Investigate Taurine to treat CHF.
clinmedjournals.org
Taurine in Congestive Heart Failure
Farrukh Ahmad, MD1*, Nitish Kumar Sharma, MD2 and Michelle Hadley, DO, FACC3
1Resident, Internal Medicine, Saint Vincent Hospital, Worcester, MA, USA
2Cardiology Fellow, Department of Cardiology, Saint Vincent Hospital, Worcester, MA, USA
3Department of Cardiology, Saint Vincent Hospital, Worcester, MA, USA
Abstract
Taurine is a ubiquitous amino acid found across the animal kingdom. It is a sulfur-containing amino acid, found in high concentration in the intracellular compartment of excitable tissue, including the myocardium. It functions as an intracellular osmolyte, involved in cell volume regulation. Being a neutral zwitterion, transport of taurine is not accompanied by a change in charge gradient across membranes. This chemical property makes taurine the perfect candidate of cellular osmoregulation. Taurine also regulates sodium and calcium homeostasis, and normal functioning of mitochondria. It has demonstrated ionotropic effects, probably due to its effect on calcium metabolism. Several clinical trials have shown that taurine supplementation improves cardiac performance in those suffering from congestive heart failure. Given its extensive safety profile, taurine supplementation may be beneficial in patients with congestive heart failure.
Introduction
Taurine [
1], is a non-proteinogenic sulfur-containing amino acid. Named after the Greek word for Bull, Taurus, Taurine was first isolated from ox bile in 1827 by Friedrich Tiedemann and Leopold Gmelin [
2]. Taurine has since been found in most human organs, with the highest concentration in excitable tissue like the heart and brain.
It plays several indispensable roles in normal physiological functions in the human body. Taurine can be considered as a semi-essential amino acid, as it can be synthesized from dietary cysteine. However, diet remains a significant source of taurine. It is considered an essential nutrient in preterm infants, as they have much lower activity of enzymes needed for taurine synthesis. Human breast milk contains about 50 mg/L [
3] of taurine compared to cow milk having 1 mg/L [
4]. Taurine has been an ingredient in commercial infant formula since the 1980s in the United States, with concentration around 10 mg/L.
Taurine metabolism
Mammalian taurine synthesis occurs in the liver via the cysteine sulfinic acid pathway [BioCyc ID: PWY-5331] from L-cysteine via the action of cysteine dioxygenase (CDO). CDO regulates intracellular cysteine levels, as high levels can be toxic, with low cysteine levels causing degradation of this enzyme and vice versa. The rate limiting step of the taurine synthesis is the enzyme cysteine sulfinic acid decarboxylase (CSAD). Certain animals like mice have a high expression of this enzyme and can synthesize taurine in sufficient quantities provided adequate cysteine in diet. Carnivorous animals like cats and dogs have a lower expression of CSAD and thus require taurine from their diet. Taurine depletion results in cardiomyopathy in these animals.
Diet is the main source of taurine in humans with meat, poultry and especially seafood being rich sources. Low taurine intake has been correlated with lower plasma and urine taurine in vegans [
5]. Total body taurine is regulated via the kidney, with increased taurine excretion under high exogenous taurine loads. Taurine supplements increase tissue taurine concentration [
6]. It is estimated that a 70 kg Human contains about 5-7g of taurine [
7].
Taurine is absorbed from the ileum via Tau-T transport protein [SLC6A6 gene, 2 Na+: 1 taurine: 1 Cl-], with high oral bioavailability. After oral administration plasma levels peak in about 1.5 hours and return to baseline by 8 hours. Cellular taurine pool is maintained by uptake via Tau-T transport protein and efflux via osmosentive channels.
Radiolabeled tracer studies have shown that taurine is present in two pools, an extracellular smaller pool and a much larger intracellular pool [
8]. Taurine has a volume of distribution of around 40 L [
9]. Extracellular taurine represents 2% of total body taurine and has a much more rapid exchange rate (t1/2-0.1 hr). This compared to a much larger intracellular pool of taurine with a much slower turnover rate (t1/2-70 hours). Therefore, most of the total body taurine is present in the intracellular compartment.
