cultures were negative. However, on day 29, the patient developed a fever. Follow-up CT showed that the abscess in the psoas muscle had enlarged (Figure 2). We chose not to surgically drain the abscess because the patient had terminal lung cancer. The patient expired 6 days later, 35 days after her hospital admission.

EMPHYSEMATOUS CYSTITIS ASSOCIATED WITH A PSOAS MUSCLE ABSCESS

Emphysematous cystitis is an uncommon urinary tract infection characterized by air within the bladder wall and lumen that is caused by gas-producing pathogens.^1,2 The disease is often found in elderly diabetic women. Treatment of emphysematous cystitis typically includes intravenous antibiotics, adequate bladder drainage, and, for diabetic patients, appropriate glycemic control.

Psoas muscle abscess is a collection of pus in the retroperitoneal space.³ It can be primary, caused by hematogenous spread from the site of an occult infection, or secondary, caused by contiguous spread from adjacent infected organs, including those of the urinary tract. Psoas muscle abscess associated with emphysematous cystitis, as in our patient, is rare. We have seen only one other report in the medical literature.⁴

TREATMENT

The treatment of psoas muscle abscess involves the use of broad-spectrum antibiotics and drainage.⁵ Small abscesses (less than 3.5 cm) can be controlled with antibiotics alone. Image-guided percutaneous drainage is a safe, minimally invasive option. Surgery is indicated for unsuccessful percutaneous drainage, loculated abscesses, and abscesses difficult to approach percutaneously, or when the underlying disease requires definitive surgical management.

As in our patient, the presence of additional comorbid immunosuppressive conditions² such as lung cancer and treatment with corticosteroids can allow the infection to become widespread and life-threatening.

A 69-year-old diabetic woman with stage 4 non–small-cell lung cancer presented with a 3-day history of abdominal pain and loss of appetite. She was being treated with corticosteroids for a brain metastasis.

Computed tomography (CT) (Figure 1) revealed air within the bladder wall and lumen; diffuse air in the intraperitoneum and retroperitoneum; air distributed from the left iliopsoas muscle to the left femur that spread around the obturator muscle; air in the left ureter; and an abscess in the psoas major muscle extending to the ala of the ilium. A diagnosis of emphysematous cystitis complicated by extensive abdominal emphysema and abscess was made.

Blood cultures were negative, but urine cultures grew extended-spectrum beta-lactamase-producing Escherichia coli, which was sensitive to meropenem. Meropenem was given intravenously for 24 days and was stopped when levels of inflammatory markers improved and urine cultures were negative. However, on day 29, the patient developed a fever. Follow-up CT showed that the abscess in the psoas muscle had enlarged (Figure 2). We chose not to surgically drain the abscess because the patient had terminal lung cancer. The patient expired 6 days later, 35 days after her hospital admission.

EMPHYSEMATOUS CYSTITIS ASSOCIATED WITH A PSOAS MUSCLE ABSCESS

Emphysematous cystitis is an uncommon urinary tract infection characterized by air within the bladder wall and lumen that is caused by gas-producing pathogens.^1,2 The disease is often found in elderly diabetic women. Treatment of emphysematous cystitis typically includes intravenous antibiotics, adequate bladder drainage, and, for diabetic patients, appropriate glycemic control.

Psoas muscle abscess is a collection of pus in the retroperitoneal space.³ It can be primary, caused by hematogenous spread from the site of an occult infection, or secondary, caused by contiguous spread from adjacent infected organs, including those of the urinary tract. Psoas muscle abscess associated with emphysematous cystitis, as in our patient, is rare. We have seen only one other report in the medical literature.⁴

TREATMENT

The treatment of psoas muscle abscess involves the use of broad-spectrum antibiotics and drainage.⁵ Small abscesses (less than 3.5 cm) can be controlled with antibiotics alone. Image-guided percutaneous drainage is a safe, minimally invasive option. Surgery is indicated for unsuccessful percutaneous drainage, loculated abscesses, and abscesses difficult to approach percutaneously, or when the underlying disease requires definitive surgical management.

As in our patient, the presence of additional comorbid immunosuppressive conditions² such as lung cancer and treatment with corticosteroids can allow the infection to become widespread and life-threatening.

Taurine—an amino acid found in abundance in the human brain, retina, heart, and reproductive organs, as well as in meat and seafood—is also a major ingredient in “energy drinks” (Table 1).^1,2 Given the tremendous popularity of these drinks in the United States, it would seem important to know and to recognize taurine’s neuroendocrine effects. Unfortunately, little is known about the effects of taurine supplementation in humans.

This paper reviews the sparse data to provide clinicians some background on the structure, synthesis, distribution, metabolism, mechanisms, effects, safety, and proposed therapeutic targets of taurine.

TAURINE’S THERAPEUTIC POTENTIAL

Taurine has been reported to have widespread anti-inflammatory actions.^3,4 Taurine supplementation has been proposed to have beneficial effects in the treatment of epilepsy,⁵ heart failure,^6,7 cystic fibrosis,⁸ and diabetes⁹ and has been shown in animal studies to protect against neurotoxic insults from alcohol, ammonia, lead, and other substances.^10–16

In addition, taurine analogues such as homotaurine and N-acetyl-homotaurine (acamprosate) have been probed for possible therapeutic applications. Homotaurine has been shown to have antiamyloid activity that could in theory protect against the progression of Alzheimer disease,¹⁷ and acam­prosate is approved by the US Food and Drug Administration (FDA) for the treatment of alcohol use disorders.¹⁸

TAURINE CONSUMPTION

Energy drinks are widely consumed in the United States, with an estimated 354 million gallons sold in 2009, or approximately 5.25 L/year per person over age 10.¹ In 2012, US sales of energy drinks exceeded $12 billion,¹⁹ with young men, particularly those in the military deployed in war zones, being the biggest consumers.^20–22 Analyses have found that of 49 nonalcoholic energy drinks tested, the average concentration of taurine was 3,180 mg/L, or approximately 750 mg per 8-oz serving.^23,24 Popular brands include Red Bull, Monster, Rockstar (Table 1), NOS, Amp, and Full Throttle.

Taurine is plentiful in the human body, which contains up to 1 g of taurine per kg.²⁵ Foods such as poultry, beef, pork, seafood, and processed meats have a high taurine content (Table 2).^26–29 People who eat meat and seafood have plentiful taurine intake, whereas vegetarians and vegans consume much less and have significantly lower circulating levels³⁰ because plants do not contain taurine in appreciable amounts.^26,29

The typical American diet provides between 123 and 178 mg of taurine daily.²⁶ Consumption of one 8-oz energy drink can increase the average intake 6 to 16 times. A lacto-ovo vegetarian diet provides only about 17 mg of taurine daily, and an 8-oz energy drink can increase the average intake by 44 to 117 mg.²⁶ And since a vegan diet provides essentially no taurine,³⁰ energy drink intake in any amount would constitute a major relative increase in taurine consumption.

ATTEMPTS TO STUDY TAURINE'S EFFECTS

Since most clinical trials to date have looked at the effects of taurine in combination with other ingredients such as caffeine, creatine, and glucose^31–35 in drinks such as Red Bull, these studies cannot be used to determine the effects of taurine alone. In the few clinical trials that have tested isolated taurine consumption, data are not sufficient to make a conclusion on direct effects on energy metabolism.

Rutherford et al³⁶ tested the effect of oral taurine supplementation (1,660 mg) on endurance in trained male cyclists 1 hour before exercise, but observed no effect on fluid intake, heart rate, subjective exertion, or time-trial performance. A small increase (16%) in total fat oxidation was observed during the 90-minute exercise period. Since mitochondria are the main location of fatty acid degradation, this effect may be attributed to taurine supplementation, with subsequent improvement in mitochondrial function.

Zhang et al³⁷ found a 30-second increase in cycling energy capacity after 7 days of 6 g oral taurine supplementation, but the study was neither blinded nor placebo-controlled.

Kammerer et al³⁸ tested the effect of 1 g of taurine supplementation on physical and mental performance in young adult soldiers 45 minutes before physical fitness and cognitive testing. This double-blind, placebo-controlled randomized trial found no effect of taurine on cardiorespiratory fitness indices, concentration, or immediate memory, nor did it find any effect of an 80-mg dose of caffeine.

In sum, the available data are far from sufficient to determine the direct effect of taurine consumption on energy metabolism in healthy people.

PHARMACOLOGY OF TAURINE

Chemical structure

Taurine, or 2-aminoethane sulfonic acid, is a conditionally essential amino acid, ie, we can usually make enough in our own bodies. It was first prepared on a large scale for physiologic investigation almost 90 years ago, through the purification of ox bile.³⁹ It can be obtained either exogenously through dietary sources or endogenously through biosynthesis from methionine and cysteine precursors, both essential sulfur-containing alpha-amino acids.⁴⁰ Both sources are important to maintain physiologic levels of taurine, and either can help compensate for the other in cases of deficiency.⁴¹

The structure of taurine has two main differences from the essential amino acids. First, taurine’s amino group is attached to the beta-carbon rather than the alpha-carbon, making it a beta-amino acid instead of an alpha-amino acid.⁴² Second, the acid group in taurine is sulfonic acid, whereas the essential amino acids have a carboxylic acid.⁴³ Because of its distinctive structure, taurine is not used as a structural unit in proteins,⁴³ existing mostly as a free amino acid within cells, readily positioned to perform several unique functions.

Synthesis

De novo synthesis of taurine involves several enzymes and at least five pathways,⁴⁴ mostly differing by the order in which sulfur is oxidized and decarboxylated.⁴⁵

The rate-limiting enzyme of the predominant pathway is thought to be cysteine sulfinate decarboxylase (CSD), and its presence within an organ indicates involvement in taurine production.⁴⁴ CSD has been found in the liver,⁴⁶ the primary site of taurine biosynthesis, as well as in the retina,⁴⁷ brain,⁴⁸ kidney,⁴⁹ mammary glands,^50,51 and reproductive organs.⁵²

Distribution

Taurine levels are highest in electrically excitable tissues such as the central nervous system, retina, and heart; in secretory structures such as the pineal gland and the pituitary gland (including the posterior lobe or neurohypophysis); and in platelets²⁵ and neutrophils.⁵³

In the fetal brain, the taurine concentration is higher than that of any other amino acid,⁵⁴ but the concentration in the brain decreases with advancing age, whereas glutamate levels increase over time to make it the predominant amino acid in the adult brain.⁵⁴ Regardless, taurine is still the second most prevalent amino acid in the adult brain, its levels comparable to those of gamma-aminobutyric acid (GABA).⁵⁵

Taurine has also been found in variable amounts in the liver, muscle, kidney, pancreas, spleen, small intestine, and lungs,⁵⁶ as well as in several other locations.^45,57

Taurine is also present in the male and female reproductive organs. In male rats, taurine and taurine biosynthesis have been localized to Leydig cells of the testes, the cellular source of testosterone in males, as well as the cremaster muscle, efferent ducts, and peritubular myoid cells surrounding seminiferous tubules.⁵⁸ More recently, taurine has been detected in the testes of humans⁵⁹ and is also found in sperm and seminal fluid.⁶⁰ Levels of taurine in spermatozoa are correlated with sperm quality, presumably by protecting against lipid peroxidation through taurine’s antioxidant effects,^61,62 as well as through contribution to the spermatozoa maturation process by facilitating the capacitation, motility, and acrosomal reaction of sperm.⁶³

In female rats, taurine has been found in uterine tissue,⁶⁴ oviducts,⁶⁵ uterine fluid (where it is the predominant amino acid),⁶⁶ and thecal cells of developing follicles of ovaries, cells responsible for the synthesis of androgens such as testosterone and androstenedione.⁶⁵ Taurine is also a major component of human breast milk⁶⁷ and is important for proper neonatal nutrition.⁶⁸

Metabolism and excretion

Ninety-five percent of taurine is excreted in urine, about 70% as taurine itself, and the rest as sulfate. Most of the sulfate derived from taurine is produced by bacterial metabolism in the gut and then absorbed.⁶⁹ However, taurine can also be conjugated with bile acids to act as a detergent in lipid emulsification.⁷⁰ In this form, it may be subjected to the enterohepatic circulation, which gives bacteria another chance to convert it into inorganic sulfate for excretion in urine.⁶⁹

MECHANISMS AND NEUROENDOCRINE EFFECTS

As a free amino acid, taurine has widespread distribution and unique biochemical and physiologic properties and exhibits several organ-specific functions; however, indisputable evidence of a taurine-specific receptor is lacking, and its putative existence⁷¹ is controversial.⁷² Nonetheless, taurine is a neuromodulator with a variety of actions.

Neurotransmission

Taurine is known to be an inhibitory neurotransmitter and neuromodulator.⁷³ It is structurally analogous to GABA, the main inhibitory neurotransmitter in the brain.⁴⁵ Accordingly, it binds to GABA receptors to serve as an agonist,^74,75 causing neuronal hyperpolarization and inhibition. Taurine has an even higher affinity for glycine receptors⁷⁵ where it has long been known to act as an agonist.⁷⁶ GABA and glycine receptors both belong to the Cys-loop receptor superfamily,⁷⁷ with conservation of subunits that allows taurine to bind each receptor, albeit at different affinities. The binding effects of taurine on GABA and glycine receptors have not been well documented quantitatively; however, it is known that taurine has a substantially lower affinity than GABA and glycine for their respective receptors.⁷⁶

Catecholamines and the sympathetic nervous system

Surprisingly little is known about the effects of taurine on norepinephrine, dopamine, and the human sympathetic nervous system.⁷⁸ Humans with borderline hypertension given 6 g of taurine orally for 7 days⁷⁹ experienced decreases in epinephrine secretion and blood pressure, but normotensive study participants did not experience similar results, possibly because of a better ability to regulate sympathetic tone. Mizushima et al⁸⁰ showed that a longer period of taurine intake (6 g orally for 3 weeks) could elicit a decrease in norepinephrine in healthy men with normal blood pressure. Other similar studies^81–83 also suggested interplay between taurine and catecholamines, but the extent is still undetermined.

Growth hormone, prolactin, sex hormones, and cortisol

Taurine appears to have a complex relationship with several hormones, although its direct effects on hormone secretion remain obscure. Clinical studies of the acute and chronic neuroendocrine effects of taurine loading in humans are needed.

In female rats, secretion of prolactin is increased by the intraventricular injection of 5 μL of 2.0 μmol taurine over a 10-minute period.⁸⁴ Ikuyama et al⁸⁵ found an increase in prolactin and growth hormone secretion in adult male rats given 10 μL of 0.25 μmol and 1.0 μmol taurine intraventricularly, yet a higher dose of 4.0 μmol had no effect on either hormone. Furthermore, prolactin receptor deficiency is seen in CSD knockout mice, but the receptor is restored with taurine supplementation.⁸⁶

Mantovani and DeVivo⁸⁷ reported that 375 to 8,000 mg/day of taurine given orally for 4 to 6 months to epileptic patients stimulated the secretion of growth hormone. However, in another study, a single 75-mg/kg dose of oral taurine did not trigger an acute increase in levels of growth hormone or prolactin in humans.⁸⁸ Energy drinks may contain up to 1,000 mg of taurine per 8-oz serving, but the effects of larger doses on growth hormone, which is banned as a supplement by major athletic organizations because of its anabolic and possible performance-enhancing effects, remain to be determined.

Taurine may have effects on human sex hormones, based on the limited observations in rodents.^89–94

Although human salivary cortisol concentrations were purportedly assessed in response to 2,000 mg of oral taurine,⁹⁵ the methods and reported data are not adequate to draw any conclusions.

