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As the common ultimate pathological feature for all cardiovascular diseases, congestive heart failure has now been considered as one of the main public health burdens with grave implications. Neurohormonal systems play a critical role in the cardiovascular homeostasis, pathophysiology, and cardiovascular diseases such as congestive heart failure. It is well established that imbalanced hormonal counterparties such as over-activation of the renin-angiotensin- aldosterone system leads to cardiac tissue injury and malignant remodeling which predispose to heart dysfunction. Hormone treatments such as the newly invented dual-acting drug valsartan/sacubitril are promising candidates for congestive heart failure, in addition to the conventional medications encompassing beta receptor blockers, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor blockers. In this review we briefly discuss the therapeutic effects of several key hormones in congestive heart failure.
Keywords: Congestive heart failure, Treatment, Hormone.
As the common ultimate pathological feature for all cardiovascular diseases, congestive heart failure (CHF) has now been considered as one of the main public health burdens with grave implications.1 It is estimated that approximately 5.3 million people suffer from CHF (2.5% of the adult American) and that approximately $60 billion per year was cost for the management of CHF in the United States.2, 3 Despite the advancement of pharmaceutical and device treatment for CHF, the long- term mortality and morbidity of CHF is still unacceptably high, and the average 5-year survival is about 50%.4
Neurohormonal systems play a critical role in the cardiovascular homeostasis, pathophysiology, and cardiovascular diseases including CHF. It is well established that imbalance of hormonal systems such as over-activation of the renin- angiotensin- aldosterone system (RAAS) leads to increased cardiac injury and vascular endothelial damage which predispose to CHF. In addition to direct hemodynamic effects, imbalanced hormonal systems may cause heart dysfunction through mechanisms including inflammation, oxidative stress, and cardiac remodeling. In this review we briefly discuss the therapeutic effects of several key hormones in CHF.
- Natriuretic peptides and neprilysin
2.1 Natriuretic peptides
Natriuretic peptides (NPs), encompassing atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP), has showed its beneficial effects in CHF such as vasodilatation via suppressing the sympathetic activity and the RAAS.5 NPs also promote natriuresis via inhibiting the reabsorption of sodium and water in the distal and proximal nephron.5 Among NPs, ANP is synthesized and secreted in atria with distension, BNP is primarily synthesized and secreted by ventricular myocytes in response to volume overload- induced ventricular stretch, and CNP is synthesized by endothelial cells under the stimulation of acetylcholine, cytokine receptor agonists, or shear stress.5
Nesiritide is a recombinant human BNP that has undergone clinical trials in patients with acute decompensate heart failure (ADHF). Nesiritide acutely reduced heart failure symptom and pulmonary capillary wedge pressure in these patients.6, 7 However, in a large randomized controlled trial although nesiritide slightly reduced dyspnea, it did not alter mortality or re-hospitalization but significantly increased rates of hypotension.8 Beside, one meta-analysis encompassing three randomized controlled trials even found patients receiving nesiritide treatment had a trend toward increase in 30-day mortality,9 but this was not confirmed by a later meta-analysis encompassing seven randomized controlled trials.10
Ularitide is a synthesized analogue of human urodilatin. Urodilatin is a 32-amino acid peptide, which shared a same structure with ANP, and is differential processed from pro-ANP.11-13 Secreted by distal renal tubule cells, urodilatin decreases sodium and water reabsorption at the level of the collecting duct.11, 14 In animal models and clinical trials, Ularitide could relieve CHF symptoms and preserve renal function. A phase III clinical study (TRUE-AHF), to evaluate the effects of ularitide on mortality in ADHF patients, is currently ongoing.15
Neprilysin (NEP) is a neutral endopeptidase mainly expressed in the kidneys. It degrades NPs and other vasoactive peptides such as angiotensin (ANG) II, endothelin-1, substance P and bradykinin. Consequently, the net physiological effect of NEP is up to the balance of its actions on vasodilators and vasoconstrictors.16 Valsartan/sacubitril (LCZ696), a combination of a neprilysin inhibitor (NEPi, sacubitril) and an ANG receptor antagonist (ARB, valsartan), is a FDA newly approved drug for CHF. In comparison to enalapril, the PARADIGM trial showed Valsartan/sacubitril reduced cardiovascular mortality and re-hospitalization in patients with heart failure with reduced ejection fraction (HFrEF). In patients with heart failure with preserved ejection fraction (HFpEF), Valsartan/Sacubitril also reduced the NT-pro-BNP levels and improved the patients’ symptoms. Therefore, in addition to the conventional medications such as angiotensin converting enzyme inhibitors (ACEis), ARBs, mineralocorticoid receptor blockers, and beta receptor blockers, Valsartan/Sacubitril is another promising medication for CHF.17