The role of taurine in mammalian physiology is diverse, but the most apparent one being cell volume regulation. Cells maintain functionality within a narrow range of cell volumes. Osmotic and metabolic factors can alter cell volumes. To maintain volume, cells must alter cytosolic osmolarity by moving osmolytes like taurine, glutamate, potassium and chloride ions in and out of the cells. Taurine is a neutral zwitterion and thus its movement does not alter membrane potentials, unlike movement of other major osmolytes like potassium and chloride ions.
To understand the fascinating role of taurine in cell volume regulation [
10], consider the following scenarios-
• Under metabolic stress, including ischemia, decrease in supply of ATP causes failure of Na-K ATPase, thus increasing intracellular sodium. This causes fluid shift into the cells leading to cell swelling. Under cell volume regulation, in response to this swelling, cells actively lose osmolytes like taurine into the extracellular fluid resulting in intracellular fluid loss thus mitigating the swelling [
11].
• A similar response of taurine loss is seen under hypotonic stress. Hypotonic conditions cause cell swelling by movement of fluid into the cell. Cells by losing taurine cause faster equilibration of the two compartments to control cell swelling. This is termed as regulatory volume decrease (RVD) [
12,
13].
• The reverse happens under hypertonic stress, such as dehydration. A hypertonic stress will cause fluid shift from the intracellular compartment into the extracellular compartment, leading to cell shrinkage. In response to this, cells increase the expression of taurine transporters, and the uptake of taurine increases cell osmolarity, holding fluid back, thus maintaining cell volume [
14,
15].
Thus by moving inert osmolytes like taurine, cells are able to regulate fluid movements and buffer cell volume. Systemic effects of this phenomenon have not been well studied.
Apart from Cell volume regulation taurine plays various physiological roles and demonstrates pleitropic pharmacological effects. Bile acid conjugation, mitochondrial function, and a potent antioxidant. It is an effective scavenger of Hypochlorous acid generated under scenarios of metabolic stress [
16,
17].
Taurine and the Heart
Taurine is an essential nutrient in certain mammals, including the cat family. The essential role of Taurine in mammalian cardiac physiology is evident because taurine depletion in cats, dogs, and foxes causes the rapid development of dilated cardiomyopathy, which is reversible on introduction of taurine [
18].
Mice have the capacity to synthesize sufficient taurine de-novo due to higher expression of CSD, and thus to study taurine depletion in mice, taurine transporter knockout mice have been generated. These mice can synthesize taurine normally, but are unable to concentrate it into the cells. These mice develop dilated cardiomyopathy at 9 months of age, and examination of heart tissue show ventricular remodeling with significant ultrastructural damage of myofilaments and mitochondria. The knockout mice also lose weight, have poor exercise tolerance and have undetectable levels of taurine in heart and skeletal muscle [
19].
Taurine has demonstrated several effects that may be beneficial in congestive heart failure.
Ionotropic effects of taurine
Taurine depleted cats develop systolic dysfunction, with a decrease in rate of pressure generation and an impaired relaxation time. Taurine deficient myocardium has a lower calcium load, increased troponin I phosphorylation, and decreased excitation-contraction coupling, leading to decreased myocardial contractility. These effects are reversed by taurine administration [
20].
The mechanism of inotropic effect of taurine is thought to be via its alteration in calcium metabolism [
21]. Acute administration of taurine increases cytosolic calcium [
22]. An increase in extracellular taurine causes an increase in taurine uptake by myocardium via the Na-Taurine, this increase in intracellular Na, causes influx of cytosolic Ca2+ via Na-Ca exchanger, similar to digoxin [
23,
24]. It also increases Ca2+ sensitivity of contractile proteins thus increasing the rate of tension development [
25]. Chronic administration of taurine by phosphorylating phospholamban, a protein on the SR, disinhibits sarcoplasmic reticulum Ca-ATPase, and increases intra-sarcoplasmic calcium concentration. This also increases relaxation time, and improves diastolic function [
26]. The calcium sensitizing effect of taurine is the probable explanation for the inotropic effect of taurine.
