Cardiovascular disease (CVD) remains the leading cause of morbidity in the USA. Heart failure (HF) is responsible for more deaths than cancer, accidents, and stroke combined, leading to healthcare costs of up to 40 billion dollars annually 1. With the growth of an aging population, therapy for HF needs to become more safe and effective. 3,5,3′-Triiodo-L-thyroxine (T3) affects cardiac performance by increasing cardiac contractility, decreasing systemic vasculature resistance, and increasing sympathetic activity and cardiac output. Thyroid hormone analogs have demonstrated preventive activity against HF, especially in patients susceptible to atherosclerosis. In 1930, Mason et al.2 first described the cholesterol lowering effect of thyroid hormone in hypothyroid patients. In the last 20 years, thyroid hormone receptor (THR) physiology has been clarified. Studies on THR knockout mice have shown that the THR-α receptor, primarily localized to the heart and brain, regulates heart rate; THR-β, found abundantly in the liver, regulates atherogenic proteins and lipids by reducing low density lipoproteins (LDL) and promoting loss of body fat. In a recent phase III trial involving 168 patients by Ladenson et al.3, eprotirome (KB 2115; THR-β selective) at doses of 25, 50, and 100 mcg was found to synergize with the pharmacological effects of statins in a dose-dependent manner. This review will focus on the role of thyroid hormones on the cardiovascular system and then discuss the potential therapeutic role of a specific carboxylic acid analog of T3, diiodothyropropionic acid (DITPA), in CVD.
Physiologic and genomic relationships between the hypothalamic–pituitary–thyroid axis and cardiovascular system
Genomic actions of T3
Genomic T3 actions are mediated through binding with nuclear thyroid receptors (TRs), which in turn bind with thyroid response elements (TREs) located in the promoter region of positively regulated genes, such as α-myosin heavy chain (MHC) (Fig. 1). In the presence of T3, TRs induce gene expression by recruiting coactivators, such as THR-associated protein-220 (TRAP-220) and steroid receptor coactivator-1 (SRC-1), which have histone acetyltransferase activity 4. In the absence of T3, TRs suppress gene expression of these proteins by recruiting corepressor complexes, such as nuclear receptor corepressor (N-CoR) 5,6. T3 positively regulates the expression of α-MHC, sarcoplasmic reticulum calcium ATPase, Na+–K+ ATPase, β1-adrenergic receptor, atrial natriuretic peptide, and voltage gated K+ channels (Kv1.5, Kv4.2, and Kv4.3). For negatively regulated genes, the presence of T3 represses and the absence of T3 induces their expression 7. Negatively regulated genes include β-MHC, phospholamban, THR-α1, adenylyl cyclase catalytic subunits, and the Na+/Ca+ exchanger 8.
The regulation of the α-MHC and β-MHC isoforms by T3 is significant for dictating myocardial activity. β-MHC is the major myofibrillar protein in the human heart. However, in CHF and the hypothyroid state, the expression of α-MHC is decreased while the expression of β-MHC either decreases or remains the same, contributing to reduced myocardial contractility. The reduced contractility is more pronounced in rodents and occurs to a lesser degree in humans 8,9. It is known that α-MHC is exquisitely sensitive to serum T3 and its transcription mirrors fluctuations in T3 levels 8. In a study on hypothyroid rats, induction of α-MHC occurred within minutes of administration of T3, whereas repression of β-MHC occurred over hours. This investigation was the first to demonstrate that the transcription rates of MHC isoforms are not temporally and mechanistically related to one another as previously thought 10. In another study involving rats, it was found that the promoter region of the β-MHC gene does not consist of TREs, and antisense (AS) RNA conducts its regulation post-transcriptionally. In the euthyroid state, AS RNA is elevated, thereby causing post-transcriptional destabilization of β-MHC sense RNA. The reverse is true in hypothyroid states, where AS RNA expression is low, and thus results in high β-MHC expression 11.
Nongenomic actions of T3
The nongenomic effects of T3 in cardiomyocytes are mediated by alterations in the transport of various ion channels for sodium, potassium, and calcium, resulting in depolarization changes of the cardiomyocyte membrane. In endothelial cells, T3 stimulates nitric oxide synthase by activating TRs and the protein kinase B, Akt 12. Nitric oxide causes relaxation of smooth muscle, lowering of systemic vascular resistance and afterload, and then augmentation of cardiac output. According to Miyamoto et al.13, Akt activation in cardiomyocytes promotes interaction with mitochondria and phosphorylation of hexokinase II enabling Akt to protect against apoptotic pathways of Ca+-induced mitochondrial depolarization and cytochrome c release. T3 is known to decrease cardiomyocyte apoptosis and phospho-Akt levels in the infarct border area after a myocardial infarction (MI) in rats. Chen et al.14 demonstrated that intraperitoneal injection of T3 at 14 μg/kg/day in rats for 3 days, shortly after MI surgery, reduced cardiac myocyte apoptosis along the infarct border.