In a blood glucose- dependent way, incretins can stimulate the pancreatic secretion of insulin. Therefore, incretin-based therapies are now widely used in diabetic patients such as glucagon- like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase (DPP)-4 inhibitors. Notably, GLP-1 can act on the heart and vasculature as well, and its receptors express on cardiomyocytes, coronary smooth muscle cells and endothelial cells, and human umbilical vein endothelial cells.18-21
Incretin-based therapies exert cardioprotective effects in animal studies.22 In dogs with pacing- induced dilated cardiomyopathy (DCM), the administration of recombinant GLP-1, GLP-1 (7-36) or GLP-1 (9-36) reduced the plasma levels of norepinephrine, decreased the left ventricle end- diastolic pressure (LVEDP), heart rate (HR), and systemic vascular resistance, and improved left ventricle (LV) function representing by stroke volume (SV), cardiac output (CO), and the LV dP/dt values.23, 24 In rats with spontaneous hypertension, GLP-1 administration for 3 months reduced cardiomyocyte apoptosis, preserved LV contractility, and further improved the survival rates.25In pigs with pacing-induced DCM, administration of a DPP-4 inhibitor sitagliptin for 3 weeks also increased SV, reduced HR, and preserved renal function.26
In patients with CHF after myocardial infarction (MI) or percutaneous coronary intervention (PCI), infusion of GLP-1 improves both the left ventricle ejection fraction (LVEF) and wall motion.23, 27 In a single-center nonrandomized study, infusion of GLP-1 for 5 weeks improved the LVEF, oxygen consumption, 6-min walk test (6MWT) scores, and quality of life in 12 patients with CHF (New York Heart Association (NYHA) class III/IV).28However, in a double-blind placebo-controlled trial, infusion of GLP-1 for 48 hours had no significant effect on LV function in 15 patients with CHF (NYHA class II–III and LVEF <40%).29 Likelya long duration of GLP-1 infusion may be required to improve the heart function.
Compared with these studies, large-scale clinical trials failed to show the cardioprotective roles for GLP-1 agonists and DPP-4 inhibitors beyond glucose regulation. The SAVOR-TIMI 53 study is a randomized trial in patients who had a history of, or were at risk for, cardiovascular events.30 Within 2.1-years of follow-up saxagliptin did not alter the incidence of cardiovascular events, whereas it increased the rates of CHF hospitalization by 27%.30 The EXAMINE study, another randomized trial among patients with type 2 diabetes and a recent history of acute coronary syndrome, found that alogliptin had no significant effects on cardiovascular events during 18-months of follow-up.31 The TECOS (Trial Evaluating Cardiovascular Outcomes with Sitagliptin) trial revealed that sitagliptin had neutral effects on cardiovascular risk and CHF hospitalization among older patients with type 2 diabetes and cardiovascular disease.32 Before other ongoing clinical trials such as the FIGHT (The Functional Impact of GLP-1 for Heart Failure Treatment) and CAROLINA (Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes) studies publish their results, the clinical benefit of incretin-based therapies in CHF remains unclear.
4. Growth hormone and ghrelin
4.1 Growth hormone
Growth hormone (GH) plays a crucial role for the maintenance of structure and function of normal adult hearts.33, 34 Since the myocardium and vessels secrete insulin-like growth factor-1 (IGF-1)35-37 and express functional receptors for both GH38-40 and IGF-1,41, 42 it is speculated that GH could directly act on the cardiovascular system as well as indirectly via the autocrine/paracrine effects of IGF-I. GH/IGF-1 can stimulate cardiac growth and contractility, and regulate vascular tone and peripheral resistance.43
In rat model with ischemic CHF, GH and IGF-I increased SV and cardiac output.44, 45 In patients with CHF due to ischemia or idiopathic DCM, both short-term infusion and chronic therapy of GH improved LVEF, cardiac output, and exercise performance.46-48 Additionally, GH treatment in patients with CHF promoted endothelial function and non-endothelium dependent vasodilation,49 and decreased the levels of circulating cytokines and apoptotic agents.50 However, in other studies in patients with CHF, although GH treatment significant increased IGF-1 levels, it did not improve cardiac performance.51-53 Meanwhile, in a further subgroup analysis with those had higher serum IGF-I levels in response to GH treatment, the LVEF was also significantly increased by GH.54
Acquired GH resistance may explain these controversial results.51 An acquired GH-resistant state has been described in CHF, with a typical pattern of high GH levels and low IGF-1 levels.55 GH levels were increased 3-fold in CHF patients with significant weight loss compared to healthy subjects and noncachectic patients; In contrast, IGF-1 levels are reduced, particularly in patients with cachexia.56 It has been shown that GH infusion produced less cardiovascular beneficial effects in patients with a lower baseline serum IGF-1.57 In a meta-analysis including 12 clinical trials, beneficial effects of GH treatment on LVEF and exercise parameters correlated to the extent of increase levels of serum IGF-1.58 Recently, in a randomized, single blind study, only CHF patients with GH deficiency were selected and treated with GH for 6 months. GH treatment significantly increased peak oxygen uptake, exercise duration, and flow-mediated vasodilation, and improved quality of life. Moreover, GH treatment led to a significant increase in LVEF and a reduction in circulating N-terminal pro-BNP levels.59 Hence, the benefit of GH treatment in selected CHF patients especial with GH deficiency might be the future direction however it needs further validation in more robust clinical trials.