Mitochondrial functioning
Taurine is intricately involved in mitochondrial functioning [
27]. It functions as a chemical buffer to maintain the pH of the mitochondrial matrix. The electron transport chain functions by pumping hydrogen ions out of the matrix into the periplasmic space to generate a concentration gradient, which is essential for the functioning of ATPase. ATPase then allows hydrogen ions to move down this gradient, converting ADP to ATP. Mitochondrial matrix has been shown to have a pH of around 8 [
28], closely coinciding with pKa of the amino group of Taurine at 8.6 at body temperature. Therefore, Taurine is a suitable buffer in the mitochondrial matrix and is shown to be present in high concentrations in this space [
28]. Under high energy demands, this buffering capacity of Taurine becomes more apparent, as TauT KO mice demonstrate decreased exercise capacity [
29]. Additionally, this buffering capacity is also essential for the citric acid cycle, as most of the enzymes of the cycle function optimally at higher pH [
30]. Congestive heart failure decreases myocardial mechanical efficiency [
31], and optimizing mitochondrial function should, in theory, improve energy metabolism.
Diuretic effects of taurine
Diuretic therapy constitutes an important element in the management of heart failure. Taurine administration in animal models has shown a diuretic effect by increasing sodium excretion [
32]. In patients suffering from cirrhosis intravenous administration of taurine was able to transiently increase diuresis and natriuresis by suppressing the renin-angiotensin aldosterone system [
33]. Taurine has also been shown to suppress vasopressin and promote free water loss [
34]. This diuretic effect of taurine may explain some of the beneficial effects seen in heart failure.
Taurine and angiotensin II signaling
ACE inhibitors are among the first line agents in the management of CHF. They have shown mortality benefits in congestive heart failure.
ACE inhibitors demonstrate these benefits by suppressing the pathological over activation of RAAS thereby augmenting cardiac remodeling and fibrosis, generally seen in untreated CHF. As above, taurine administration has been shown to suppress renin via its effects of renal salt delivery.
In vitro studies of rat cardiomyocytes have shown that taurine also prevents angiotensin II induced [H]3-phenylalanine and [H]3-thymidine uptake, demonstrating that taurine is preventing angiotensin induced protein synthesis and DNA replication. Taurine has also shown to downregulate angiotensin 2 receptors, in cardiac myocytes [
35].
Angiotensin II is also released by cardiac myocytes in a paracrine fashion as a response to activation of cellular stretch receptors. Taurine plays an important role in cell volume regulation, and efflux of taurine has been demonstrated in cardiac myocytes as a response to cell swelling. This loss of taurine better controls cell swelling and prevents activation of stretch receptors. Thus suppressing Angiotensin signaling by taurine may have similar benefits as ACE inhibitors, in CHF.
Sympatholytic effects of taurine
One of the hallmarks of congestive heart failure is increased sympathetic activity, which has been shown to accelerate ventricular remodelling and vascular resistance. Taurine has been shown to prevent isoprenaline-induced cardiotoxicity in chick hearts [
36]. Taurine also suppresses downstream effects of norepinephrine in the heart, as seen by decreased norepinephrine- induced activation of calpain, a calcium-dependent protease that contributes to cardiomyocyte injury [
37]. In another study, isolated mice mesenteric arteries, vasoconstriction induced by norepinephrine was significantly decreased by incubation in taurine containing media [
38].
Taurine as an anti-hypertensive
Taurine administration has shown to improve blood pressure control in pre-hypertensive individuals [
39]. In a 2016 study, Sun, et al. randomly assigned 120 pre-hypertensives patients to receive 1.6 g of taurine per day or placebo for 12 weeks. Taurine supplementation significantly decreased the clinic and 24-hour ambulatory BPs, especially in those with high-normal BP. Mean clinic systolic BP reduction for taurine/placebo was 7.2/2.6 mmHg, and diastolic BP was 4.7/1.3 mmHg. The mean ambulatory systolic BP reduction for taurine/placebo was 3.8/0.3 mmHg, and diastolic BP was 3.5/0.6 mm Hg. Taurine supplementation has shown to improve endothelium dependent vasodilation and increase responsiveness to Nitric oxide [
40]. Taurine also increases plasma H2S, which has vasodilatory effects similar to NO.
Diuretics, ACE inhibitors and sympatholytics are the mainstay of CHF management. Taurine demonstrates these effects at clinically relevant doses, along with inotropic and cardioprotective effects [
11].