In patients with HF, as with other chronic illnesses, T3 levels are often low, and accompanied by normal to low L-thyroxine (T4) and thyroid-stimulating hormone levels. In this setting, T3 levels are an independent predictor of poor short-term prognosis 15. There is much controversy as to whether low T3 levels are protective or contribute to morbidity with HF. In the hypothyroid state, there is impaired myocardial contractility and relaxation, increased systemic vascular resistance, and low cardiac output 16. Various studies have been conducted to demonstrate the effects of T4 and T3 replacement in patients with HF (Table 1) 15,17–19. However, the effect of T4 is mitigated because of decreased peripheral conversion of T4–T3 during HF 20. Therefore, T3 administration might demonstrate beneficial effects by targeting cardiac TREs directly.
In a study by Henderson et al.21, HF models of rats were created by ligating the left anterior descending artery and the response to continuous intravenous T3 infusion was measured. These investigators found that T3 administration, started a week after myocardial injury, can improve left ventricular contractility, end-diastolic volume, and the relaxation time by increasing α-MHC expression. However, there was no effect on LV remodeling. Thus, T3 has the capacity to reduce features of systolic and diastolic dysfunction seen post-MI.
In a study on 23 patients, Hamilton et al.15 demonstrated that a 6–12 h continuous intravenous infusion of T3 (cumulative dose 0.15–2.7 μg/kg) in advanced HF improves cardiac output and reduces afterload. In another study on 20 patients with dilated cardiomyopathy, Pingitore et al.18 described that continuous intravenous administration of synthetic T3 (initial dose 20 μg/m2 diluted in 100 ml saline) decreases plasma levels of noradrenaline, aldosterone, and N-terminal prohormone B-type natriuretic peptide. The outcome led to significant improvements in end-diastolic and stroke volumes, preventing exacerbation of HF 17.
Of note, there have been no adverse effects in restoring T3 to euthyroid levels in any human study 15,22–25. However, there are still concerns regarding the nonspecific action of T3, including dramatic effects on the metabolism, oxygen demand, increase in bone loss, muscle wasting, rise in heart rate, and predisposition to arrhythmias. In addition, a continuous low dose of T3 improves the cardiac profile more favorably than a bolus dose 7. The half-life of T3 is estimated to be ∼8 h in hypothyroid patients with once-daily oral administration, with rapid increase in supraphysiological levels and an equally rapid fall to undetectable measures 26. The pharmacokinetics of T3 makes it difficult to maintain a constant low blood level. These limitations can be circumvented by thyroid hormone analogs.
There has been a fascination to utilize thyroid hormone derivatives and selectively enhance the beneficial outcomes. Earlier thyroid hormone analogs such as dextrothyroxine and triiodothyroacetic acid were investigated for cholesterol reduction, but had narrow therapeutic windows with systemic adverse effects ranging from increased heart rate to bone turnover. However, a further understanding of THR physiology in the last 10–15 years has propelled the development of thyroid analogs with selective receptor subtype activities. THRβ-selective mimetics, such as eprotirome and sobetirome, have shown encouraging results in human trials of lowering plasma LDL levels with liver specificity and less chronotropic effects 27.
Diiodothyropropionic acid – a novel T3 analog
DITPA differs from T3 by lacking the structural outer ring iodide and the amine in the carboxylic acid side chain, thus poorly binding to certain thyroid receptor isoforms. This may explain the varying effects of increased cardiac index and decreased vascular resistance, but no significant rise in heart rate, with DITPA administration. In addition, the lowering of serum total cholesterol and LDL is consistent with the thyromimetic activity of DITPA 28. The physiological effects of DITPA are summarized in Fig. 2.
Therapeutic potential of diiodothyropropionic acid
In a study by Morkin et al.29, the response to DITPA was determined in post-MI rat and rabbit models. The efficacy of DITPA with captopril was measured against captopril monotherapy. It was found that DITPA significantly improved left ventricular contractility, with little effect on heart rate. There were beneficial effects on the resting and stressed cardiac index, as well as the left ventricular end-diastolic pressure.
In another investigation by Kuzman et al.30, DITPA and T4 were administered to hamster models with dilated cardiomyopathy. The combination allowed for a substantial improvement in cellular and chamber remodeling, as well as coronary blood flow. Surprisingly, there were no significant changes in ventricular contractility with either treatment. In several other studies, it was found that DITPA does not alter systolic function, but rather improves diastolic function by restoring isovolumetric relaxation 31–33. Further research is needed to understand the interconnection between improved contractility and cardiac remodeling.