Energy metabolism

Mammals are unable to directly use taurine in energy production because they cannot directly reduce it.²⁵ Instead, bacteria in the gut use it as a source of energy, carbon, nitrogen, and sulfur.⁹⁶ However, taurine deficiency appears to impair the cellular respiratory chain, resulting in diminished production of adenosine triphosphate and diminished uptake of long-chain fatty acids by mitochondria, at least in the heart.⁹⁷

Taurine is present in human mitochondria and regulates mitochondrial function. For example, taurine in mitochondria assists in conjugation of transfer RNA for leucine, lysine, glutamate, and glutamine.⁹⁸ In TauT knockout mice, deficiency of taurine causes mitochondrial dysfunction, triggering a greater than 80% decrease in exercise capacity.⁹⁹ Several studies in rodents have shown increased exercise capacity after taurine supplementation.^100–102 In addition, taurine is critical for the growth of blastocytes, skeletal muscle, and myocardium; it is necessary for mitochondrial development and is also important for muscular endurance.^103,104

Antioxidation, anti-inflammation, and other functions

Taurine is a major antioxidant, scavenging reactive oxygen and protecting against oxidative stress to organs including the brain,^97,105,106 where it increasingly appears to have neuroprotective effects.^107,108

Cellular taurine also has anti-inflammatory actions.³ One of the proposed mechanisms is taurine inhibition of NF-kappa B, an important transcription factor for the synthesis of pro-inflammatory cytokines.⁴ This function may be important in protecting polyunsaturated fatty acids from oxidative stress—helping to maintain and stabilize the structure and function of plasma membranes within the lungs,¹⁰⁹ heart,¹¹⁰ brain,¹¹¹ liver,¹¹² and spermatozoa.^61,62

Taurine is also conjugated to bile acids synthesized in the liver, forming bile salts⁷⁰ that act as detergents to help emulsify and digest lipids in the body. In addition, taurine facilitates xenobiotic detoxification in the liver by conjugating with several drugs to aid in their excretion.²⁵ Taurine is also implicated in calcium modulation¹¹³ and homeostasis.¹¹⁴ Through inhibition of several types of calcium channels, taurine has been shown to decrease calcium influx into cells, effectively serving a cytoprotective role against calcium overload.^115,116

TAURINE DEFICIENCY

Fetal and neonatal deficiency

Though taurine is considered nonessential in adults because it can be readily synthesized endogenously, it is thought to be conditionally essential in neonatal nutrition.⁶⁸ It is the second most abundant free amino acid in human breast milk¹¹⁷ and the most abundant free amino acid in fetal brain.¹¹⁸ In cases of long-term parenteral nutrition, neonates can become drastically taurine deficient¹¹⁹ due to suboptimal CSD activity,¹¹⁸ leading to retinal dysfunction.⁴¹ Taurine deficiencies can lead to functional and structural brain damage.¹¹⁸ Moreover, maternal taurine deficiency results in neurologic abnormalities in offspring¹²⁰ and may lead to oxidative stress throughout life.¹²¹

In 1984, the FDA approved the inclusion of taurine in infant formulas based on research showing that taurine-deficient infants had impaired fat absorption, bile acid secretion, retinal function, and hepatic function.¹²² But still under debate are the amount and duration of taurine supplementation required by preterm and low-birth-weight infants, as several randomized controlled trials failed to show statistically significant effects on growth.¹²³ Nonetheless, given the alleged detrimental ramifications of a lack of taurine supplementation, as well as the ethical dilemma of performing additional research trials on infants, it is presumed that infant formulas and parenteral nutrition for preterm and low-birth-weight infants will continue to contain taurine.

Age- and disease-related deficiency

Although taurine deficiency is rare in neonates, it is perhaps inevitable with advancing age. Healthy elderly patients ages 61 to 81 have up to a 49% decrease in plasma taurine concentration compared with healthy individuals ages 27 to 57.¹²⁴ While reduced renal retention¹²⁵ and taurine intake¹²⁶ can account for depressed taurine levels, Eppler and Dawson¹²⁷ found that tissue and circulating taurine concentrations decrease over the human life span primarily due to an age-dependent depletion of CSD activity in the liver. This effectively impairs the biosynthesis of endogenous taurine from cysteine or methionine or both, forcing a greater reliance on exogenous sources.

While specific mechanisms have not been fully elucidated, taurine deficiency has also been identified in patients suffering from diseases including but not limited to disorders of bone (osteogenesis imperfecta, osteoporosis),¹²⁸ blood (acute myelogenous leukemia),¹²⁹ central nervous system (schizophrenia, Friedreich ataxia-spinocerebellar degeneration),^130,131 retina (retinitis pigmentosa),¹³² circulatory system and heart (essential hypertension, atherosclerosis),¹³³ digestion (Gaucher disease),¹³⁴ absorption (short-bowel syndrome),¹³⁵ cellular proliferation (cancer),¹³⁶ and membrane channels (cystic fibrosis),¹³⁷ as well as in patients restricted to long-term parenteral nutrition.¹³⁸ However, the apparent correlation between taurine deficiency and these conditions does not necessarily mean causation; more study is needed to elucidate a direct connection.

SAFETY AND TOXICITY OF TAURINE SUPPLEMENTATION

An upper safe level of intake for taurine has not been established. To date, several studies have involved heavy taurine supplementation without serious adverse effects. While the largest dosage of taurine tested in humans appears to be 10 g/day for 6 months,¹³⁹ a number of studies have used 1 to 6 g/day for periods of 1 week to 1 year.¹⁴⁰ However, the assessment of potential acute, subacute, and chronic adverse effects has not been comprehensive. The Scientific Committee on Food of the European Commission¹⁴¹ reviewed several toxicologic studies on taurine through 2003 and were unable to expose any carcinogenic or teratogenic potential. Nevertheless, based on the available data from trials in humans and lower animals, Shao and Hathcock¹⁴⁰ suggested an observed safe level of taurine of 3 g/day, a conservatively smaller dose that carries a higher level of confidence. Because there is no “observed adverse effect level” for daily taurine intake,¹⁴¹ more research must be done to ensure safety of higher amounts of taurine administration and to define a tolerable upper limit of intake.

Interactions with medications

To date, the literature is scarce regarding potential interactions between taurine and commonly used medications.

Although no evidence specifically links taurine with adverse effects when used concurrently with other medications, there may be a link between taurine supplementation and various cytochrome P450 systems responsible for hepatic drug metabolism. Specifically, taurine inhibits cytochrome P450 2E1, a highly conserved xenobiotic-metabolizing P450 responsible for the breakdown of more than 70 substrates, including several commonly used anesthetics, analgesics, antidepressants, antibacterials, and antiepileptics.¹⁴² Of note, taurine may contribute to the attenuation of oxidative stress in the liver in the presence of alcohol¹⁴³ and acetaminophen,¹⁴⁴ two substances frequently used and abused. Since the P450 2E1 system catalyzes comparable reactions in rodents and humans,¹⁴² rodents should plausibly serve as a model for further testing of the effects of taurine on various substrates.

POTENTIAL THERAPEUTIC APPLICATIONS

More analysis is needed to fully unlock and understand taurine’s potential value in healthcare.

Correction of late-life taurine decline in humans could be beneficial for cognitive performance, energy metabolism, sexual function, and vision, but clinical studies remain to be performed. While a decline in taurine with age may intensify the stress caused by reactive oxygen species, taurine supplementation has been shown to decrease the presence of oxidative markers¹²⁷ and to serve a neuroprotective role in rodents.^145,146 Taurine levels increase in the hippocampus after experimentally induced gliosis¹⁴⁷ and are neuroprotective against glutamate excitotoxicity.^148,149 Furthermore, data in Alzheimer disease, Huntington disease, and brain ischemia experimental models show that taurine inhibits neuronal death (apoptosis).^13,150,151 Taurine has even been proposed as a potential preventive treatment for Alzheimer dementia, as it stabilizes protein conformations to prevent their aggregation and subsequent dysfunction.¹⁵² Although improvement in memory and cognitive performance has been linked to taurine supplementation in old mice,^145,153 similar results have not been found in adult mice whose taurine levels are within normal limits. Taurine also has transient anticonvulsant effects in some epileptic humans.¹⁵⁴

Within the male reproductive organs, the age-related decline in taurine may or may not have implications regarding sexuality, as only very limited rat data are available.^89–91

In cats, taurine supplementation has been found to prevent the progressive degeneration of retinal photoreceptors seen in retinitis pigmentosa, a genetic disease that causes the loss of vision.¹⁵⁵

While several energy drink companies have advertised that taurine plays a role in improving cognitive and physical performance, there are few human studies that examine this contention in the absence of confounding factors such as caffeine or glucose.^36,37,95 Taurine supplementation in patients with heart failure has been shown to increase exercise capacity vs placebo.¹⁵⁶ This supports the idea that in cases of taurine deficiency, such as those seen in cardiomyopathy,¹⁵⁷ taurine supplementation could have restorative effects. However, we are not aware of any double-blind, placebo-controlled clinical trial of taurine alone in healthy patients that measured energy parameters as clinical outcomes.

Although it remains possible that acute supraphysiologic taurine levels achieved by supplementation could transiently trigger various psychoneuroendocrine responses in healthy people, clinical research is needed in which taurine is the sole intervention. At present, the most compelling clinical reason to prescribe or recommend taurine supplementation is taurine deficiency.

Taurine—an amino acid found in abundance in the human brain, retina, heart, and reproductive organs, as well as in meat and seafood—is also a major ingredient in “energy drinks” (Table 1).^1,2 Given the tremendous popularity of these drinks in the United States, it would seem important to know and to recognize taurine’s neuroendocrine effects. Unfortunately, little is known about the effects of taurine supplementation in humans.

This paper reviews the sparse data to provide clinicians some background on the structure, synthesis, distribution, metabolism, mechanisms, effects, safety, and proposed therapeutic targets of taurine.

TAURINE’S THERAPEUTIC POTENTIAL

Taurine has been reported to have widespread anti-inflammatory actions.^3,4 Taurine supplementation has been proposed to have beneficial effects in the treatment of epilepsy,⁵ heart failure,^6,7 cystic fibrosis,⁸ and diabetes⁹ and has been shown in animal studies to protect against neurotoxic insults from alcohol, ammonia, lead, and other substances.^10–16

In addition, taurine analogues such as homotaurine and N-acetyl-homotaurine (acamprosate) have been probed for possible therapeutic applications. Homotaurine has been shown to have antiamyloid activity that could in theory protect against the progression of Alzheimer disease,¹⁷ and acam­prosate is approved by the US Food and Drug Administration (FDA) for the treatment of alcohol use disorders.¹⁸

TAURINE CONSUMPTION

Energy drinks are widely consumed in the United States, with an estimated 354 million gallons sold in 2009, or approximately 5.25 L/year per person over age 10.¹ In 2012, US sales of energy drinks exceeded $12 billion,¹⁹ with young men, particularly those in the military deployed in war zones, being the biggest consumers.^20–22 Analyses have found that of 49 nonalcoholic energy drinks tested, the average concentration of taurine was 3,180 mg/L, or approximately 750 mg per 8-oz serving.^23,24 Popular brands include Red Bull, Monster, Rockstar (Table 1), NOS, Amp, and Full Throttle.

Taurine is plentiful in the human body, which contains up to 1 g of taurine per kg.²⁵ Foods such as poultry, beef, pork, seafood, and processed meats have a high taurine content (Table 2).^26–29 People who eat meat and seafood have plentiful taurine intake, whereas vegetarians and vegans consume much less and have significantly lower circulating levels³⁰ because plants do not contain taurine in appreciable amounts.^26,29

The typical American diet provides between 123 and 178 mg of taurine daily.²⁶ Consumption of one 8-oz energy drink can increase the average intake 6 to 16 times. A lacto-ovo vegetarian diet provides only about 17 mg of taurine daily, and an 8-oz energy drink can increase the average intake by 44 to 117 mg.²⁶ And since a vegan diet provides essentially no taurine,³⁰ energy drink intake in any amount would constitute a major relative increase in taurine consumption.

ATTEMPTS TO STUDY TAURINE'S EFFECTS

Since most clinical trials to date have looked at the effects of taurine in combination with other ingredients such as caffeine, creatine, and glucose^31–35 in drinks such as Red Bull, these studies cannot be used to determine the effects of taurine alone. In the few clinical trials that have tested isolated taurine consumption, data are not sufficient to make a conclusion on direct effects on energy metabolism.

Rutherford et al³⁶ tested the effect of oral taurine supplementation (1,660 mg) on endurance in trained male cyclists 1 hour before exercise, but observed no effect on fluid intake, heart rate, subjective exertion, or time-trial performance. A small increase (16%) in total fat oxidation was observed during the 90-minute exercise period. Since mitochondria are the main location of fatty acid degradation, this effect may be attributed to taurine supplementation, with subsequent improvement in mitochondrial function.

Zhang et al³⁷ found a 30-second increase in cycling energy capacity after 7 days of 6 g oral taurine supplementation, but the study was neither blinded nor placebo-controlled.

Kammerer et al³⁸ tested the effect of 1 g of taurine supplementation on physical and mental performance in young adult soldiers 45 minutes before physical fitness and cognitive testing. This double-blind, placebo-controlled randomized trial found no effect of taurine on cardiorespiratory fitness indices, concentration, or immediate memory, nor did it find any effect of an 80-mg dose of caffeine.

In sum, the available data are far from sufficient to determine the direct effect of taurine consumption on energy metabolism in healthy people.

PHARMACOLOGY OF TAURINE

Chemical structure

Taurine, or 2-aminoethane sulfonic acid, is a conditionally essential amino acid, ie, we can usually make enough in our own bodies. It was first prepared on a large scale for physiologic investigation almost 90 years ago, through the purification of ox bile.³⁹ It can be obtained either exogenously through dietary sources or endogenously through biosynthesis from methionine and cysteine precursors, both essential sulfur-containing alpha-amino acids.⁴⁰ Both sources are important to maintain physiologic levels of taurine, and either can help compensate for the other in cases of deficiency.⁴¹

The structure of taurine has two main differences from the essential amino acids. First, taurine’s amino group is attached to the beta-carbon rather than the alpha-carbon, making it a beta-amino acid instead of an alpha-amino acid.⁴² Second, the acid group in taurine is sulfonic acid, whereas the essential amino acids have a carboxylic acid.⁴³ Because of its distinctive structure, taurine is not used as a structural unit in proteins,⁴³ existing mostly as a free amino acid within cells, readily positioned to perform several unique functions.

Synthesis

De novo synthesis of taurine involves several enzymes and at least five pathways,⁴⁴ mostly differing by the order in which sulfur is oxidized and decarboxylated.⁴⁵

The rate-limiting enzyme of the predominant pathway is thought to be cysteine sulfinate decarboxylase (CSD), and its presence within an organ indicates involvement in taurine production.⁴⁴ CSD has been found in the liver,⁴⁶ the primary site of taurine biosynthesis, as well as in the retina,⁴⁷ brain,⁴⁸ kidney,⁴⁹ mammary glands,^50,51 and reproductive organs.⁵²

Distribution

Taurine levels are highest in electrically excitable tissues such as the central nervous system, retina, and heart; in secretory structures such as the pineal gland and the pituitary gland (including the posterior lobe or neurohypophysis); and in platelets²⁵ and neutrophils.⁵³

In the fetal brain, the taurine concentration is higher than that of any other amino acid,⁵⁴ but the concentration in the brain decreases with advancing age, whereas glutamate levels increase over time to make it the predominant amino acid in the adult brain.⁵⁴ Regardless, taurine is still the second most prevalent amino acid in the adult brain, its levels comparable to those of gamma-aminobutyric acid (GABA).⁵⁵

Taurine has also been found in variable amounts in the liver, muscle, kidney, pancreas, spleen, small intestine, and lungs,⁵⁶ as well as in several other locations.^45,57

Taurine is also present in the male and female reproductive organs. In male rats, taurine and taurine biosynthesis have been localized to Leydig cells of the testes, the cellular source of testosterone in males, as well as the cremaster muscle, efferent ducts, and peritubular myoid cells surrounding seminiferous tubules.⁵⁸ More recently, taurine has been detected in the testes of humans⁵⁹ and is also found in sperm and seminal fluid.⁶⁰ Levels of taurine in spermatozoa are correlated with sperm quality, presumably by protecting against lipid peroxidation through taurine’s antioxidant effects,^61,62 as well as through contribution to the spermatozoa maturation process by facilitating the capacitation, motility, and acrosomal reaction of sperm.⁶³

In female rats, taurine has been found in uterine tissue,⁶⁴ oviducts,⁶⁵ uterine fluid (where it is the predominant amino acid),⁶⁶ and thecal cells of developing follicles of ovaries, cells responsible for the synthesis of androgens such as testosterone and androstenedione.⁶⁵ Taurine is also a major component of human breast milk⁶⁷ and is important for proper neonatal nutrition.⁶⁸

Metabolism and excretion

Ninety-five percent of taurine is excreted in urine, about 70% as taurine itself, and the rest as sulfate. Most of the sulfate derived from taurine is produced by bacterial metabolism in the gut and then absorbed.⁶⁹ However, taurine can also be conjugated with bile acids to act as a detergent in lipid emulsification.⁷⁰ In this form, it may be subjected to the enterohepatic circulation, which gives bacteria another chance to convert it into inorganic sulfate for excretion in urine.⁶⁹

MECHANISMS AND NEUROENDOCRINE EFFECTS

As a free amino acid, taurine has widespread distribution and unique biochemical and physiologic properties and exhibits several organ-specific functions; however, indisputable evidence of a taurine-specific receptor is lacking, and its putative existence⁷¹ is controversial.⁷² Nonetheless, taurine is a neuromodulator with a variety of actions.