Ghrelin, a growth hormone-releasing peptide, is an endogenous ligand of growth hormone secretagogue receptors (GHSRs).60The high expression of GHSR1a in the heart and large vessels provides evidence of its cardiac activity, indicating ghrelin is a promising new therapeutic agent for cardiovascular diseases.61
In rats with chronic heart failure, ghrelin treatment attenuates the development of LV remodeling and improves LV dysfunction as indicated by the increases in cardiac output and LV fractional shortening.62 Activation of cardiac sympathetic nervous activity (SNA) and maladaptive remodeling is also manifested in ghrelin deficient mice with CHF at 2 weeks after MI, accounting for the high mortality, particularly in cases that have been caused directly by HF.63, 64 Chronic treatment with metoprolol or ghrelin, which are associated with cardiac SNA inhibition and a decrease in plasma catecholamine levels, improves heart dysfunction and mortality.63In patients with CHF, ghrelin administration significantly decreases systemic vascular resistance and increases the cardiac output and SV.65, 66 Further, intravenous administration of ghrelin (2 µg/kg, twice a day for 3 weeks) significantly improves LVEF from 27% to 31% and increases peak workload and oxygen consumption during exercise, while dramatically decreasing plasma norepinephrine.67 Taken together, these findings indicate that both exogenous and endogenous ghrelin are crucial in balancing the autonomic nervous system, protecting cardiac function, and improving prognosis in CHF.68 However, these effects have not been confirmed by large scale controlled clinical trials.
5. Vasopressin-receptor antagonists
Arginine vasopressin (AVP) is a neurohypophysial hormone secreted from the posterior pituitary in response to decreased blood pressure and increased plasma osmolality. AVP regulates vascular tone by nonosmotic AVP V1a receptor on vascular smooth muscle cells, and modulates volume homeostasis by osmotic AVP V2 receptor on principal cells of the renal collecting duct.69, 70 Further, AVP contributes to cardiac fibrosis and hypertrophy at the later stages of CHF.
AVP V2 receptor selective antagonists, like tolvaptan and lixivaptan, have been profoundly studied in animal and human CHF.71-74 In patients with CHF and preserved renal function, single doses of tolvaptan (30 mg) or furosemide (80 mg) led to a similar urine output.56 In rats with CHF, tolvaptan dose-dependently increased the concentration of plasma sodium, whereas furosemide almost decreased it. Notably, furosemide obviously increased plasma renin activity and aldosterone concentration, whereas tolvaptan did not, implying that tolvaptan is superior to furosemide in the treatment of CHF with volume overload.75 Besides, without inducing renal injury, the progression of left ventricular dysfunction was halted by chronic tolvaptan treatment in rats with CHF.76 In rats with MI, chronic tolvaptan treatment also improved LVEF and reduced MI-induced remodeling such as macrophage infiltration, interstitial fibrosis, and mineralocorticoid receptor expression in the LV.77-79 These studies indicated that tolvaptan is cardioprotective for CHF, which may be mediated by the suppression of the RAAS and inflammation.
However, neither short- nor long-term morbidity/mortality has been improved by these agents in large scale clinical trials. The ACTIV in CHF trial (Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure) evaluated the short- and intermediate- effects of tolvaptan in symptomatic HFrEF patients.80 Compared to the standard therapy group, the tolvaptan therapy group had a lower body weight and higher net fluid loss. Although it did not affect blood pressure, HR, or electrolytes, tolvaptan did not reduce the exacerbation rate of CHF.80 The EVEREST trial (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) evaluated the short- and long-term effects of tolvaptan in CHF patients when added to standard therapy within 48 hours of hospitalization.81 A 60-day tolvaptan treatment symptomatically improved heart failure without any serious side effects, but did not improve mortality.81 The ECLIPSE trial (Effect of Tolvaptan on Hemodynamic Parameters in Subjects with Heart Failure) evaluated the hemodynamic effects of tolvaptan in symptomatic HFrEF patients.82 Tolvaptan dose-dependently increased urine output and levels of serum sodium without change in BP, HR, pulmonary and systemic vascular resistance, or cardiac index.82
To explain the discrepancy between basic studies and clinical trials, as most clinical trials evaluated the effects of AVP antagonists in CHF patients who had been taking diuretics, these results can be confounded. Therefore, head to head studies are warranted to directly compare the effects of AVP antagonists to standard diuretics in the clinical setting.