Role in cardiac electrophysiology
Wickenden et al.34 demonstrated that DITPA reversed the electrical remodeling in a post-MI rat model by restoring repolarizing transient K+ currents. DITPA treatment increased the expression of Kv4.2 channels and decreased Kv1.4 channels to sham levels. As a result of these changes, the action potential duration was normalized and cardiac contractility was maintained. Consistent effects were also indicated by thyroid hormone administration, but the increase in heart rate, metabolic rate, and effects on other organ systems attenuated any observed benefit 34. Similarly, Ferrer et al.35 demonstrated that DITPA induced the recovery of calcium-independent voltage-activated potassium current densities (Itof and Iss) in the ventricular myocardium of diabetic rats. There was no alteration in control models, suggesting that DITPA upregulates the channels only when they are deficient. The mechanism of action is likely through direct upregulation of T3 responsive genes, with augmentation due to increased levels of T3 35. The blunting of electrical remodeling is essential in decreasing the risk of mortality due to HF.
Thyroid hormone analogs have been found to be proangiogenic. In a study by Liu et al.36, DITPA and T4 were administered to thyroidectomized rats to study their efficacy in reversing vascular loss. With DITPA, coronary vascular density was maintained, although there was progression to overt hypothyroidism. T4 also prevented arteriolar loss, but unlike DITPA, this occurred by maintaining cardiac function and hemodynamic integrity 36. These results suggest that DITPA promotes angiogenesis independent of its actions on thyroid receptors, although the exact mechanism remains unclear.
DITPA reversed cardiac remodeling in cardiomyopathic hamsters, most likely by promoting angiogenesis and enhancing myocardial blood flow 30. One study showed that DITPA induced endothelial proliferation and vascular smooth muscle relaxation after MI through nitric oxide and β-adrenergic pathways 37. Mousa et al.38 reported that DITPA promoted angiogenesis in a chick chorioallantoic membrane model by initiating a signal at the integrin αvβ3 on the cell surface, with downstream activation of mitogen-activated protein kinase (MAPK) pathways. These pathways dictate activation of extracelluar regulated kinases (ERK 1/2), which control plasma Na/H antiporter expression in the myocardium, increase the activity of Na, K-ATPase pump, and shuttle cellular proteins involved in angiogenesis 38. Wang et al.39 showed that DITPA related coronary angiogenesis in nonischemic Sprague–Dawley rats is associated with increased angiogenic factors such as fibroblast growth factor, vascular endothelial growth factor (VEGF), angiopoietin-1, and tyrosine kinase with immunoglobulin-like and EGF-like domains (Tie-2) in the first few days of treatment. After 3 weeks of treatment with DITPA, the arteriolar length density and the number of terminal arterioles also increased. VEGF is involved in the angiogenic cascade, which includes endothelial cell proliferation, migration and tube formation. Fibroblast growth factor is responsible for the arterial growth and enlargement, while angiopoietin-1 and Tie-2 signaling is also imperative for neovascularization and endothelial cell survival. Interestingly, angiopoietin expression is present on pericytes and is induced by VEGF 39.
The exact molecular mechanism of thyroid stimulated angiogenesis is open to debate. However, the proangiogenic effect of DITPA may be highly desirable for maintaining perfusion of a hypertrophied myocardium in HF or a post-MI affected myocardial tissue.
It also appears that, as opposed to levothyroxine, DITPA has a lower affinity for integrin αvβ3 receptors on platelets, leading to reduced platelet aggregation 40. This may translate into a lower thrombogenic potential than levothyroxine.
Clinical trial evidence
After the encouraging results obtained with animal studies, preliminary studies were conducted on humans. In a study by Morkin et al.29, DITPA was administered to normal healthy volunteers at two doses of 1.875 and 3.75 mg/kg. The DITPA doses were well-tolerated with no changes in body weight, heart rate, nor blood pressure. At the end of 2 weeks, thyroid-stimulating hormone and total T4 decreased significantly, free T4 remained unchanged, and reverse T3 (rT3) increased. DITPA was subsequently administered to NYHA class II and III HF patients and it significantly increased cardiac index, decreased systemic vascular resistance, decreased duration of isovolumetric relaxation, and decreased total serum cholesterol and triglycerides. There was no increase in frequency or severity of anginal attacks or arrhythmias and no evidence of clinical hyperthyroidism 29. DITPA did not interact with other CHF medications like angiotensin-converting enzyme inhibitors or digoxin. Overall, these studies suggest DITPA to be promising in enhancing cardiac output and hemodynamic stability for CHF patients, with possible synergistic implications when combined with other HF medications.