Neurotransmission

Taurine is known to be an inhibitory neurotransmitter and neuromodulator.⁷³ It is structurally analogous to GABA, the main inhibitory neurotransmitter in the brain.⁴⁵ Accordingly, it binds to GABA receptors to serve as an agonist,^74,75 causing neuronal hyperpolarization and inhibition. Taurine has an even higher affinity for glycine receptors⁷⁵ where it has long been known to act as an agonist.⁷⁶ GABA and glycine receptors both belong to the Cys-loop receptor superfamily,⁷⁷ with conservation of subunits that allows taurine to bind each receptor, albeit at different affinities. The binding effects of taurine on GABA and glycine receptors have not been well documented quantitatively; however, it is known that taurine has a substantially lower affinity than GABA and glycine for their respective receptors.⁷⁶

Catecholamines and the sympathetic nervous system

Surprisingly little is known about the effects of taurine on norepinephrine, dopamine, and the human sympathetic nervous system.⁷⁸ Humans with borderline hypertension given 6 g of taurine orally for 7 days⁷⁹ experienced decreases in epinephrine secretion and blood pressure, but normotensive study participants did not experience similar results, possibly because of a better ability to regulate sympathetic tone. Mizushima et al⁸⁰ showed that a longer period of taurine intake (6 g orally for 3 weeks) could elicit a decrease in norepinephrine in healthy men with normal blood pressure. Other similar studies^81–83 also suggested interplay between taurine and catecholamines, but the extent is still undetermined.

Growth hormone, prolactin, sex hormones, and cortisol

Taurine appears to have a complex relationship with several hormones, although its direct effects on hormone secretion remain obscure. Clinical studies of the acute and chronic neuroendocrine effects of taurine loading in humans are needed.

In female rats, secretion of prolactin is increased by the intraventricular injection of 5 μL of 2.0 μmol taurine over a 10-minute period.⁸⁴ Ikuyama et al⁸⁵ found an increase in prolactin and growth hormone secretion in adult male rats given 10 μL of 0.25 μmol and 1.0 μmol taurine intraventricularly, yet a higher dose of 4.0 μmol had no effect on either hormone. Furthermore, prolactin receptor deficiency is seen in CSD knockout mice, but the receptor is restored with taurine supplementation.⁸⁶

Mantovani and DeVivo⁸⁷ reported that 375 to 8,000 mg/day of taurine given orally for 4 to 6 months to epileptic patients stimulated the secretion of growth hormone. However, in another study, a single 75-mg/kg dose of oral taurine did not trigger an acute increase in levels of growth hormone or prolactin in humans.⁸⁸ Energy drinks may contain up to 1,000 mg of taurine per 8-oz serving, but the effects of larger doses on growth hormone, which is banned as a supplement by major athletic organizations because of its anabolic and possible performance-enhancing effects, remain to be determined.

Taurine may have effects on human sex hormones, based on the limited observations in rodents.^89–94

Although human salivary cortisol concentrations were purportedly assessed in response to 2,000 mg of oral taurine,⁹⁵ the methods and reported data are not adequate to draw any conclusions.

Energy metabolism

Mammals are unable to directly use taurine in energy production because they cannot directly reduce it.²⁵ Instead, bacteria in the gut use it as a source of energy, carbon, nitrogen, and sulfur.⁹⁶ However, taurine deficiency appears to impair the cellular respiratory chain, resulting in diminished production of adenosine triphosphate and diminished uptake of long-chain fatty acids by mitochondria, at least in the heart.⁹⁷

Taurine is present in human mitochondria and regulates mitochondrial function. For example, taurine in mitochondria assists in conjugation of transfer RNA for leucine, lysine, glutamate, and glutamine.⁹⁸ In TauT knockout mice, deficiency of taurine causes mitochondrial dysfunction, triggering a greater than 80% decrease in exercise capacity.⁹⁹ Several studies in rodents have shown increased exercise capacity after taurine supplementation.^100–102 In addition, taurine is critical for the growth of blastocytes, skeletal muscle, and myocardium; it is necessary for mitochondrial development and is also important for muscular endurance.^103,104

Antioxidation, anti-inflammation, and other functions

Taurine is a major antioxidant, scavenging reactive oxygen and protecting against oxidative stress to organs including the brain,^97,105,106 where it increasingly appears to have neuroprotective effects.^107,108

Cellular taurine also has anti-inflammatory actions.³ One of the proposed mechanisms is taurine inhibition of NF-kappa B, an important transcription factor for the synthesis of pro-inflammatory cytokines.⁴ This function may be important in protecting polyunsaturated fatty acids from oxidative stress—helping to maintain and stabilize the structure and function of plasma membranes within the lungs,¹⁰⁹ heart,¹¹⁰ brain,¹¹¹ liver,¹¹² and spermatozoa.^61,62

Taurine is also conjugated to bile acids synthesized in the liver, forming bile salts⁷⁰ that act as detergents to help emulsify and digest lipids in the body. In addition, taurine facilitates xenobiotic detoxification in the liver by conjugating with several drugs to aid in their excretion.²⁵ Taurine is also implicated in calcium modulation¹¹³ and homeostasis.¹¹⁴ Through inhibition of several types of calcium channels, taurine has been shown to decrease calcium influx into cells, effectively serving a cytoprotective role against calcium overload.^115,116

TAURINE DEFICIENCY

Fetal and neonatal deficiency

Though taurine is considered nonessential in adults because it can be readily synthesized endogenously, it is thought to be conditionally essential in neonatal nutrition.⁶⁸ It is the second most abundant free amino acid in human breast milk¹¹⁷ and the most abundant free amino acid in fetal brain.¹¹⁸ In cases of long-term parenteral nutrition, neonates can become drastically taurine deficient¹¹⁹ due to suboptimal CSD activity,¹¹⁸ leading to retinal dysfunction.⁴¹ Taurine deficiencies can lead to functional and structural brain damage.¹¹⁸ Moreover, maternal taurine deficiency results in neurologic abnormalities in offspring¹²⁰ and may lead to oxidative stress throughout life.¹²¹

In 1984, the FDA approved the inclusion of taurine in infant formulas based on research showing that taurine-deficient infants had impaired fat absorption, bile acid secretion, retinal function, and hepatic function.¹²² But still under debate are the amount and duration of taurine supplementation required by preterm and low-birth-weight infants, as several randomized controlled trials failed to show statistically significant effects on growth.¹²³ Nonetheless, given the alleged detrimental ramifications of a lack of taurine supplementation, as well as the ethical dilemma of performing additional research trials on infants, it is presumed that infant formulas and parenteral nutrition for preterm and low-birth-weight infants will continue to contain taurine.

Age- and disease-related deficiency

Although taurine deficiency is rare in neonates, it is perhaps inevitable with advancing age. Healthy elderly patients ages 61 to 81 have up to a 49% decrease in plasma taurine concentration compared with healthy individuals ages 27 to 57.¹²⁴ While reduced renal retention¹²⁵ and taurine intake¹²⁶ can account for depressed taurine levels, Eppler and Dawson¹²⁷ found that tissue and circulating taurine concentrations decrease over the human life span primarily due to an age-dependent depletion of CSD activity in the liver. This effectively impairs the biosynthesis of endogenous taurine from cysteine or methionine or both, forcing a greater reliance on exogenous sources.

While specific mechanisms have not been fully elucidated, taurine deficiency has also been identified in patients suffering from diseases including but not limited to disorders of bone (osteogenesis imperfecta, osteoporosis),¹²⁸ blood (acute myelogenous leukemia),¹²⁹ central nervous system (schizophrenia, Friedreich ataxia-spinocerebellar degeneration),^130,131 retina (retinitis pigmentosa),¹³² circulatory system and heart (essential hypertension, atherosclerosis),¹³³ digestion (Gaucher disease),¹³⁴ absorption (short-bowel syndrome),¹³⁵ cellular proliferation (cancer),¹³⁶ and membrane channels (cystic fibrosis),¹³⁷ as well as in patients restricted to long-term parenteral nutrition.¹³⁸ However, the apparent correlation between taurine deficiency and these conditions does not necessarily mean causation; more study is needed to elucidate a direct connection.

SAFETY AND TOXICITY OF TAURINE SUPPLEMENTATION

An upper safe level of intake for taurine has not been established. To date, several studies have involved heavy taurine supplementation without serious adverse effects. While the largest dosage of taurine tested in humans appears to be 10 g/day for 6 months,¹³⁹ a number of studies have used 1 to 6 g/day for periods of 1 week to 1 year.¹⁴⁰ However, the assessment of potential acute, subacute, and chronic adverse effects has not been comprehensive. The Scientific Committee on Food of the European Commission¹⁴¹ reviewed several toxicologic studies on taurine through 2003 and were unable to expose any carcinogenic or teratogenic potential. Nevertheless, based on the available data from trials in humans and lower animals, Shao and Hathcock¹⁴⁰ suggested an observed safe level of taurine of 3 g/day, a conservatively smaller dose that carries a higher level of confidence. Because there is no “observed adverse effect level” for daily taurine intake,¹⁴¹ more research must be done to ensure safety of higher amounts of taurine administration and to define a tolerable upper limit of intake.

Interactions with medications

To date, the literature is scarce regarding potential interactions between taurine and commonly used medications.

Although no evidence specifically links taurine with adverse effects when used concurrently with other medications, there may be a link between taurine supplementation and various cytochrome P450 systems responsible for hepatic drug metabolism. Specifically, taurine inhibits cytochrome P450 2E1, a highly conserved xenobiotic-metabolizing P450 responsible for the breakdown of more than 70 substrates, including several commonly used anesthetics, analgesics, antidepressants, antibacterials, and antiepileptics.¹⁴² Of note, taurine may contribute to the attenuation of oxidative stress in the liver in the presence of alcohol¹⁴³ and acetaminophen,¹⁴⁴ two substances frequently used and abused. Since the P450 2E1 system catalyzes comparable reactions in rodents and humans,¹⁴² rodents should plausibly serve as a model for further testing of the effects of taurine on various substrates.

POTENTIAL THERAPEUTIC APPLICATIONS

More analysis is needed to fully unlock and understand taurine’s potential value in healthcare.

Correction of late-life taurine decline in humans could be beneficial for cognitive performance, energy metabolism, sexual function, and vision, but clinical studies remain to be performed. While a decline in taurine with age may intensify the stress caused by reactive oxygen species, taurine supplementation has been shown to decrease the presence of oxidative markers¹²⁷ and to serve a neuroprotective role in rodents.^145,146 Taurine levels increase in the hippocampus after experimentally induced gliosis¹⁴⁷ and are neuroprotective against glutamate excitotoxicity.^148,149 Furthermore, data in Alzheimer disease, Huntington disease, and brain ischemia experimental models show that taurine inhibits neuronal death (apoptosis).^13,150,151 Taurine has even been proposed as a potential preventive treatment for Alzheimer dementia, as it stabilizes protein conformations to prevent their aggregation and subsequent dysfunction.¹⁵² Although improvement in memory and cognitive performance has been linked to taurine supplementation in old mice,^145,153 similar results have not been found in adult mice whose taurine levels are within normal limits. Taurine also has transient anticonvulsant effects in some epileptic humans.¹⁵⁴

Within the male reproductive organs, the age-related decline in taurine may or may not have implications regarding sexuality, as only very limited rat data are available.^89–91

In cats, taurine supplementation has been found to prevent the progressive degeneration of retinal photoreceptors seen in retinitis pigmentosa, a genetic disease that causes the loss of vision.¹⁵⁵

While several energy drink companies have advertised that taurine plays a role in improving cognitive and physical performance, there are few human studies that examine this contention in the absence of confounding factors such as caffeine or glucose.^36,37,95 Taurine supplementation in patients with heart failure has been shown to increase exercise capacity vs placebo.¹⁵⁶ This supports the idea that in cases of taurine deficiency, such as those seen in cardiomyopathy,¹⁵⁷ taurine supplementation could have restorative effects. However, we are not aware of any double-blind, placebo-controlled clinical trial of taurine alone in healthy patients that measured energy parameters as clinical outcomes.

Although it remains possible that acute supraphysiologic taurine levels achieved by supplementation could transiently trigger various psychoneuroendocrine responses in healthy people, clinical research is needed in which taurine is the sole intervention. At present, the most compelling clinical reason to prescribe or recommend taurine supplementation is taurine deficiency.

Taurine—an amino acid found in abundance in the human brain, retina, heart, and reproductive organs, as well as in meat and seafood—is also a major ingredient in “energy drinks” (Table 1).^1,2 Given the tremendous popularity of these drinks in the United States, it would seem important to know and to recognize taurine’s neuroendocrine effects. Unfortunately, little is known about the effects of taurine supplementation in humans.

This paper reviews the sparse data to provide clinicians some background on the structure, synthesis, distribution, metabolism, mechanisms, effects, safety, and proposed therapeutic targets of taurine.

TAURINE’S THERAPEUTIC POTENTIAL

Taurine has been reported to have widespread anti-inflammatory actions.^3,4 Taurine supplementation has been proposed to have beneficial effects in the treatment of epilepsy,⁵ heart failure,^6,7 cystic fibrosis,⁸ and diabetes⁹ and has been shown in animal studies to protect against neurotoxic insults from alcohol, ammonia, lead, and other substances.^10–16

In addition, taurine analogues such as homotaurine and N-acetyl-homotaurine (acamprosate) have been probed for possible therapeutic applications. Homotaurine has been shown to have antiamyloid activity that could in theory protect against the progression of Alzheimer disease,¹⁷ and acam­prosate is approved by the US Food and Drug Administration (FDA) for the treatment of alcohol use disorders.¹⁸

TAURINE CONSUMPTION

Energy drinks are widely consumed in the United States, with an estimated 354 million gallons sold in 2009, or approximately 5.25 L/year per person over age 10.¹ In 2012, US sales of energy drinks exceeded $12 billion,¹⁹ with young men, particularly those in the military deployed in war zones, being the biggest consumers.^20–22 Analyses have found that of 49 nonalcoholic energy drinks tested, the average concentration of taurine was 3,180 mg/L, or approximately 750 mg per 8-oz serving.^23,24 Popular brands include Red Bull, Monster, Rockstar (Table 1), NOS, Amp, and Full Throttle.

Taurine is plentiful in the human body, which contains up to 1 g of taurine per kg.²⁵ Foods such as poultry, beef, pork, seafood, and processed meats have a high taurine content (Table 2).^26–29 People who eat meat and seafood have plentiful taurine intake, whereas vegetarians and vegans consume much less and have significantly lower circulating levels³⁰ because plants do not contain taurine in appreciable amounts.^26,29

The typical American diet provides between 123 and 178 mg of taurine daily.²⁶ Consumption of one 8-oz energy drink can increase the average intake 6 to 16 times. A lacto-ovo vegetarian diet provides only about 17 mg of taurine daily, and an 8-oz energy drink can increase the average intake by 44 to 117 mg.²⁶ And since a vegan diet provides essentially no taurine,³⁰ energy drink intake in any amount would constitute a major relative increase in taurine consumption.

ATTEMPTS TO STUDY TAURINE'S EFFECTS

Since most clinical trials to date have looked at the effects of taurine in combination with other ingredients such as caffeine, creatine, and glucose^31–35 in drinks such as Red Bull, these studies cannot be used to determine the effects of taurine alone. In the few clinical trials that have tested isolated taurine consumption, data are not sufficient to make a conclusion on direct effects on energy metabolism.

Rutherford et al³⁶ tested the effect of oral taurine supplementation (1,660 mg) on endurance in trained male cyclists 1 hour before exercise, but observed no effect on fluid intake, heart rate, subjective exertion, or time-trial performance. A small increase (16%) in total fat oxidation was observed during the 90-minute exercise period. Since mitochondria are the main location of fatty acid degradation, this effect may be attributed to taurine supplementation, with subsequent improvement in mitochondrial function.

Zhang et al³⁷ found a 30-second increase in cycling energy capacity after 7 days of 6 g oral taurine supplementation, but the study was neither blinded nor placebo-controlled.

Kammerer et al³⁸ tested the effect of 1 g of taurine supplementation on physical and mental performance in young adult soldiers 45 minutes before physical fitness and cognitive testing. This double-blind, placebo-controlled randomized trial found no effect of taurine on cardiorespiratory fitness indices, concentration, or immediate memory, nor did it find any effect of an 80-mg dose of caffeine.

In sum, the available data are far from sufficient to determine the direct effect of taurine consumption on energy metabolism in healthy people.