6. Glucocorticoids and urocortins
Stresses play a significant role in the exacerbation and progression of CHF. Glucocorticoids are primary hormones in response to a vast array of stresses. The actions of glucocorticoids are mediated by their glucocorticoid receptors (GR). In certain cells such as cardiomyocytes, the mineralocorticoid receptors (MR) may also be activated by glucocorticoids.83
The acute increases in glucocorticoids can enhance cardiomyocytes contractility and promote survival under stresses; whereas sustained high levels due to chronic stress or therapeutic intervention could be cardiovascular hazardous through its systemic and local effects.83 An association of supraphysiological levels of glucocorticoids and incidence of CHF has been revealed in epidemiological studies.84, 85 Patients who have sustained high levels of glucocorticoids such as Cushing’s syndrome will develop hypertension and metabolic syndrome, two well recognized risk factors for CHF. Chronic glucocorticoids administration in healthy volunteers can reduce heart rate,86 and induce cardiac hypertrophy.87-90 The local effects of glucocorticoids are mediated by over-activation of cardiomyocyte MR and cardiomyocyte GR, both of which lead to metabolic impairment, and translate into tissue damage, impairment of exercise capacity, and worsening symptoms.83 Results from transgenic mice suggest that GR signaling in cardiomyocytes is critical for the normal heart function, while MR signaling participates in the development and progression of heart dysfunction.83 Therefore, a combination of selective GR agonist and MR antagonist might be a new therapeutic target.
Further, diuretic resistance is very common in CHF and associated with poor outcomes. Recent evidence showed that glucocorticoids may help to overcome diuretic resistance.91, 92 In a study in patients with refractory ADHF, adding prednisone (1 mg/kg/d, maximum dosage of 60 mg/d) to standard treatment doubled daily urine output, and improved CHF symptoms in 80% of the patients.93 Besides, the levels of serum creatinine were reduced in patients received prednisone whereas unchanged in patients received standard treatment.93
Urocortin 1, 2 and 3 are a group of endogenous peptide hormones belonging to the corticotropin-releasing hormone (CRH) family. The effects of urocortins are mediated by activation of central CRH receptor 1 (CRH-R1) and peripheral CRH-R2.94 It has been shown that urocortins produce vasodilation and positive inotropic effects, and exert cardioprotective effects against ischemia- reperfusion injury. They can also regulate the sympathetic nervous system and the RAAS.94 In 8 HFrEF patients, intravenous Urocortin 1 infusion was associated with high ACTH and cortisol levels and no changes in the levels of ANP or ghrelin, or any significant hemodynamic or renal effects compared with the placebo group.95 In 8 HFrEF patients (6 subjects with non-ischemic etiology and 2 with ischemic cardiomyopathy) who received low and high doses (25 microg and 100 microg) of intravenous urocortin 2, the urocortin group had increases in cardiac output and LVEF that proportionally correlated with urocortin doses, accompanied by a reduction in mean arterial pressure, systemic peripheral resistance, and cardiac work.96 In an ongoing phase II study administration of urocortin 3 in patients with HFrEF (LVEF <35%) caused dose-dependent increases in cardiac index and reduction in systemic vascular resistance, without any effects on pulmonary capillary wedge pressure, HR or systolic BP.97 The above reports indicated that urocortins may be a potential therapeutic target of CHF.