In a phase II trial by Goldman et al.28, DITPA was administered at uptitrated doses to a maximum of 360 mg/day to determine the efficacy at the presumed maximum tolerated dose. DITPA improved cardiac performance and lowered the systemic vascular resistance with minimal chronotropic effect, even at the low dose range of 90 mg/day. At higher doses, however, adverse effects like weight loss, fatigue, and gastrointestinal symptoms were noted that limited patient compliance 28. The study was terminated early because of the intolerable adverse effects, which in turn could be due to high dose.
In another randomized control trial to determine safety and efficacy of DITPA in patients with NYHA classes III and IV HF, DITPA was given at doses of 90 and 180 mg twice daily. The study was terminated early because of significant adverse effects (http://clinicaltrials.gov/ct2/show/NCT00103519?term=DITPA+in+heart+failure&rank=1).
Recent molecular evidence again questions the earlier studies supporting the biological role of DITPA. Talukder et al. 41 studied the dose-dependent baseline cardiovascular effects and postischemic myocardial function in mice pretreated with DITPA. According to their results, DITPA-treated mice had mildly increased blood pressure, impaired baseline contraction function, and higher fatal cardiac rhythm abnormalities during in-vivo ischemia and reperfusion. Moreover, there were no improvements in cardiac function during MI and no enhancement of postischemic fractional shortening (difference between the end-diastolic length and the end-systolic length divided by the end-diastolic length) with DITPA treatment. Interestingly, high doses of DITPA significantly lowered total T3 levels, which was concurrent with impaired cardiac function and increased mortality during myocardial ischemia and reperfusion. Protective molecular changes such as production of myocardial sarcoplasmic reticulum Ca2+-ATPase, phospholamban, and heat shock proteins did not respond to DITPA treatment either. Therefore, Talukder et al.41 argue that DITPA had negligible cardioprotective benefits in their investigation and future clinical trials must account for the narrow therapeutic window at high doses of DITPA.
Evidently, DITPA has intolerable side effects at higher doses 32 (http://clinicaltrials.gov/ct2/show/NCT00103519?term=DITPA+in+heart+failure&rank=1). It would be interesting to note whether the response to a lower dose or a sustained release preparation would decrease adverse effects by minimizing the peaking of DITPA in blood.
The volume of positive basic science data and discouraging clinical results can either shelve DITPA as a potential treatment for HF or incite further clinical research. DITPA is a selective thyroid analog that was developed to address certain limitations of thyroid hormone treatment, namely nonselective adverse effects and difficulty in maintaining therapeutic levels after administration. DITPA is orally bioavailable, efficacious at once-a-day dosing, and has selective thyromimetic action on the ventricular myocardium, improving cardiac contractility and diastolic function. These specific findings have been supported by molecular, preclinical, and subsequent clinical studies. The thyroid analog lowers the systemic vascular resistance and has no significant effect on the heart rate. It appears that DITPA does not increase myocardial oxygen demand significantly and alters the basal metabolic rate to a lower extent than the thyroid hormones 29. In additon, DITPA has some hepatic thyromimetic action by lowering serum cholesterol and LDL levels. Furthermore, the role of DITPA in promoting angiogenesis is intriguing and appears to be mediated by alternate pathways other than thyroid receptors, more specifically, through integrin αvβ3 signaling of downstream MAPK pathways. The proangiogenic effect can have a critical therapeutic effect on the survivability of the myocardium. It may have a lower thrombogenic potential than levothyroxine. With these pharmacodynamic implications, DITPA may have a salutary role in HF and hypertension management. DITPA’s mechanism of action is unlike angiotensin-converting enzyme inhibitors and statins; and further studies looking at the potential combination therapy in HF would be worthwhile. Reversal of electrophysiological changes of the heart in diabetes, post-MI, and CHF that predispose to cardiac hypertrophy, arrhythmias, and sudden cardiac death would improve patient prognosis. Animal studies with DITPA demonstrate that it reverses electrophysiological remodeling; more studies are required to expound this benefit. DITPA may also reverse cellular remodeling in the heart, thereby making it useful in post-MI and cardiomyopathy patients.
There have been several observed downsides to DITPA. Clinical trials have shown DITPA to have a narrow therapeutic window and further studies are needed to evaluate if it has a better tolerability and safety profile at lower doses. If this is achieved, DITPA may have the therapeutic potential to optimize CVD treatment; most specifically in patients susceptible to hypertensive heart disease and HF. Lack of adverse effects such as liver and skeletal muscle involvement allows it to be used in atherosclerosis, obesity and type 2 diabetes. Nevertheless, extensive human trials are needed to understand the ionotropic and lipid-lowering outcomes. With further progress in understanding the potential of DITPA, this drug may cause a paradigm shift in the CVD and HF therapeutic armamentarium.
S.A. and M.A. would like to thank Anubhav Kaul for his assistance in the preparation of this manuscript.
Conflicts of interest
There are no conflicts of interest.
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