PHARMACOLOGY OF TAURINE

Chemical structure

Taurine, or 2-aminoethane sulfonic acid, is a conditionally essential amino acid, ie, we can usually make enough in our own bodies. It was first prepared on a large scale for physiologic investigation almost 90 years ago, through the purification of ox bile.³⁹ It can be obtained either exogenously through dietary sources or endogenously through biosynthesis from methionine and cysteine precursors, both essential sulfur-containing alpha-amino acids.⁴⁰ Both sources are important to maintain physiologic levels of taurine, and either can help compensate for the other in cases of deficiency.⁴¹

The structure of taurine has two main differences from the essential amino acids. First, taurine’s amino group is attached to the beta-carbon rather than the alpha-carbon, making it a beta-amino acid instead of an alpha-amino acid.⁴² Second, the acid group in taurine is sulfonic acid, whereas the essential amino acids have a carboxylic acid.⁴³ Because of its distinctive structure, taurine is not used as a structural unit in proteins,⁴³ existing mostly as a free amino acid within cells, readily positioned to perform several unique functions.

Synthesis

De novo synthesis of taurine involves several enzymes and at least five pathways,⁴⁴ mostly differing by the order in which sulfur is oxidized and decarboxylated.⁴⁵

The rate-limiting enzyme of the predominant pathway is thought to be cysteine sulfinate decarboxylase (CSD), and its presence within an organ indicates involvement in taurine production.⁴⁴ CSD has been found in the liver,⁴⁶ the primary site of taurine biosynthesis, as well as in the retina,⁴⁷ brain,⁴⁸ kidney,⁴⁹ mammary glands,^50,51 and reproductive organs.⁵²

Distribution

Taurine levels are highest in electrically excitable tissues such as the central nervous system, retina, and heart; in secretory structures such as the pineal gland and the pituitary gland (including the posterior lobe or neurohypophysis); and in platelets²⁵ and neutrophils.⁵³

In the fetal brain, the taurine concentration is higher than that of any other amino acid,⁵⁴ but the concentration in the brain decreases with advancing age, whereas glutamate levels increase over time to make it the predominant amino acid in the adult brain.⁵⁴ Regardless, taurine is still the second most prevalent amino acid in the adult brain, its levels comparable to those of gamma-aminobutyric acid (GABA).⁵⁵

Taurine has also been found in variable amounts in the liver, muscle, kidney, pancreas, spleen, small intestine, and lungs,⁵⁶ as well as in several other locations.^45,57

Taurine is also present in the male and female reproductive organs. In male rats, taurine and taurine biosynthesis have been localized to Leydig cells of the testes, the cellular source of testosterone in males, as well as the cremaster muscle, efferent ducts, and peritubular myoid cells surrounding seminiferous tubules.⁵⁸ More recently, taurine has been detected in the testes of humans⁵⁹ and is also found in sperm and seminal fluid.⁶⁰ Levels of taurine in spermatozoa are correlated with sperm quality, presumably by protecting against lipid peroxidation through taurine’s antioxidant effects,^61,62 as well as through contribution to the spermatozoa maturation process by facilitating the capacitation, motility, and acrosomal reaction of sperm.⁶³

In female rats, taurine has been found in uterine tissue,⁶⁴ oviducts,⁶⁵ uterine fluid (where it is the predominant amino acid),⁶⁶ and thecal cells of developing follicles of ovaries, cells responsible for the synthesis of androgens such as testosterone and androstenedione.⁶⁵ Taurine is also a major component of human breast milk⁶⁷ and is important for proper neonatal nutrition.⁶⁸

Metabolism and excretion

Ninety-five percent of taurine is excreted in urine, about 70% as taurine itself, and the rest as sulfate. Most of the sulfate derived from taurine is produced by bacterial metabolism in the gut and then absorbed.⁶⁹ However, taurine can also be conjugated with bile acids to act as a detergent in lipid emulsification.⁷⁰ In this form, it may be subjected to the enterohepatic circulation, which gives bacteria another chance to convert it into inorganic sulfate for excretion in urine.⁶⁹

MECHANISMS AND NEUROENDOCRINE EFFECTS

As a free amino acid, taurine has widespread distribution and unique biochemical and physiologic properties and exhibits several organ-specific functions; however, indisputable evidence of a taurine-specific receptor is lacking, and its putative existence⁷¹ is controversial.⁷² Nonetheless, taurine is a neuromodulator with a variety of actions.

Neurotransmission

Taurine is known to be an inhibitory neurotransmitter and neuromodulator.⁷³ It is structurally analogous to GABA, the main inhibitory neurotransmitter in the brain.⁴⁵ Accordingly, it binds to GABA receptors to serve as an agonist,^74,75 causing neuronal hyperpolarization and inhibition. Taurine has an even higher affinity for glycine receptors⁷⁵ where it has long been known to act as an agonist.⁷⁶ GABA and glycine receptors both belong to the Cys-loop receptor superfamily,⁷⁷ with conservation of subunits that allows taurine to bind each receptor, albeit at different affinities. The binding effects of taurine on GABA and glycine receptors have not been well documented quantitatively; however, it is known that taurine has a substantially lower affinity than GABA and glycine for their respective receptors.⁷⁶

Catecholamines and the sympathetic nervous system

Surprisingly little is known about the effects of taurine on norepinephrine, dopamine, and the human sympathetic nervous system.⁷⁸ Humans with borderline hypertension given 6 g of taurine orally for 7 days⁷⁹ experienced decreases in epinephrine secretion and blood pressure, but normotensive study participants did not experience similar results, possibly because of a better ability to regulate sympathetic tone. Mizushima et al⁸⁰ showed that a longer period of taurine intake (6 g orally for 3 weeks) could elicit a decrease in norepinephrine in healthy men with normal blood pressure. Other similar studies^81–83 also suggested interplay between taurine and catecholamines, but the extent is still undetermined.

Growth hormone, prolactin, sex hormones, and cortisol

Taurine appears to have a complex relationship with several hormones, although its direct effects on hormone secretion remain obscure. Clinical studies of the acute and chronic neuroendocrine effects of taurine loading in humans are needed.

In female rats, secretion of prolactin is increased by the intraventricular injection of 5 μL of 2.0 μmol taurine over a 10-minute period.⁸⁴ Ikuyama et al⁸⁵ found an increase in prolactin and growth hormone secretion in adult male rats given 10 μL of 0.25 μmol and 1.0 μmol taurine intraventricularly, yet a higher dose of 4.0 μmol had no effect on either hormone. Furthermore, prolactin receptor deficiency is seen in CSD knockout mice, but the receptor is restored with taurine supplementation.⁸⁶

Mantovani and DeVivo⁸⁷ reported that 375 to 8,000 mg/day of taurine given orally for 4 to 6 months to epileptic patients stimulated the secretion of growth hormone. However, in another study, a single 75-mg/kg dose of oral taurine did not trigger an acute increase in levels of growth hormone or prolactin in humans.⁸⁸ Energy drinks may contain up to 1,000 mg of taurine per 8-oz serving, but the effects of larger doses on growth hormone, which is banned as a supplement by major athletic organizations because of its anabolic and possible performance-enhancing effects, remain to be determined.

Taurine may have effects on human sex hormones, based on the limited observations in rodents.^89–94

Although human salivary cortisol concentrations were purportedly assessed in response to 2,000 mg of oral taurine,⁹⁵ the methods and reported data are not adequate to draw any conclusions.

Energy metabolism

Mammals are unable to directly use taurine in energy production because they cannot directly reduce it.²⁵ Instead, bacteria in the gut use it as a source of energy, carbon, nitrogen, and sulfur.⁹⁶ However, taurine deficiency appears to impair the cellular respiratory chain, resulting in diminished production of adenosine triphosphate and diminished uptake of long-chain fatty acids by mitochondria, at least in the heart.⁹⁷

Taurine is present in human mitochondria and regulates mitochondrial function. For example, taurine in mitochondria assists in conjugation of transfer RNA for leucine, lysine, glutamate, and glutamine.⁹⁸ In TauT knockout mice, deficiency of taurine causes mitochondrial dysfunction, triggering a greater than 80% decrease in exercise capacity.⁹⁹ Several studies in rodents have shown increased exercise capacity after taurine supplementation.^100–102 In addition, taurine is critical for the growth of blastocytes, skeletal muscle, and myocardium; it is necessary for mitochondrial development and is also important for muscular endurance.^103,104

Antioxidation, anti-inflammation, and other functions

Taurine is a major antioxidant, scavenging reactive oxygen and protecting against oxidative stress to organs including the brain,^97,105,106 where it increasingly appears to have neuroprotective effects.^107,108

Cellular taurine also has anti-inflammatory actions.³ One of the proposed mechanisms is taurine inhibition of NF-kappa B, an important transcription factor for the synthesis of pro-inflammatory cytokines.⁴ This function may be important in protecting polyunsaturated fatty acids from oxidative stress—helping to maintain and stabilize the structure and function of plasma membranes within the lungs,¹⁰⁹ heart,¹¹⁰ brain,¹¹¹ liver,¹¹² and spermatozoa.^61,62

Taurine is also conjugated to bile acids synthesized in the liver, forming bile salts⁷⁰ that act as detergents to help emulsify and digest lipids in the body. In addition, taurine facilitates xenobiotic detoxification in the liver by conjugating with several drugs to aid in their excretion.²⁵ Taurine is also implicated in calcium modulation¹¹³ and homeostasis.¹¹⁴ Through inhibition of several types of calcium channels, taurine has been shown to decrease calcium influx into cells, effectively serving a cytoprotective role against calcium overload.^115,116

TAURINE DEFICIENCY

Fetal and neonatal deficiency

Though taurine is considered nonessential in adults because it can be readily synthesized endogenously, it is thought to be conditionally essential in neonatal nutrition.⁶⁸ It is the second most abundant free amino acid in human breast milk¹¹⁷ and the most abundant free amino acid in fetal brain.¹¹⁸ In cases of long-term parenteral nutrition, neonates can become drastically taurine deficient¹¹⁹ due to suboptimal CSD activity,¹¹⁸ leading to retinal dysfunction.⁴¹ Taurine deficiencies can lead to functional and structural brain damage.¹¹⁸ Moreover, maternal taurine deficiency results in neurologic abnormalities in offspring¹²⁰ and may lead to oxidative stress throughout life.¹²¹

In 1984, the FDA approved the inclusion of taurine in infant formulas based on research showing that taurine-deficient infants had impaired fat absorption, bile acid secretion, retinal function, and hepatic function.¹²² But still under debate are the amount and duration of taurine supplementation required by preterm and low-birth-weight infants, as several randomized controlled trials failed to show statistically significant effects on growth.¹²³ Nonetheless, given the alleged detrimental ramifications of a lack of taurine supplementation, as well as the ethical dilemma of performing additional research trials on infants, it is presumed that infant formulas and parenteral nutrition for preterm and low-birth-weight infants will continue to contain taurine.

Age- and disease-related deficiency

Although taurine deficiency is rare in neonates, it is perhaps inevitable with advancing age. Healthy elderly patients ages 61 to 81 have up to a 49% decrease in plasma taurine concentration compared with healthy individuals ages 27 to 57.¹²⁴ While reduced renal retention¹²⁵ and taurine intake¹²⁶ can account for depressed taurine levels, Eppler and Dawson¹²⁷ found that tissue and circulating taurine concentrations decrease over the human life span primarily due to an age-dependent depletion of CSD activity in the liver. This effectively impairs the biosynthesis of endogenous taurine from cysteine or methionine or both, forcing a greater reliance on exogenous sources.

While specific mechanisms have not been fully elucidated, taurine deficiency has also been identified in patients suffering from diseases including but not limited to disorders of bone (osteogenesis imperfecta, osteoporosis),¹²⁸ blood (acute myelogenous leukemia),¹²⁹ central nervous system (schizophrenia, Friedreich ataxia-spinocerebellar degeneration),^130,131 retina (retinitis pigmentosa),¹³² circulatory system and heart (essential hypertension, atherosclerosis),¹³³ digestion (Gaucher disease),¹³⁴ absorption (short-bowel syndrome),¹³⁵ cellular proliferation (cancer),¹³⁶ and membrane channels (cystic fibrosis),¹³⁷ as well as in patients restricted to long-term parenteral nutrition.¹³⁸ However, the apparent correlation between taurine deficiency and these conditions does not necessarily mean causation; more study is needed to elucidate a direct connection.

SAFETY AND TOXICITY OF TAURINE SUPPLEMENTATION

An upper safe level of intake for taurine has not been established. To date, several studies have involved heavy taurine supplementation without serious adverse effects. While the largest dosage of taurine tested in humans appears to be 10 g/day for 6 months,¹³⁹ a number of studies have used 1 to 6 g/day for periods of 1 week to 1 year.¹⁴⁰ However, the assessment of potential acute, subacute, and chronic adverse effects has not been comprehensive. The Scientific Committee on Food of the European Commission¹⁴¹ reviewed several toxicologic studies on taurine through 2003 and were unable to expose any carcinogenic or teratogenic potential. Nevertheless, based on the available data from trials in humans and lower animals, Shao and Hathcock¹⁴⁰ suggested an observed safe level of taurine of 3 g/day, a conservatively smaller dose that carries a higher level of confidence. Because there is no “observed adverse effect level” for daily taurine intake,¹⁴¹ more research must be done to ensure safety of higher amounts of taurine administration and to define a tolerable upper limit of intake.

Interactions with medications

To date, the literature is scarce regarding potential interactions between taurine and commonly used medications.

Although no evidence specifically links taurine with adverse effects when used concurrently with other medications, there may be a link between taurine supplementation and various cytochrome P450 systems responsible for hepatic drug metabolism. Specifically, taurine inhibits cytochrome P450 2E1, a highly conserved xenobiotic-metabolizing P450 responsible for the breakdown of more than 70 substrates, including several commonly used anesthetics, analgesics, antidepressants, antibacterials, and antiepileptics.¹⁴² Of note, taurine may contribute to the attenuation of oxidative stress in the liver in the presence of alcohol¹⁴³ and acetaminophen,¹⁴⁴ two substances frequently used and abused. Since the P450 2E1 system catalyzes comparable reactions in rodents and humans,¹⁴² rodents should plausibly serve as a model for further testing of the effects of taurine on various substrates.

POTENTIAL THERAPEUTIC APPLICATIONS

More analysis is needed to fully unlock and understand taurine’s potential value in healthcare.

Correction of late-life taurine decline in humans could be beneficial for cognitive performance, energy metabolism, sexual function, and vision, but clinical studies remain to be performed. While a decline in taurine with age may intensify the stress caused by reactive oxygen species, taurine supplementation has been shown to decrease the presence of oxidative markers¹²⁷ and to serve a neuroprotective role in rodents.^145,146 Taurine levels increase in the hippocampus after experimentally induced gliosis¹⁴⁷ and are neuroprotective against glutamate excitotoxicity.^148,149 Furthermore, data in Alzheimer disease, Huntington disease, and brain ischemia experimental models show that taurine inhibits neuronal death (apoptosis).^13,150,151 Taurine has even been proposed as a potential preventive treatment for Alzheimer dementia, as it stabilizes protein conformations to prevent their aggregation and subsequent dysfunction.¹⁵² Although improvement in memory and cognitive performance has been linked to taurine supplementation in old mice,^145,153 similar results have not been found in adult mice whose taurine levels are within normal limits. Taurine also has transient anticonvulsant effects in some epileptic humans.¹⁵⁴

Within the male reproductive organs, the age-related decline in taurine may or may not have implications regarding sexuality, as only very limited rat data are available.^89–91

In cats, taurine supplementation has been found to prevent the progressive degeneration of retinal photoreceptors seen in retinitis pigmentosa, a genetic disease that causes the loss of vision.¹⁵⁵

While several energy drink companies have advertised that taurine plays a role in improving cognitive and physical performance, there are few human studies that examine this contention in the absence of confounding factors such as caffeine or glucose.^36,37,95 Taurine supplementation in patients with heart failure has been shown to increase exercise capacity vs placebo.¹⁵⁶ This supports the idea that in cases of taurine deficiency, such as those seen in cardiomyopathy,¹⁵⁷ taurine supplementation could have restorative effects. However, we are not aware of any double-blind, placebo-controlled clinical trial of taurine alone in healthy patients that measured energy parameters as clinical outcomes.

Although it remains possible that acute supraphysiologic taurine levels achieved by supplementation could transiently trigger various psychoneuroendocrine responses in healthy people, clinical research is needed in which taurine is the sole intervention. At present, the most compelling clinical reason to prescribe or recommend taurine supplementation is taurine deficiency.

In this issue of the Journal, Ataya et al¹ provide a comprehensive review of thrombolysis in submassive pulmonary embolism, a subject of much debate. In massive pulmonary embolism, thrombolytic therapy is usually indicated²; in submassive pulmonary embolism, the decision is not so clear. Which patients with submassive embolism would benefit from thrombolysis, and which patients require only anticoagulant therapy? The answer lies in finding the balance between the potential benefit of thrombolytic therapy—preventing death or hemodynamic collapse—and the numerically low but potentially catastrophic risk of intracranial bleeding.