7. Testosterone and estrogen
7.1 Testosterone supplementation
Low testosterone levels are common in men with CHF and are an independent risk predictor for decreased exercise capacity and poor prognosis in patients with CHF of both sexes.98-100 Furthermore, intravenous testosterone administration in patients with CHF acutely reduces peripheral vascular resistance and increases cardiac output. 101 A meta-analysis revealed that in patients with HFrEF testosterone supplementation for 12 to 52 weeks is associated with an increase of exercise capacity represented by 6MWT;102 despite their sample size was modest and the routes of testosterone administration were different.103-106 This degree of improvement is greater than that seen with other therapies which are currently used for morbidity and mortality reduction in patients with CHF such as ACEis, beta-blockers, and cardiac resynchronization therapy.107-109 Further, there is an improvement in NYHA functional class; 35% of patients in the testosterone group (vs. 10% in the placebo group) had an improvement of at least 1 class.102 However, these improvement occurred in the absence of cardiac structure or function change on Echocardiography; hence the improvement in exercise capacity is likely via a peripheral mechanisms.110 Nevertheless, testosterone therapy can cause water and salt retention and pose a potential safety concern. The TOM (Testosterone in Older Men with Mobility Limitations) trial was discontinued early due to significant higher cardiovascular events in the testosterone group.111
7.2 Hormone replacement treatment (HRT)
Several large scale clinical trials have been conducted in examining the effects of postmenopausal HRT on cardiovascular health. In a primary prevention trial with 16, 608 women and an average of 5.2 yours follow-up, HRT did not reduce the incidence of stroke, CHD, and pulmonary embolism.112 In a secondary prevention clinical trial in women with CHD, HRT did not decrease the cardiovascular events.113 However, recent studies proposed a timing related benefit of HRT on CHD. When initiated HRT in younger women (< 60 yr) and earlier stage of menopause (< 10 yr after onset), it did reduce the total mortality and cardiovascular events; when initiated HRT in older women (> 60 yr) or later stage of menopause (> 10 yr after onset), it had no effect or a possible adverse effect on these end points.114-116 A large meta-analysis, including 23 randomized controlled clinical trials and 39, 000 women, confirmed a 32% reduction of CHD incidence in women initiating HRT before 60 yr of age and < 10 yr after menopause.117 This risk reduction was lost in women older than 60 yr of age or >10 yr after menopause.117 These results support the timing related benefit hypothesis.118 Although none of these clinical trials examined the impact of HRT on heart function or dysfunction, its involvement is nearly certain as ischemia precedes both diastolic and systolic CHF.
8. Thyroid Hormones
Many critical cardiovascular functions such as heart contraction, relaxation, and coronary blood flow are regulated by thyroid hormones.119 Proper balance of thyroid hormones is necessary to maintain cardiovascular homeostasis, as both hyperthyroidism and hypothyroidism result in pathological conditions.120
A large body of evidence suggested an increase of cardiovascular events with borderline low thyroid hormones conditions such as subclinical hypothyroidism,121-125 which were improved after thyroid hormone treatment.124-127 In fact, recent studies in CHF patients have also shown an increased mortality with low thyroid function.128-130 However, this association is controversial, as one meta-analysis did not reveal a link131 and two others did.132, 133 Moreover, there have no data examined the effects of thyroid hormone treatment on mortality in CHF patients.
Notably, the high incidence of borderline low thyroid hormones conditions implied that nearly half of CHF patients could suffer from this condition.123 Animal experiments in CHF have indicated that low cardiac tissue T3 levels may be present even in the background of normal serum thyroid hormones.134, 135 The restoration of cardiac tissue T3 levels was associated the improvement of LV function in rats.134, 136 However, the doses of thyroid hormone treatment needed to fully restore cardiac tissue T3 levels and improve LV function resulted in higher than normal levels of serum thyroid hormone. The actual incidence of low cardiac tissue T3 levels in CHF patients remains unknown at this time.
The prevalence of CHF has increased in the past several decades. Despite considerable advances and innovations in both medications and medical devices, the prognosis of CHF is still very poor. There is an unmet need to develop alternative or additional treatment modalities. Hormonal imbalance is a key finding and common feature in CHF, such as the over-activated RAAS translates into progression of the underlying disease, development of cardiovascular comorbidities, and increases in major adverse cardiovascular events. Hormonal modulation is therefore an important therapeutic target for CHF.
Among the discussed hormones in this review, neprilysin inhibitor is a promising drug candidate for the treatment of CHF on the top of current conventional medications. Secondary, by using an approach in the selection of CHF patients with low IGF-1 levels or low thyroid hormone levels, supplement treatment with GH or thyroid hormone seems to be reasonable and cardioprotective. Nonetheless, there have no clinical trials examining the long-term effects of GH or thyroid hormone treatment on cardiovascular mortality in CHF patients. Moreover, in the clinical settings of CHF with volume overload or edematous status, the AVP antagonists can relieve the symptoms superior to loop diuretics. A combination of selective GR agonist and MR antagonist may represent an improved approach for glucocorticoids in the treatment of CHF, specifically in patients with diuretic resistance. Finally, the potential cardiovascular efficacy and safety of incretin-based therapies, testosterone supplementation, or HRT needs to be prudently evaluated in large scale clinical studies.
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