See related article

In general, submassive pulmonary embolism refers to an acute pulmonary embolus serious enough to cause evidence of right ventricular dysfunction or necrosis but not hemodynamic instability (ie, with systolic blood pressure > 90 mm Hg) on presentation.³ It accounts for about 25% of cases of pulmonary embolism,^4,5 and perhaps 0.5 to 1% of patients admitted to intensive care units across the country.⁶ The 30-day mortality rate can be as high as 30%, making it a condition that requires prompt identification and appropriate management.

But clinical trials have failed to demonstrate a substantial improvement in mortality rates with thrombolytic therapy in patients with submassive pulmonary embolism, and have shown improvement only in other clinical end points.⁷ Part of the problem is that this is a heterogeneous condition, posing a challenge for the optimal design and interpretation of studies.

WHO IS AT RISK OF DEATH OR DETERIORATION?

If clinicians could ascertain in each patient whether the risk-benefit ratio is favorable for thrombolytic therapy, it would be easier to provide optimal care. This is not a straightforward task, and it requires integration of clinical judgment, high index of suspicion for deterioration, and clinical tools.

One of the challenges is that it is difficult to identify normotensive patients at the highest risk of poor outcomes. Several factors are associated with a higher risk of death within 30 days (Table 1). While each of these has a negative predictive value of about 95% or even higher (meaning that it is very good at predicting who will not die), they all have very low positive predictive values (meaning that none of them, by itself, is very good at predicting who will die).

For this reason, a multimodal approach to risk stratification has emerged. For example, Jiménez et al⁸ showed that normotensive patients with acute pulmonary embolism and a combination of abnormal Simplified Pulmonary Embolism Severity Index, elevated B-type natriuretic peptide level, elevated troponin level, and lower-extremity deep vein thrombosis had a 26% rate of complications (death, hemodynamic collapse, or recurrent pulmonary embolism) within 30 days.

Bova et al⁹ showed that the combination of borderline low systolic blood pressure (90–100 mm Hg), tachycardia (heart rate ≥ 110 beats per minute), elevated troponin, and right ventricular dysfunction by echocardiography or computed tomography allowed for the separation of three groups with significantly different rates of poor outcomes.

WHO IS AT RISK OF BLEEDING?

Estimation of the risk of bleeding is currently less sophisticated, and we need a bleeding score to use in the setting of acute pulmonary embolism. A few studies have shed some light on this issue beyond the known absolute and relative contraindications to thrombolysis.

Ataya et al¹ note a meta-analysis¹⁰ showing that systemic thrombolytic therapy was not associated with an increased risk of major bleeding in patients age 65 or younger. Similarly, a large observational study showed a strong association between the risk of intracerebral hemorrhage and increasing age¹¹ and also identified comorbidities such as kidney disease as risk factors. While the frequently cited Pulmonary Embolism Thrombolysis trial¹² showed a significantly higher risk of stroke with tenecteplase, careful review of its data reveals that all 10 of the 506 patients in the tenecteplase group who sustained a hemorrhagic stroke were age 65 or older.¹²

A TEAM APPROACH

Thus, in patients with acute pulmonary embolism, clinicians face the difficult task of assessing the patient’s risk of death and clinical worsening and balancing that risk against the risk of bleeding, to identify those who may benefit from early reperfusion therapies, including systemic thrombolysis, catheter-directed thrombolysis, mechanical treatment, and surgical embolectomy.

Given the absence of high-quality evidence to guide these decisions, several institutions have developed multidisciplinary pulmonary embolism response teams to provide rapid evaluation and risk stratification and to recommend and implement advanced therapies, as appropriate. This is a novel concept that is still evolving but holds promise, as it integrates the experience and expertise of physicians in multiple specialties, such as pulmonary and critical care medicine, vascular medicine, interventional radiology, interventional cardiology, emergency medicine, and cardiothoracic surgery, who can then fill the currently existing knowledge gaps for clinical care and, possibly, research.¹³

Early published experience has documented the feasibility of this multidisciplinary approach.¹⁴ The first 95 patients treated at  Cleveland Clinic had a 30-day mortality rate of 3.2%, which was lower than the expected 9% rate predicted by the Pulmonary Embolism Severity Index score (unpublished observation).

Figure 1 shows the algorithm currently used by Cleveland Clinic’s pulmonary embolism response team, with the caveat that no algorithm can fully capture the extent of the complexities and discussions that each case triggers within the team.

TOWARD BETTER UNDERSTANDING

As Ataya et al point out,¹ the current state of the evidence does not allow a clear, simplistic, one-size-fits-all approach. A question that arises from this controversial topic is whether we should look for markers of right ventricular dysfunction in every patient admitted with a diagnosis of pulmonary embolism, or only in those with a significant anatomic burden of clot on imaging. Would testing everyone be an appropriate way to identify patients at risk of further deterioration early and therefore prevent adverse outcomes in a timely manner? Or would it not be cost-effective and translate into ordering more diagnostic testing, as well as an increase in downstream workup with higher healthcare costs?

Once we better understand this condition and the factors that predict a higher risk of deterioration, we should be able to design prospective studies that can help elucidate the most appropriate diagnostic and therapeutic approach for such challenging cases. In the meantime, it is important to appraise the evidence in a critical way, as Ataya et al have done in their review.

In this issue of the Journal, Ataya et al¹ provide a comprehensive review of thrombolysis in submassive pulmonary embolism, a subject of much debate. In massive pulmonary embolism, thrombolytic therapy is usually indicated²; in submassive pulmonary embolism, the decision is not so clear. Which patients with submassive embolism would benefit from thrombolysis, and which patients require only anticoagulant therapy? The answer lies in finding the balance between the potential benefit of thrombolytic therapy—preventing death or hemodynamic collapse—and the numerically low but potentially catastrophic risk of intracranial bleeding.

See related article

In general, submassive pulmonary embolism refers to an acute pulmonary embolus serious enough to cause evidence of right ventricular dysfunction or necrosis but not hemodynamic instability (ie, with systolic blood pressure > 90 mm Hg) on presentation.³ It accounts for about 25% of cases of pulmonary embolism,^4,5 and perhaps 0.5 to 1% of patients admitted to intensive care units across the country.⁶ The 30-day mortality rate can be as high as 30%, making it a condition that requires prompt identification and appropriate management.

But clinical trials have failed to demonstrate a substantial improvement in mortality rates with thrombolytic therapy in patients with submassive pulmonary embolism, and have shown improvement only in other clinical end points.⁷ Part of the problem is that this is a heterogeneous condition, posing a challenge for the optimal design and interpretation of studies.

WHO IS AT RISK OF DEATH OR DETERIORATION?

If clinicians could ascertain in each patient whether the risk-benefit ratio is favorable for thrombolytic therapy, it would be easier to provide optimal care. This is not a straightforward task, and it requires integration of clinical judgment, high index of suspicion for deterioration, and clinical tools.

One of the challenges is that it is difficult to identify normotensive patients at the highest risk of poor outcomes. Several factors are associated with a higher risk of death within 30 days (Table 1). While each of these has a negative predictive value of about 95% or even higher (meaning that it is very good at predicting who will not die), they all have very low positive predictive values (meaning that none of them, by itself, is very good at predicting who will die).

For this reason, a multimodal approach to risk stratification has emerged. For example, Jiménez et al⁸ showed that normotensive patients with acute pulmonary embolism and a combination of abnormal Simplified Pulmonary Embolism Severity Index, elevated B-type natriuretic peptide level, elevated troponin level, and lower-extremity deep vein thrombosis had a 26% rate of complications (death, hemodynamic collapse, or recurrent pulmonary embolism) within 30 days.

Bova et al⁹ showed that the combination of borderline low systolic blood pressure (90–100 mm Hg), tachycardia (heart rate ≥ 110 beats per minute), elevated troponin, and right ventricular dysfunction by echocardiography or computed tomography allowed for the separation of three groups with significantly different rates of poor outcomes.

WHO IS AT RISK OF BLEEDING?

Estimation of the risk of bleeding is currently less sophisticated, and we need a bleeding score to use in the setting of acute pulmonary embolism. A few studies have shed some light on this issue beyond the known absolute and relative contraindications to thrombolysis.

Ataya et al¹ note a meta-analysis¹⁰ showing that systemic thrombolytic therapy was not associated with an increased risk of major bleeding in patients age 65 or younger. Similarly, a large observational study showed a strong association between the risk of intracerebral hemorrhage and increasing age¹¹ and also identified comorbidities such as kidney disease as risk factors. While the frequently cited Pulmonary Embolism Thrombolysis trial¹² showed a significantly higher risk of stroke with tenecteplase, careful review of its data reveals that all 10 of the 506 patients in the tenecteplase group who sustained a hemorrhagic stroke were age 65 or older.¹²

A TEAM APPROACH

Thus, in patients with acute pulmonary embolism, clinicians face the difficult task of assessing the patient’s risk of death and clinical worsening and balancing that risk against the risk of bleeding, to identify those who may benefit from early reperfusion therapies, including systemic thrombolysis, catheter-directed thrombolysis, mechanical treatment, and surgical embolectomy.

Given the absence of high-quality evidence to guide these decisions, several institutions have developed multidisciplinary pulmonary embolism response teams to provide rapid evaluation and risk stratification and to recommend and implement advanced therapies, as appropriate. This is a novel concept that is still evolving but holds promise, as it integrates the experience and expertise of physicians in multiple specialties, such as pulmonary and critical care medicine, vascular medicine, interventional radiology, interventional cardiology, emergency medicine, and cardiothoracic surgery, who can then fill the currently existing knowledge gaps for clinical care and, possibly, research.¹³

Early published experience has documented the feasibility of this multidisciplinary approach.¹⁴ The first 95 patients treated at  Cleveland Clinic had a 30-day mortality rate of 3.2%, which was lower than the expected 9% rate predicted by the Pulmonary Embolism Severity Index score (unpublished observation).

Figure 1 shows the algorithm currently used by Cleveland Clinic’s pulmonary embolism response team, with the caveat that no algorithm can fully capture the extent of the complexities and discussions that each case triggers within the team.

TOWARD BETTER UNDERSTANDING

As Ataya et al point out,¹ the current state of the evidence does not allow a clear, simplistic, one-size-fits-all approach. A question that arises from this controversial topic is whether we should look for markers of right ventricular dysfunction in every patient admitted with a diagnosis of pulmonary embolism, or only in those with a significant anatomic burden of clot on imaging. Would testing everyone be an appropriate way to identify patients at risk of further deterioration early and therefore prevent adverse outcomes in a timely manner? Or would it not be cost-effective and translate into ordering more diagnostic testing, as well as an increase in downstream workup with higher healthcare costs?

Once we better understand this condition and the factors that predict a higher risk of deterioration, we should be able to design prospective studies that can help elucidate the most appropriate diagnostic and therapeutic approach for such challenging cases. In the meantime, it is important to appraise the evidence in a critical way, as Ataya et al have done in their review.

In this issue of the Journal, Ataya et al¹ provide a comprehensive review of thrombolysis in submassive pulmonary embolism, a subject of much debate. In massive pulmonary embolism, thrombolytic therapy is usually indicated²; in submassive pulmonary embolism, the decision is not so clear. Which patients with submassive embolism would benefit from thrombolysis, and which patients require only anticoagulant therapy? The answer lies in finding the balance between the potential benefit of thrombolytic therapy—preventing death or hemodynamic collapse—and the numerically low but potentially catastrophic risk of intracranial bleeding.

See related article

In general, submassive pulmonary embolism refers to an acute pulmonary embolus serious enough to cause evidence of right ventricular dysfunction or necrosis but not hemodynamic instability (ie, with systolic blood pressure > 90 mm Hg) on presentation.³ It accounts for about 25% of cases of pulmonary embolism,^4,5 and perhaps 0.5 to 1% of patients admitted to intensive care units across the country.⁶ The 30-day mortality rate can be as high as 30%, making it a condition that requires prompt identification and appropriate management.

But clinical trials have failed to demonstrate a substantial improvement in mortality rates with thrombolytic therapy in patients with submassive pulmonary embolism, and have shown improvement only in other clinical end points.⁷ Part of the problem is that this is a heterogeneous condition, posing a challenge for the optimal design and interpretation of studies.

WHO IS AT RISK OF DEATH OR DETERIORATION?

If clinicians could ascertain in each patient whether the risk-benefit ratio is favorable for thrombolytic therapy, it would be easier to provide optimal care. This is not a straightforward task, and it requires integration of clinical judgment, high index of suspicion for deterioration, and clinical tools.

One of the challenges is that it is difficult to identify normotensive patients at the highest risk of poor outcomes. Several factors are associated with a higher risk of death within 30 days (Table 1). While each of these has a negative predictive value of about 95% or even higher (meaning that it is very good at predicting who will not die), they all have very low positive predictive values (meaning that none of them, by itself, is very good at predicting who will die).

For this reason, a multimodal approach to risk stratification has emerged. For example, Jiménez et al⁸ showed that normotensive patients with acute pulmonary embolism and a combination of abnormal Simplified Pulmonary Embolism Severity Index, elevated B-type natriuretic peptide level, elevated troponin level, and lower-extremity deep vein thrombosis had a 26% rate of complications (death, hemodynamic collapse, or recurrent pulmonary embolism) within 30 days.

Bova et al⁹ showed that the combination of borderline low systolic blood pressure (90–100 mm Hg), tachycardia (heart rate ≥ 110 beats per minute), elevated troponin, and right ventricular dysfunction by echocardiography or computed tomography allowed for the separation of three groups with significantly different rates of poor outcomes.

WHO IS AT RISK OF BLEEDING?

Estimation of the risk of bleeding is currently less sophisticated, and we need a bleeding score to use in the setting of acute pulmonary embolism. A few studies have shed some light on this issue beyond the known absolute and relative contraindications to thrombolysis.

Ataya et al¹ note a meta-analysis¹⁰ showing that systemic thrombolytic therapy was not associated with an increased risk of major bleeding in patients age 65 or younger. Similarly, a large observational study showed a strong association between the risk of intracerebral hemorrhage and increasing age¹¹ and also identified comorbidities such as kidney disease as risk factors. While the frequently cited Pulmonary Embolism Thrombolysis trial¹² showed a significantly higher risk of stroke with tenecteplase, careful review of its data reveals that all 10 of the 506 patients in the tenecteplase group who sustained a hemorrhagic stroke were age 65 or older.¹²

A TEAM APPROACH

Thus, in patients with acute pulmonary embolism, clinicians face the difficult task of assessing the patient’s risk of death and clinical worsening and balancing that risk against the risk of bleeding, to identify those who may benefit from early reperfusion therapies, including systemic thrombolysis, catheter-directed thrombolysis, mechanical treatment, and surgical embolectomy.

Given the absence of high-quality evidence to guide these decisions, several institutions have developed multidisciplinary pulmonary embolism response teams to provide rapid evaluation and risk stratification and to recommend and implement advanced therapies, as appropriate. This is a novel concept that is still evolving but holds promise, as it integrates the experience and expertise of physicians in multiple specialties, such as pulmonary and critical care medicine, vascular medicine, interventional radiology, interventional cardiology, emergency medicine, and cardiothoracic surgery, who can then fill the currently existing knowledge gaps for clinical care and, possibly, research.¹³

Early published experience has documented the feasibility of this multidisciplinary approach.¹⁴ The first 95 patients treated at  Cleveland Clinic had a 30-day mortality rate of 3.2%, which was lower than the expected 9% rate predicted by the Pulmonary Embolism Severity Index score (unpublished observation).

Figure 1 shows the algorithm currently used by Cleveland Clinic’s pulmonary embolism response team, with the caveat that no algorithm can fully capture the extent of the complexities and discussions that each case triggers within the team.

TOWARD BETTER UNDERSTANDING

As Ataya et al point out,¹ the current state of the evidence does not allow a clear, simplistic, one-size-fits-all approach. A question that arises from this controversial topic is whether we should look for markers of right ventricular dysfunction in every patient admitted with a diagnosis of pulmonary embolism, or only in those with a significant anatomic burden of clot on imaging. Would testing everyone be an appropriate way to identify patients at risk of further deterioration early and therefore prevent adverse outcomes in a timely manner? Or would it not be cost-effective and translate into ordering more diagnostic testing, as well as an increase in downstream workup with higher healthcare costs?

Once we better understand this condition and the factors that predict a higher risk of deterioration, we should be able to design prospective studies that can help elucidate the most appropriate diagnostic and therapeutic approach for such challenging cases. In the meantime, it is important to appraise the evidence in a critical way, as Ataya et al have done in their review.

Innovations are dominating the early part of the 21st century and the impact on cardiovascular medicine has been especially remarkable. Keeping up and evaluating the relevance of these innovations and the role in patient care is a constant challenge and opportunity for providers and scientists alike.

This Cleveland Clinic Journal of Medicine supplement on cardiovascular disease presents healthcare providers with evidenced-based reviews of important innovations and a glimpse into their potential for an exciting future.

In this supplement, Amar Krishnaswamy, MD, and colleagues look to new frontiers in valve replacement therapies. The success of transcatheter aortic valve replacement has led to extending the technique to the mitral valve. While technical challenges exist with transcatheter mitral valve replacement, methods to overcome these challenges are feasible. The authors review the various valve devices currently under development and examine their potential implications in practice.

The introduction of stents in percutaneous coronary interventions has been one of the most revolutionary innovations in cardiovascular medicine, resulting in impressive outcomes during the past few decades. Despite the dramatic advancement, persistent rates of restenosis and thrombosis continue to cause substantial morbidity and mortality. Stephen Ellis, MD, and Haris Riaz, MD, discuss the evolution of stent design from bare-metal stents through drug-eluting stents and their impact on outcomes. The evolution continues with the development of bioresorbable polymers and stents without polymers. The authors consider the promise of these innovations, especially bioresorbable stents, to further reduce restenosis and stent thrombosis.

Erich Kiehl, MD, and Daniel Cantillon, MD, present information about the latest innovation in cardiac pacing—leadless pacemakers. The first leadless pacemaker was approved earlier this year. In over 50 years of use of transvenous pacemakers, long-term complications have primarily involved the endovascular leads and surgical pocket. The authors discuss the promise of leadless cardiac pacing using catheter-based delivery of a self-contained device in the right ventricle to favorably reduce these complications, as well the current limitation of single-chamber pacing and possible future directions.

Innovations in monoclonal antibody therapy have resulted in a new class of biologic drugs to lower low-density-lipoprotein (LDL) in the blood—PCSK9 inhibitors. These new biologics target the overexpression of the PCSK9 protein in the liver, thereby increasing LDL receptors available to metabolize and remove LDL from the blood. Khendi White, MD, Chaitra Mohan, MD, and Michael Rocco, MD, discuss potential candidates for recently approved PCSK9 inhibitor therapy.

Ellen Brinza, MS, and Heather Gornik, MD, discuss new findings in our understanding of fibromuscular dysplasia (FMD). This uncommon nonatherosclerotic disease leads to narrowing, dissection, or aneurysm of medium-sized arteries. FMD is caused by abnormal development of the arterial cell wall and can cause symptoms if narrowing or a tear decreases blood flow through the artery. The authors discuss evaluation, management, and surveillance strategies as well as important lifestyle modifications and appropriate treatment of symptoms.

We hope this presentation of recent innovations in cardiovascular medicine is useful and informative to you and your clinical practice.

Innovations are dominating the early part of the 21st century and the impact on cardiovascular medicine has been especially remarkable. Keeping up and evaluating the relevance of these innovations and the role in patient care is a constant challenge and opportunity for providers and scientists alike.

This Cleveland Clinic Journal of Medicine supplement on cardiovascular disease presents healthcare providers with evidenced-based reviews of important innovations and a glimpse into their potential for an exciting future.

In this supplement, Amar Krishnaswamy, MD, and colleagues look to new frontiers in valve replacement therapies. The success of transcatheter aortic valve replacement has led to extending the technique to the mitral valve. While technical challenges exist with transcatheter mitral valve replacement, methods to overcome these challenges are feasible. The authors review the various valve devices currently under development and examine their potential implications in practice.

The introduction of stents in percutaneous coronary interventions has been one of the most revolutionary innovations in cardiovascular medicine, resulting in impressive outcomes during the past few decades. Despite the dramatic advancement, persistent rates of restenosis and thrombosis continue to cause substantial morbidity and mortality. Stephen Ellis, MD, and Haris Riaz, MD, discuss the evolution of stent design from bare-metal stents through drug-eluting stents and their impact on outcomes. The evolution continues with the development of bioresorbable polymers and stents without polymers. The authors consider the promise of these innovations, especially bioresorbable stents, to further reduce restenosis and stent thrombosis.

Erich Kiehl, MD, and Daniel Cantillon, MD, present information about the latest innovation in cardiac pacing—leadless pacemakers. The first leadless pacemaker was approved earlier this year. In over 50 years of use of transvenous pacemakers, long-term complications have primarily involved the endovascular leads and surgical pocket. The authors discuss the promise of leadless cardiac pacing using catheter-based delivery of a self-contained device in the right ventricle to favorably reduce these complications, as well the current limitation of single-chamber pacing and possible future directions.

Innovations in monoclonal antibody therapy have resulted in a new class of biologic drugs to lower low-density-lipoprotein (LDL) in the blood—PCSK9 inhibitors. These new biologics target the overexpression of the PCSK9 protein in the liver, thereby increasing LDL receptors available to metabolize and remove LDL from the blood. Khendi White, MD, Chaitra Mohan, MD, and Michael Rocco, MD, discuss potential candidates for recently approved PCSK9 inhibitor therapy.

Ellen Brinza, MS, and Heather Gornik, MD, discuss new findings in our understanding of fibromuscular dysplasia (FMD). This uncommon nonatherosclerotic disease leads to narrowing, dissection, or aneurysm of medium-sized arteries. FMD is caused by abnormal development of the arterial cell wall and can cause symptoms if narrowing or a tear decreases blood flow through the artery. The authors discuss evaluation, management, and surveillance strategies as well as important lifestyle modifications and appropriate treatment of symptoms.

We hope this presentation of recent innovations in cardiovascular medicine is useful and informative to you and your clinical practice.

Innovations are dominating the early part of the 21st century and the impact on cardiovascular medicine has been especially remarkable. Keeping up and evaluating the relevance of these innovations and the role in patient care is a constant challenge and opportunity for providers and scientists alike.

This Cleveland Clinic Journal of Medicine supplement on cardiovascular disease presents healthcare providers with evidenced-based reviews of important innovations and a glimpse into their potential for an exciting future.

In this supplement, Amar Krishnaswamy, MD, and colleagues look to new frontiers in valve replacement therapies. The success of transcatheter aortic valve replacement has led to extending the technique to the mitral valve. While technical challenges exist with transcatheter mitral valve replacement, methods to overcome these challenges are feasible. The authors review the various valve devices currently under development and examine their potential implications in practice.

The introduction of stents in percutaneous coronary interventions has been one of the most revolutionary innovations in cardiovascular medicine, resulting in impressive outcomes during the past few decades. Despite the dramatic advancement, persistent rates of restenosis and thrombosis continue to cause substantial morbidity and mortality. Stephen Ellis, MD, and Haris Riaz, MD, discuss the evolution of stent design from bare-metal stents through drug-eluting stents and their impact on outcomes. The evolution continues with the development of bioresorbable polymers and stents without polymers. The authors consider the promise of these innovations, especially bioresorbable stents, to further reduce restenosis and stent thrombosis.

Erich Kiehl, MD, and Daniel Cantillon, MD, present information about the latest innovation in cardiac pacing—leadless pacemakers. The first leadless pacemaker was approved earlier this year. In over 50 years of use of transvenous pacemakers, long-term complications have primarily involved the endovascular leads and surgical pocket. The authors discuss the promise of leadless cardiac pacing using catheter-based delivery of a self-contained device in the right ventricle to favorably reduce these complications, as well the current limitation of single-chamber pacing and possible future directions.

Innovations in monoclonal antibody therapy have resulted in a new class of biologic drugs to lower low-density-lipoprotein (LDL) in the blood—PCSK9 inhibitors. These new biologics target the overexpression of the PCSK9 protein in the liver, thereby increasing LDL receptors available to metabolize and remove LDL from the blood. Khendi White, MD, Chaitra Mohan, MD, and Michael Rocco, MD, discuss potential candidates for recently approved PCSK9 inhibitor therapy.

Ellen Brinza, MS, and Heather Gornik, MD, discuss new findings in our understanding of fibromuscular dysplasia (FMD). This uncommon nonatherosclerotic disease leads to narrowing, dissection, or aneurysm of medium-sized arteries. FMD is caused by abnormal development of the arterial cell wall and can cause symptoms if narrowing or a tear decreases blood flow through the artery. The authors discuss evaluation, management, and surveillance strategies as well as important lifestyle modifications and appropriate treatment of symptoms.

We hope this presentation of recent innovations in cardiovascular medicine is useful and informative to you and your clinical practice.

In the last 10 years, we have seen a revolution in transcatheter therapies for structural heart disease. The most widely embraced, transcatheter aortic valve replacement (TAVR) was originally intended for patients in whom surgery was considered impossible, but it has now been established as an excellent alternative to surgical aortic valve replacement in patients at high or intermediate risk.^1–3 As TAVR has become established, with well-designed devices and acceptable safety and efficacy, it has inspired operators and inventors to push the envelope of innovation to transcatheter mitral valve replacement (TMVR).

This review summarizes the newest data available for the TMVR devices currently being tested in patients with native mitral regurgitation, bioprosthetic degeneration, and degenerative mitral stenosis.

THE MITRAL VALVE: THE NEW FRONTIER

Whereas the pathologic mechanisms of aortic stenosis generally all result in the same anatomic consequence (ie, calcification of the valve leaflets and commissures resulting in reduced mobility), mitral valve regurgitation is much more heterogeneous. Primary (degenerative) mitral regurgitation is caused by intrinsic valve pathology such as myxomatous degeneration, chordal detachment, fibroelastic deficiency, endocarditis, and other conditions that prevent the leaflets from coapting properly. In contrast, in secondary or functional mitral regurgitation, the leaflets are normal but do not coapt properly because of apical tethering to a dilated left ventricle, reduced closing forces with left ventricular dysfunction, or annular dilation as the result of either left ventricular or left atrial dilation.

Surgical mitral valve repair is safe and effective in patients with degenerative mitral regurgitation caused by leaflet prolapse and flail. However, some patients cannot undergo surgery because they have comorbid conditions that place them at extreme risk.⁴ For example, most patients with functional mitral regurgitation due to ischemic or dilated cardiomyopathy have significant surgical risk and multiple comorbidities, and in this group surgical repair has limited efficacy.⁵ A sizeable proportion of patients with mitral regurgitation may not be offered surgery because their risk is too high.⁶ Therefore, alternatives to the current surgical treatments have the potential to benefit a large number of patients.

Similarly, many patients with degenerative mitral stenosis caused by calcification of the mitral annulus also cannot undergo cardiac surgery because of prohibitively high risk. While rheumatic disease is the most common cause of mitral stenosis worldwide, degenerative mitral stenosis may be the cause in up to one-fourth of patients overall and up to 60% of patients older than 80 years.⁷ In the latter group, not only do old age and comorbidities such as diabetes mellitus and chronic kidney disease pose surgical risks, the technical challenge of surgically implanting a prosthetic mitral valve in the setting of a calcified annulus may be significant.⁸

The mitral valve is, therefore, the perfect new frontier for percutaneous valve replacement therapies, and TMVR is emerging as a potential option for patients with mitral regurgitation and degenerative mitral stenosis. The currently available percutaneous treatment options for mitral regurgitation include edge-to-edge leaflet repair, direct and indirect annuloplasty, spacers, and left ventricular remodeling devices (Table 1).^9,10 As surgical mitral valve repair is strongly preferred over mitral valve replacement, the percutaneous procedures and the devices that are used are engineered to approximate the current standard surgical techniques. However, given the complex pathologies involved, surgical repair often requires the use of multiple repair techniques in the same patient. Therefore, percutaneous repair may also require more than one type of device in the same patient and may not be anatomically feasible in many patients. Replacing the entire valve may obviate some of these challenges.

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

Compared with the aortic valve, the mitral valve poses a greater challenge to percutaneous treatment due to its structure and dynamic relationship with the left ventricle. Some specific challenges facing the development of TMVR are that the mitral valve is large, it is difficult to access, it is asymmetrical, it lacks an anatomically well-defined annulus to which to anchor the replacement valve, its geometry changes throughout the cardiac cycle, and placing a replacement valve in it entails the risk of left ventricular outflow tract obstruction. Despite these challenges, a number of devices are undergoing preclinical testing, a few are in phase 1 clinical trials, and registries are being kept. Depending on the specific device, an antegrade transseptal approach to the mitral valve (via the femoral vein) or a retrograde transapical approach (via direct left ventricular access) may be used (Figure 1).

NATIVE MITRAL VALVE REGURGITATION

For degenerative mitral regurgitation, the standard of care is cardiac surgery at a hospital experienced with mitral valve repair, and with very low rates of mortality and morbidity. For patients in whom the surgical risk is prohibitive, percutaneous edge-to-edge leaflet repair using the MitraClip (Abbott Vascular, Minneapolis, MN) is the best option if the anatomy permits. If the mitral valve pathology is not amenable to MitraClip repair, the patient may be evaluated for TMVR under a clinical trial protocol.

For functional mitral regurgitation, the decisions are more complex. If the patient has chronic atrial fibrillation, electrical cardioversion and antiarrhythmic drug therapy may restore and maintain sinus rhythm, though if the left atrium is large, sinus rhythm may not be possible. If the patient has left ventricular dysfunction, guideline-directed medical therapy should be optimized; this reduces the risk of exacerbations, hospitalizations, and death and may also reduce the degree of regurgitation. If the patient has severe left ventricular dysfunction and a wide QRS duration, cardiac resynchronization therapy (biventricular pacing) may also be beneficial and reduce functional mitral regurgitation. If symptoms and severe functional mitral regurgitation persist despite these measures and the patient’s surgical risk is deemed to be extreme, options include MitraClip placement as part of the randomized Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) trial, which compares guideline-directed medical therapy with guideline-directed therapy plus MitraClip. Another option is enrollment in a clinical trial or registry of TMVR.

At this writing, six TMVR devices have been implanted in humans:

• Fortis (Edwards Lifesciences, Irvine, CA)
• Tendyne (Tendyne Holding Inc, Roseville, MN)
• NaviGate (NaviGate Cardiac Structures, Inc, Lake Forest, CA)
• Intrepid (Medtronic, Minneapolis, MN)
• CardiAQ (Edwards Lifesciences, Irvine, CA)
• Tiara (Neovasc Inc, Richmond, BC).

Most of the early experience with these valves has not yet been published, but some data have been presented at national and international meetings.

The Fortis valve

Courtesy of Edwards Lifesciences.

The Fortis valve consists of a self-expanding nitinol frame and leaflets made of bovine pericardium and is implanted via a transapical approach.

The device was successfully implanted in three patients in Quebec City, Canada, and at 6 months, all had improved significantly in functional class and none had needed to be hospitalized.¹¹ Echocardiographic assessment demonstrated trace or less mitral regurgitation and a mean transvalvular gradient less than 4 mm Hg in all.

Bapat and colleagues¹² attempted to implant the device in 13 patients in Europe and Canada. The average left ventricular ejection fraction was 34%, and 12 of 13 patients (92%) had functional mitral regurgitation. Procedural success was achieved in 10 patients, but five patients died within 30 days. While the deaths were due to nonvalvular issues (multi­organ failure, septic shock, intestinal ischemia after failed valve implantation and conversion to open surgery, malnutrition leading to respiratory failure, and valve thrombosis), the trial is currently on hold as more data are collected and reviewed. Among the eight patients who survived the first month, all were still alive at 6 months, and echocardiography demonstrated no or trivial mitral regurgitation in six patients (80%) and mild regurgitation in two patients (20%); the average mitral gradient was 4 mm Hg, and there was no change in mean left ventricular ejection fraction.

The Tendyne valve

Reprinted from EuroIntervention (Perpetua EM, et al. The Tendyne transcatheter mitral valve implantation system. EuroIntervention 2015; 11:W78-W79.) © 2015 with permission from Europa Digital Publishing.

The Tendyne valve is a self-expanding prosthesis with porcine pericardial leaflets. It is delivered transapically and is held in place by a tether from the valve to the left ventricular apex.

In the first 12 patients enrolled in an early feasibility trial,¹³ the average left ventricular ejection fraction was 40%, and 11 of the 12 patients had functional mitral regurgitation. The device was successfully implanted in 11 patients, while one patient developed left ventricular outflow tract obstruction and the device was uneventfully removed. All patients were still alive at 30 days, and the 11 patients who still had a prosthetic valve did not have any residual mitral regurgitation.

As of this writing, almost 80 patients have received the device, though the data have not yet been presented. Patients are being enrolled in phase 1 trials.

The NaviGate valve

Courtesy of Jose Navia.

The NaviGate valve consists of a trileaflet subassembly fabricated from bovine pericardium, mounted on a self-expanding nitinol stent, and is only implanted transatrially.

NaviGate valves were successfully implanted in two patients via a transatrial approach (Figure 2). Both patients had excellent valve performance without residual mitral regurgitation or left ventricular outflow tract obstruction. The first patient showed significant improvement in functional class and freedom from hospitalization at 6 months, but the second patient died within a week of the implant due to advanced heart failure.¹⁴ A US clinical trial is expected soon.

The Intrepid valve

Courtesy of Medtronic.

The Intrepid valve consists of an outer stent to provide fixation to the annulus and an inner stent that houses a bovine pericardial valve. The device is a self-expanding system that is delivered transapically.

In a series of 15 patients, 11 had functional mitral regurgitation (with an average left ventricular ejection fraction of 35%) and four had degenerative mitral regurgitation (with an average left ventricular ejection fraction of 57%).¹⁵ The device was successfully implanted in 14 patients, after which the average mitral valve gradient was 4 mm Hg. All patients but one were left with no regurgitation (the other patient had 1+ regurgitation).

A trial is currently under way in Europe.

The CardiAQ valve

Courtesy of Edwards Lifesciences.

The CardiAQ is constructed of bovine pericardium and can be delivered by the transseptal or transapical route.

Of 12 patients treated under compassionate use,¹⁶ two-thirds (eight patients) had functional mitral regurgitation. Two patients died during the procedure, three died of noncardiac complications within 30 days, and one more died of sepsis shortly after 30 days. This early experience demonstrates the importance of careful patient selection and postprocedural management in the feasibility assessment of these new technologies.

Patients are being enrolled in phase 1 trials.

The Tiara valve

Reprinted from EuroIntervention (Cheung A, et al. Transcatheter mitral valve implantation with Tiara bioprosthesis. EuroIntervention 2014; 10:U115-U119.) © 2014 with permission from Europa Digital & Publishing.

The Tiara valve, a self-expanding prosthesis with bovine pericardial leaflets, is delivered by the transapical route.

Eleven patients underwent Tiara implantation as part of either a Canadian special access registry or an international feasibility trial. Their average Society of Thoracic Surgeons score (ie, their calculated risk of major morbidity or operative mortality) was 15.6%, and their average left ventricular ejection fraction was 29%. Only two patients had degenerative mitral regurgitation. Nine patients had uneventful procedures and demonstrated no residual mitral regurgitation and no left ventricular outflow tract obstruction. The procedure was converted to open surgery in two patients owing to valve malpositioning, and both of them died within 30 days. One patient in whom the procedure was successful suffered erosion of the septum and died on day 4.¹⁷

Patients are being enrolled in phase 1 trials.

DEGENERATIVE MITRAL STENOSIS

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

In patients with degenerative mitral stenosis, extensive mitral annular calcification may provide an adequate “frame” to hold a transcatheter valve prosthesis (Figure 3). Exploiting this feature, numerous investigators have successfully deployed prosthetic valves designed for TAVR in the calcified mitral annulus via the retrograde transapical and antegrade transseptal routes.

Guerrero and colleagues presented results from the first global registry of TMVR in mitral annular calcification at the 2016 EuroPCR Congress.¹⁸ Of 104 patients analyzed, almost all received an Edwards’ Sapien balloon-expandable valve (first-generation, Sapien XT, or Sapien 3); the others received Boston Scientific’s Lotus or Direct Flow Medical (Direct Flow Medical, Santa Clara, CA) valves. With an average age of 73 years and a high prevalence of comorbidities such as diabetes, chronic obstructive pulmonary disease, atrial fibrillation, chronic kidney disease, and prior cardiac surgery, the group presented extreme surgical risk, with an average Society of Thoracic Surgeons risk score of 14.4%. Slightly more than 40% of the patients underwent transapical implantation, slightly less than 40% underwent transfemoral or transseptal implantation, and just under 20% had a direct atrial approach.

The implantation was technically successful in 78 of 104 patients (75%); 13 patients (12.5%) required a second mitral valve to be placed, 11 patients (10.5%) had left ventricular outflow tract obstruction, four patients (4%) had valve embolization, and two patients (2%) had left ventricular perforation. At 30 days, 11 of 104 patients (10.6%) had died of cardiac causes and 15 patients (14.4%) had died of noncardiac causes. When divided roughly into three equal groups by chronological order, the last third of patients, compared with the first third of patients, enjoyed greater technical success (80%, n = 32/40 vs 62.5%, n = 20/32), better 30-day survival (85%, n = 34/40 vs 62.5%, n = 20/32), and no conversion to open surgery (0 vs 12.5%, n = 4/32), likely demonstrating both improved patient selection and lessons learned from shared experience. At 1 year, almost 90% of patients had New York Heart Association class I or II symptoms. Prior to the procedure, 91.5% had New York Heart Association class III or IV symptoms.

At present, TMVR in mitral annular calcification is not approved in the United States or elsewhere. However, multiple registries are currently enrolling patients or are in formative stages to push the frontier of the currently available technologies until better, dedicated devices are available for this group of patients.

BIOPROSTHETIC VALVE OR VALVE RING FAILURE

Implantation of a TAVR prosthetic inside a degenerated bioprosthetic mitral valve (valve-in-valve) and mitral valve ring (valve-in-ring) is generally limited to case series with short-term results using the Edwards Sapien series, Boston Scientific Lotus, Medtronic Melody (Medtronic, Minneapolis, MN), and Direct Flow Medical valves (Figure 4).^19–23

The largest collective experience was presented in the Valve-in-Valve International Data (VIVID) registry, which included 349 patients who had mitral valve-in-valve placement and 88 patients who had mitral valve-in-ring procedures. Their average age was 74 and the mean Society of Thoracic Surgeons score was 12.9% in both groups.24 Of the 437 patients, 345 patients (78.9%) underwent transapical implantation, and 391 patients (89.5%) received  a Sapien XT or Sapien 3 valve. In the valve-in-valve group, 41% of the patients had regurgitation, 25% had stenosis, and 34% had both. In the valve-in-ring group, 60% of the patients had regurgitation, 17% had stenosis, and 23% had both.

Valve placement was successful in most patients. The rate of stroke was low (2.9% with valve-in-valve placement, 1.1% with valve-in-ring placement), though the rate of moderate or greater residual mitral regurgitation was significantly higher in patients undergoing valve-in-ring procedures (14.8% vs 2.6%, P < .001), as was the rate of left ventricular outflow tract obstruction (8% vs 2.6%, P = .03). There was also a trend toward worse 30-day mortality in the valve-in-ring group (11.4% vs 7.7%, P = .15). As with aortic valve-in-valve procedures, small surgical mitral valves (≤ 25 mm) were associated with higher postprocedural gradients.

Eleid and colleagues²⁵ published their experience with antegrade transseptal TMVR in 48 patients with an average Society of Thoracic Surgeons score of 13.2%, 33 of whom underwent valve-in-valve procedures and nine of whom underwent valve-in-ring procedures. (The other six patients underwent mitral valve implantation for severe mitral annular calcification.) In the valve-in-valve group, 31 patients successfully underwent implant procedures, but two patients died during the procedure from left ventricular perforation. Of the nine valve-in-ring patients, two had acute embolization of the valve and were converted to open surgery. Among the seven patients in whom implantation was successful, two developed significant left ventricular outflow tract obstruction; one was treated with surgical resection of the anterior mitral valve leaflet and the other was medically managed.

CONCLUSION

Transcatheter mitral valve replacement in regurgitant mitral valves, failing mitral valve bioprosthetics and rings, and calcified mitral annuli has been effectively conducted in a number of patients who had no surgical options due to prohibitive surgical risk. International registries and our experience have demonstrated that the valve-in-valve procedure using a TAVR prosthesis carries the greatest likelihood of success, given the rigid frame of the surgical bioprosthetic that allows stable valve deployment. While approved in Europe for this indication, use of these devices for this application in the United States is considered “off label” and is performed only in clinically extenuating circumstances. Implantation of TAVR prosthetics in patients with prior mitral ring repair or for native mitral stenosis also has been performed successfully, although left ventricular outflow tract obstruction is a significant risk in this early experience.

Devices designed specifically for TMVR are in their clinical infancy and have been implanted successfully in only small numbers of patients, most of whom had functional mitral regurgitation. Despite reasonable technical success, most of these trials have been plagued by high mortality rates at 30 days in large part due to the extreme risk of the patients in whom these procedures have been conducted. At present, enrollment in TMVR trials for patients with degenerative or functional mitral regurgitation is limited to those without a surgical option and who conform to very specific anatomic criteria.

In the last 10 years, we have seen a revolution in transcatheter therapies for structural heart disease. The most widely embraced, transcatheter aortic valve replacement (TAVR) was originally intended for patients in whom surgery was considered impossible, but it has now been established as an excellent alternative to surgical aortic valve replacement in patients at high or intermediate risk.^1–3 As TAVR has become established, with well-designed devices and acceptable safety and efficacy, it has inspired operators and inventors to push the envelope of innovation to transcatheter mitral valve replacement (TMVR).

This review summarizes the newest data available for the TMVR devices currently being tested in patients with native mitral regurgitation, bioprosthetic degeneration, and degenerative mitral stenosis.

THE MITRAL VALVE: THE NEW FRONTIER

Whereas the pathologic mechanisms of aortic stenosis generally all result in the same anatomic consequence (ie, calcification of the valve leaflets and commissures resulting in reduced mobility), mitral valve regurgitation is much more heterogeneous. Primary (degenerative) mitral regurgitation is caused by intrinsic valve pathology such as myxomatous degeneration, chordal detachment, fibroelastic deficiency, endocarditis, and other conditions that prevent the leaflets from coapting properly. In contrast, in secondary or functional mitral regurgitation, the leaflets are normal but do not coapt properly because of apical tethering to a dilated left ventricle, reduced closing forces with left ventricular dysfunction, or annular dilation as the result of either left ventricular or left atrial dilation.

Surgical mitral valve repair is safe and effective in patients with degenerative mitral regurgitation caused by leaflet prolapse and flail. However, some patients cannot undergo surgery because they have comorbid conditions that place them at extreme risk.⁴ For example, most patients with functional mitral regurgitation due to ischemic or dilated cardiomyopathy have significant surgical risk and multiple comorbidities, and in this group surgical repair has limited efficacy.⁵ A sizeable proportion of patients with mitral regurgitation may not be offered surgery because their risk is too high.⁶ Therefore, alternatives to the current surgical treatments have the potential to benefit a large number of patients.

Similarly, many patients with degenerative mitral stenosis caused by calcification of the mitral annulus also cannot undergo cardiac surgery because of prohibitively high risk. While rheumatic disease is the most common cause of mitral stenosis worldwide, degenerative mitral stenosis may be the cause in up to one-fourth of patients overall and up to 60% of patients older than 80 years.⁷ In the latter group, not only do old age and comorbidities such as diabetes mellitus and chronic kidney disease pose surgical risks, the technical challenge of surgically implanting a prosthetic mitral valve in the setting of a calcified annulus may be significant.⁸

The mitral valve is, therefore, the perfect new frontier for percutaneous valve replacement therapies, and TMVR is emerging as a potential option for patients with mitral regurgitation and degenerative mitral stenosis. The currently available percutaneous treatment options for mitral regurgitation include edge-to-edge leaflet repair, direct and indirect annuloplasty, spacers, and left ventricular remodeling devices (Table 1).^9,10 As surgical mitral valve repair is strongly preferred over mitral valve replacement, the percutaneous procedures and the devices that are used are engineered to approximate the current standard surgical techniques. However, given the complex pathologies involved, surgical repair often requires the use of multiple repair techniques in the same patient. Therefore, percutaneous repair may also require more than one type of device in the same patient and may not be anatomically feasible in many patients. Replacing the entire valve may obviate some of these challenges.

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

Compared with the aortic valve, the mitral valve poses a greater challenge to percutaneous treatment due to its structure and dynamic relationship with the left ventricle. Some specific challenges facing the development of TMVR are that the mitral valve is large, it is difficult to access, it is asymmetrical, it lacks an anatomically well-defined annulus to which to anchor the replacement valve, its geometry changes throughout the cardiac cycle, and placing a replacement valve in it entails the risk of left ventricular outflow tract obstruction. Despite these challenges, a number of devices are undergoing preclinical testing, a few are in phase 1 clinical trials, and registries are being kept. Depending on the specific device, an antegrade transseptal approach to the mitral valve (via the femoral vein) or a retrograde transapical approach (via direct left ventricular access) may be used (Figure 1).

NATIVE MITRAL VALVE REGURGITATION

For degenerative mitral regurgitation, the standard of care is cardiac surgery at a hospital experienced with mitral valve repair, and with very low rates of mortality and morbidity. For patients in whom the surgical risk is prohibitive, percutaneous edge-to-edge leaflet repair using the MitraClip (Abbott Vascular, Minneapolis, MN) is the best option if the anatomy permits. If the mitral valve pathology is not amenable to MitraClip repair, the patient may be evaluated for TMVR under a clinical trial protocol.

For functional mitral regurgitation, the decisions are more complex. If the patient has chronic atrial fibrillation, electrical cardioversion and antiarrhythmic drug therapy may restore and maintain sinus rhythm, though if the left atrium is large, sinus rhythm may not be possible. If the patient has left ventricular dysfunction, guideline-directed medical therapy should be optimized; this reduces the risk of exacerbations, hospitalizations, and death and may also reduce the degree of regurgitation. If the patient has severe left ventricular dysfunction and a wide QRS duration, cardiac resynchronization therapy (biventricular pacing) may also be beneficial and reduce functional mitral regurgitation. If symptoms and severe functional mitral regurgitation persist despite these measures and the patient’s surgical risk is deemed to be extreme, options include MitraClip placement as part of the randomized Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) trial, which compares guideline-directed medical therapy with guideline-directed therapy plus MitraClip. Another option is enrollment in a clinical trial or registry of TMVR.

At this writing, six TMVR devices have been implanted in humans:

• Fortis (Edwards Lifesciences, Irvine, CA)
• Tendyne (Tendyne Holding Inc, Roseville, MN)
• NaviGate (NaviGate Cardiac Structures, Inc, Lake Forest, CA)
• Intrepid (Medtronic, Minneapolis, MN)
• CardiAQ (Edwards Lifesciences, Irvine, CA)
• Tiara (Neovasc Inc, Richmond, BC).

Most of the early experience with these valves has not yet been published, but some data have been presented at national and international meetings.

The Fortis valve

Courtesy of Edwards Lifesciences.

The Fortis valve consists of a self-expanding nitinol frame and leaflets made of bovine pericardium and is implanted via a transapical approach.

The device was successfully implanted in three patients in Quebec City, Canada, and at 6 months, all had improved significantly in functional class and none had needed to be hospitalized.¹¹ Echocardiographic assessment demonstrated trace or less mitral regurgitation and a mean transvalvular gradient less than 4 mm Hg in all.

Bapat and colleagues¹² attempted to implant the device in 13 patients in Europe and Canada. The average left ventricular ejection fraction was 34%, and 12 of 13 patients (92%) had functional mitral regurgitation. Procedural success was achieved in 10 patients, but five patients died within 30 days. While the deaths were due to nonvalvular issues (multi­organ failure, septic shock, intestinal ischemia after failed valve implantation and conversion to open surgery, malnutrition leading to respiratory failure, and valve thrombosis), the trial is currently on hold as more data are collected and reviewed. Among the eight patients who survived the first month, all were still alive at 6 months, and echocardiography demonstrated no or trivial mitral regurgitation in six patients (80%) and mild regurgitation in two patients (20%); the average mitral gradient was 4 mm Hg, and there was no change in mean left ventricular ejection fraction.

The Tendyne valve

Reprinted from EuroIntervention (Perpetua EM, et al. The Tendyne transcatheter mitral valve implantation system. EuroIntervention 2015; 11:W78-W79.) © 2015 with permission from Europa Digital Publishing.

The Tendyne valve is a self-expanding prosthesis with porcine pericardial leaflets. It is delivered transapically and is held in place by a tether from the valve to the left ventricular apex.

In the first 12 patients enrolled in an early feasibility trial,¹³ the average left ventricular ejection fraction was 40%, and 11 of the 12 patients had functional mitral regurgitation. The device was successfully implanted in 11 patients, while one patient developed left ventricular outflow tract obstruction and the device was uneventfully removed. All patients were still alive at 30 days, and the 11 patients who still had a prosthetic valve did not have any residual mitral regurgitation.

As of this writing, almost 80 patients have received the device, though the data have not yet been presented. Patients are being enrolled in phase 1 trials.

The NaviGate valve

Courtesy of Jose Navia.

The NaviGate valve consists of a trileaflet subassembly fabricated from bovine pericardium, mounted on a self-expanding nitinol stent, and is only implanted transatrially.

NaviGate valves were successfully implanted in two patients via a transatrial approach (Figure 2). Both patients had excellent valve performance without residual mitral regurgitation or left ventricular outflow tract obstruction. The first patient showed significant improvement in functional class and freedom from hospitalization at 6 months, but the second patient died within a week of the implant due to advanced heart failure.¹⁴ A US clinical trial is expected soon.

The Intrepid valve

Courtesy of Medtronic.

The Intrepid valve consists of an outer stent to provide fixation to the annulus and an inner stent that houses a bovine pericardial valve. The device is a self-expanding system that is delivered transapically.

In a series of 15 patients, 11 had functional mitral regurgitation (with an average left ventricular ejection fraction of 35%) and four had degenerative mitral regurgitation (with an average left ventricular ejection fraction of 57%).¹⁵ The device was successfully implanted in 14 patients, after which the average mitral valve gradient was 4 mm Hg. All patients but one were left with no regurgitation (the other patient had 1+ regurgitation).

A trial is currently under way in Europe.

The CardiAQ valve

Courtesy of Edwards Lifesciences.

The CardiAQ is constructed of bovine pericardium and can be delivered by the transseptal or transapical route.

Of 12 patients treated under compassionate use,¹⁶ two-thirds (eight patients) had functional mitral regurgitation. Two patients died during the procedure, three died of noncardiac complications within 30 days, and one more died of sepsis shortly after 30 days. This early experience demonstrates the importance of careful patient selection and postprocedural management in the feasibility assessment of these new technologies.

Patients are being enrolled in phase 1 trials.

The Tiara valve

Reprinted from EuroIntervention (Cheung A, et al. Transcatheter mitral valve implantation with Tiara bioprosthesis. EuroIntervention 2014; 10:U115-U119.) © 2014 with permission from Europa Digital &amp; Publishing.

The Tiara valve, a self-expanding prosthesis with bovine pericardial leaflets, is delivered by the transapical route.

Eleven patients underwent Tiara implantation as part of either a Canadian special access registry or an international feasibility trial. Their average Society of Thoracic Surgeons score (ie, their calculated risk of major morbidity or operative mortality) was 15.6%, and their average left ventricular ejection fraction was 29%. Only two patients had degenerative mitral regurgitation. Nine patients had uneventful procedures and demonstrated no residual mitral regurgitation and no left ventricular outflow tract obstruction. The procedure was converted to open surgery in two patients owing to valve malpositioning, and both of them died within 30 days. One patient in whom the procedure was successful suffered erosion of the septum and died on day 4.¹⁷

Patients are being enrolled in phase 1 trials.

DEGENERATIVE MITRAL STENOSIS

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

In patients with degenerative mitral stenosis, extensive mitral annular calcification may provide an adequate “frame” to hold a transcatheter valve prosthesis (Figure 3). Exploiting this feature, numerous investigators have successfully deployed prosthetic valves designed for TAVR in the calcified mitral annulus via the retrograde transapical and antegrade transseptal routes.

Guerrero and colleagues presented results from the first global registry of TMVR in mitral annular calcification at the 2016 EuroPCR Congress.¹⁸ Of 104 patients analyzed, almost all received an Edwards’ Sapien balloon-expandable valve (first-generation, Sapien XT, or Sapien 3); the others received Boston Scientific’s Lotus or Direct Flow Medical (Direct Flow Medical, Santa Clara, CA) valves. With an average age of 73 years and a high prevalence of comorbidities such as diabetes, chronic obstructive pulmonary disease, atrial fibrillation, chronic kidney disease, and prior cardiac surgery, the group presented extreme surgical risk, with an average Society of Thoracic Surgeons risk score of 14.4%. Slightly more than 40% of the patients underwent transapical implantation, slightly less than 40% underwent transfemoral or transseptal implantation, and just under 20% had a direct atrial approach.

The implantation was technically successful in 78 of 104 patients (75%); 13 patients (12.5%) required a second mitral valve to be placed, 11 patients (10.5%) had left ventricular outflow tract obstruction, four patients (4%) had valve embolization, and two patients (2%) had left ventricular perforation. At 30 days, 11 of 104 patients (10.6%) had died of cardiac causes and 15 patients (14.4%) had died of noncardiac causes. When divided roughly into three equal groups by chronological order, the last third of patients, compared with the first third of patients, enjoyed greater technical success (80%, n = 32/40 vs 62.5%, n = 20/32), better 30-day survival (85%, n = 34/40 vs 62.5%, n = 20/32), and no conversion to open surgery (0 vs 12.5%, n = 4/32), likely demonstrating both improved patient selection and lessons learned from shared experience. At 1 year, almost 90% of patients had New York Heart Association class I or II symptoms. Prior to the procedure, 91.5% had New York Heart Association class III or IV symptoms.

At present, TMVR in mitral annular calcification is not approved in the United States or elsewhere. However, multiple registries are currently enrolling patients or are in formative stages to push the frontier of the currently available technologies until better, dedicated devices are available for this group of patients.

BIOPROSTHETIC VALVE OR VALVE RING FAILURE

Implantation of a TAVR prosthetic inside a degenerated bioprosthetic mitral valve (valve-in-valve) and mitral valve ring (valve-in-ring) is generally limited to case series with short-term results using the Edwards Sapien series, Boston Scientific Lotus, Medtronic Melody (Medtronic, Minneapolis, MN), and Direct Flow Medical valves (Figure 4).^19–23

The largest collective experience was presented in the Valve-in-Valve International Data (VIVID) registry, which included 349 patients who had mitral valve-in-valve placement and 88 patients who had mitral valve-in-ring procedures. Their average age was 74 and the mean Society of Thoracic Surgeons score was 12.9% in both groups.24 Of the 437 patients, 345 patients (78.9%) underwent transapical implantation, and 391 patients (89.5%) received  a Sapien XT or Sapien 3 valve. In the valve-in-valve group, 41% of the patients had regurgitation, 25% had stenosis, and 34% had both. In the valve-in-ring group, 60% of the patients had regurgitation, 17% had stenosis, and 23% had both.

Valve placement was successful in most patients. The rate of stroke was low (2.9% with valve-in-valve placement, 1.1% with valve-in-ring placement), though the rate of moderate or greater residual mitral regurgitation was significantly higher in patients undergoing valve-in-ring procedures (14.8% vs 2.6%, P < .001), as was the rate of left ventricular outflow tract obstruction (8% vs 2.6%, P = .03). There was also a trend toward worse 30-day mortality in the valve-in-ring group (11.4% vs 7.7%, P = .15). As with aortic valve-in-valve procedures, small surgical mitral valves (≤ 25 mm) were associated with higher postprocedural gradients.

Eleid and colleagues²⁵ published their experience with antegrade transseptal TMVR in 48 patients with an average Society of Thoracic Surgeons score of 13.2%, 33 of whom underwent valve-in-valve procedures and nine of whom underwent valve-in-ring procedures. (The other six patients underwent mitral valve implantation for severe mitral annular calcification.) In the valve-in-valve group, 31 patients successfully underwent implant procedures, but two patients died during the procedure from left ventricular perforation. Of the nine valve-in-ring patients, two had acute embolization of the valve and were converted to open surgery. Among the seven patients in whom implantation was successful, two developed significant left ventricular outflow tract obstruction; one was treated with surgical resection of the anterior mitral valve leaflet and the other was medically managed.

CONCLUSION

Transcatheter mitral valve replacement in regurgitant mitral valves, failing mitral valve bioprosthetics and rings, and calcified mitral annuli has been effectively conducted in a number of patients who had no surgical options due to prohibitive surgical risk. International registries and our experience have demonstrated that the valve-in-valve procedure using a TAVR prosthesis carries the greatest likelihood of success, given the rigid frame of the surgical bioprosthetic that allows stable valve deployment. While approved in Europe for this indication, use of these devices for this application in the United States is considered “off label” and is performed only in clinically extenuating circumstances. Implantation of TAVR prosthetics in patients with prior mitral ring repair or for native mitral stenosis also has been performed successfully, although left ventricular outflow tract obstruction is a significant risk in this early experience.

Devices designed specifically for TMVR are in their clinical infancy and have been implanted successfully in only small numbers of patients, most of whom had functional mitral regurgitation. Despite reasonable technical success, most of these trials have been plagued by high mortality rates at 30 days in large part due to the extreme risk of the patients in whom these procedures have been conducted. At present, enrollment in TMVR trials for patients with degenerative or functional mitral regurgitation is limited to those without a surgical option and who conform to very specific anatomic criteria.

In the last 10 years, we have seen a revolution in transcatheter therapies for structural heart disease. The most widely embraced, transcatheter aortic valve replacement (TAVR) was originally intended for patients in whom surgery was considered impossible, but it has now been established as an excellent alternative to surgical aortic valve replacement in patients at high or intermediate risk.^1–3 As TAVR has become established, with well-designed devices and acceptable safety and efficacy, it has inspired operators and inventors to push the envelope of innovation to transcatheter mitral valve replacement (TMVR).

This review summarizes the newest data available for the TMVR devices currently being tested in patients with native mitral regurgitation, bioprosthetic degeneration, and degenerative mitral stenosis.

THE MITRAL VALVE: THE NEW FRONTIER

Whereas the pathologic mechanisms of aortic stenosis generally all result in the same anatomic consequence (ie, calcification of the valve leaflets and commissures resulting in reduced mobility), mitral valve regurgitation is much more heterogeneous. Primary (degenerative) mitral regurgitation is caused by intrinsic valve pathology such as myxomatous degeneration, chordal detachment, fibroelastic deficiency, endocarditis, and other conditions that prevent the leaflets from coapting properly. In contrast, in secondary or functional mitral regurgitation, the leaflets are normal but do not coapt properly because of apical tethering to a dilated left ventricle, reduced closing forces with left ventricular dysfunction, or annular dilation as the result of either left ventricular or left atrial dilation.

Surgical mitral valve repair is safe and effective in patients with degenerative mitral regurgitation caused by leaflet prolapse and flail. However, some patients cannot undergo surgery because they have comorbid conditions that place them at extreme risk.⁴ For example, most patients with functional mitral regurgitation due to ischemic or dilated cardiomyopathy have significant surgical risk and multiple comorbidities, and in this group surgical repair has limited efficacy.⁵ A sizeable proportion of patients with mitral regurgitation may not be offered surgery because their risk is too high.⁶ Therefore, alternatives to the current surgical treatments have the potential to benefit a large number of patients.

Similarly, many patients with degenerative mitral stenosis caused by calcification of the mitral annulus also cannot undergo cardiac surgery because of prohibitively high risk. While rheumatic disease is the most common cause of mitral stenosis worldwide, degenerative mitral stenosis may be the cause in up to one-fourth of patients overall and up to 60% of patients older than 80 years.⁷ In the latter group, not only do old age and comorbidities such as diabetes mellitus and chronic kidney disease pose surgical risks, the technical challenge of surgically implanting a prosthetic mitral valve in the setting of a calcified annulus may be significant.⁸

The mitral valve is, therefore, the perfect new frontier for percutaneous valve replacement therapies, and TMVR is emerging as a potential option for patients with mitral regurgitation and degenerative mitral stenosis. The currently available percutaneous treatment options for mitral regurgitation include edge-to-edge leaflet repair, direct and indirect annuloplasty, spacers, and left ventricular remodeling devices (Table 1).^9,10 As surgical mitral valve repair is strongly preferred over mitral valve replacement, the percutaneous procedures and the devices that are used are engineered to approximate the current standard surgical techniques. However, given the complex pathologies involved, surgical repair often requires the use of multiple repair techniques in the same patient. Therefore, percutaneous repair may also require more than one type of device in the same patient and may not be anatomically feasible in many patients. Replacing the entire valve may obviate some of these challenges.

Reprinted with permission from Wolters Kluwer Health, Inc. (Sud K, et al. Degenerated mitral stenosis: unmet need for percutaneous interventions. Circulation 2016; 133:1594–1604).

Compared with the aortic valve, the mitral valve poses a greater challenge to percutaneous treatment due to its structure and dynamic relationship with the left ventricle. Some specific challenges facing the development of TMVR are that the mitral valve is large, it is difficult to access, it is asymmetrical, it lacks an anatomically well-defined annulus to which to anchor the replacement valve, its geometry changes throughout the cardiac cycle, and placing a replacement valve in it entails the risk of left ventricular outflow tract obstruction. Despite these challenges, a number of devices are undergoing preclinical testing, a few are in phase 1 clinical trials, and registries are being kept. Depending on the specific device, an antegrade transseptal approach to the mitral valve (via the femoral vein) or a retrograde transapical approach (via direct left ventricular access) may be used (Figure 1).

NATIVE MITRAL VALVE REGURGITATION

For degenerative mitral regurgitation, the standard of care is cardiac surgery at a hospital experienced with mitral valve repair, and with very low rates of mortality and morbidity. For patients in whom the surgical risk is prohibitive, percutaneous edge-to-edge leaflet repair using the MitraClip (Abbott Vascular, Minneapolis, MN) is the best option if the anatomy permits. If the mitral valve pathology is not amenable to MitraClip repair, the patient may be evaluated for TMVR under a clinical trial protocol.

For functional mitral regurgitation, the decisions are more complex. If the patient has chronic atrial fibrillation, electrical cardioversion and antiarrhythmic drug therapy may restore and maintain sinus rhythm, though if the left atrium is large, sinus rhythm may not be possible. If the patient has left ventricular dysfunction, guideline-directed medical therapy should be optimized; this reduces the risk of exacerbations, hospitalizations, and death and may also reduce the degree of regurgitation. If the patient has severe left ventricular dysfunction and a wide QRS duration, cardiac resynchronization therapy (biventricular pacing) may also be beneficial and reduce functional mitral regurgitation. If symptoms and severe functional mitral regurgitation persist despite these measures and the patient’s surgical risk is deemed to be extreme, options include MitraClip placement as part of the randomized Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy (COAPT) trial, which compares guideline-directed medical therapy with guideline-directed therapy plus MitraClip. Another option is enrollment in a clinical trial or registry of TMVR.

At this writing, six TMVR devices have been implanted in humans:

• Fortis (Edwards Lifesciences, Irvine, CA)
• Tendyne (Tendyne Holding Inc, Roseville, MN)
• NaviGate (NaviGate Cardiac Structures, Inc, Lake Forest, CA)
• Intrepid (Medtronic, Minneapolis, MN)
• CardiAQ (Edwards Lifesciences, Irvine, CA)
• Tiara (Neovasc Inc, Richmond, BC).

Most of the early experience with these valves has not yet been published, but some data have been presented at national and international meetings.

The Fortis valve

Courtesy of Edwards Lifesciences.

The Fortis valve consists of a self-expanding nitinol frame and leaflets made of bovine pericardium and is implanted via a transapical approach.

The device was successfully implanted in three patients in Quebec City, Canada, and at 6 months, all had improved significantly in functional class and none had needed to be hospitalized.¹¹ Echocardiographic assessment demonstrated trace or less mitral regurgitation and a mean transvalvular gradient less than 4 mm Hg in all.

Bapat and colleagues¹² attempted to implant the device in 13 patients in Europe and Canada. The average left ventricular ejection fraction was 34%, and 12 of 13 patients (92%) had functional mitral regurgitation. Procedural success was achieved in 10 patients, but five patients died within 30 days. While the deaths were due to nonvalvular issues (multi­organ failure, septic shock, intestinal ischemia after failed valve implantation and conversion to open surgery, malnutrition leading to respiratory failure, and valve thrombosis), the trial is currently on hold as more data are collected and reviewed. Among the eight patients who survived the first month, all were still alive at 6 months, and echocardiography demonstrated no or trivial mitral regurgitation in six patients (80%) and mild regurgitation in two patients (20%); the average mitral gradient was 4 mm Hg, and there was no change in mean left ventricular ejection fraction.

The Tendyne valve

Reprinted from EuroIntervention (Perpetua EM, et al. The Tendyne transcatheter mitral valve implantation system. EuroIntervention 2015; 11:W78-W79.) © 2015 with permission from Europa Digital Publishing.

The Tendyne valve is a self-expanding prosthesis with porcine pericardial leaflets. It is delivered transapically and is held in place by a tether from the valve to the left ventricular apex.

In the first 12 patients enrolled in an early feasibility trial,¹³ the average left ventricular ejection fraction was 40%, and 11 of the 12 patients had functional mitral regurgitation. The device was successfully implanted in 11 patients, while one patient developed left ventricular outflow tract obstruction and the device was uneventfully removed. All patients were still alive at 30 days, and the 11 patients who still had a prosthetic valve did not have any residual mitral regurgitation.

As of this writing, almost 80 patients have received the device, though the data have not yet been presented. Patients are being enrolled in phase 1 trials.

The NaviGate valve