Aldosterone Receptor Antagonists

A growing body of evidence suggests that aldosterone plays an important role in the pathophysiology of diastolic heart failure (see Chapters 27 and 32 ). Myocardial aldosterone has been implicated in myocyte hypertrophy and cardiac fibrosis leading to diastolic dysfunction. In patients with systolic heart failure, treatment with aldosterone receptor antagonists resulted in reduction in collagen turnover and in cardiac fibrosis. Several small-scale investigations have demonstrated that in hypertensive subjects, treatment with spironolactone can lead to improvement in myocardial strain and strain rate, measured by echocardiography, as well as reduction in LV mass, measured by magnetic resonance imaging. These results appear to be synergistic with the use of ACE inhibitors, or even with angiotensin receptor blockers (ARBs).

For now, aldosterone receptor antagonists are not indicated for treating diastolic heart failure, and their broad adoption has been hampered by their risks of developing hyperkalemia and renal insufficiency. Several mechanistic clinical studies are under way to better identify changes in various clinical and echocardiographic features with either spironolactone or eplerenone. A large, National Institutes of Health-sponsored multicenter clinical trial is currently under way to study whether spironolactone can reduce morbidity and mortality. The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) study will enroll 4500 adult patients with heart failure and preserved systolic function (LV ejection fraction >45%, plus heart failure hospitalization within 12 months or elevated natriuretic peptides). Patients will be recruited over 2½ years, treated, and followed for a minimum of 2 years, with the primary endpoint being a composite of cardiovascular mortality, aborted cardiac arrest, and hospitalization for the management of heart failure (i.e., hospitalization for nonfatal myocardial infarction or nonfatal stroke). This is, however, quite a challenging task, because the study population will primarily be elderly patients with a wide range of comorbid conditions that may confound the endpoints.

Endothelin Receptor Antagonists

Researchers have had a long-standing interest in the development of endothelin receptor antagonists for the treatment of heart failure (see Chapter 27 ). However, attempts to use bosentan, darusentan, and tezosentan in patients with systolic heart failure have not been successful. More recently, it has been recognized that endothelin may play an important role in the development of diastolic dysfunction. Endothelin interacts with the renin-angiotensin-aldosterone system and matrix metalloproteinases (MMPs) in the development of diastolic dysfunction, and this pathophysiology can be attenuated by endothelin type A receptor antagonists. Sitaxsentan sodium, a potent antagonist of the endothelin receptor (isoform ET _A ), is currently being evaluated in a Phase II multicenter clinical trial in patients with diastolic heart failure, defined as symptoms of chronic heart failure, with a left ventricular ejection fraction (LVEF) greater than 50% and abnormal diastolic function on echocardiography. Although the primary objective of this exploratory study is to demonstrate improvement in impaired exercise tolerance with sitaxsentan sodium in patients with diastolic heart failure, it will provide valuable data to assess the safety of a drug class that has previously raised concerns in the systolic heart failure population.

Vasopressin Receptor Antagonists

Arginine vasopressin levels have been found to be elevated in patients with clinical evidence of both systolic and diastolic heart failure (see Chapter 27 ). Since patients with diastolic heart failure demonstrate the same clinical presentation of fluid retention and functional impairment, antagonizing vasopressin V2 receptors may provide some added benefits. However, current clinical trials of vasopressin receptor antagonists such as tolvaptan and lixivaptan are limited either to those with LV systolic dysfunction or to those with evidence of hyponatremia. If beneficial in these settings, it will be logical to explore the potential benefits of these agents in patients with diastolic heart failure, although there have been no specific studies to address the role of vasopressin and its antagonist in diastolic heart failure.

Targeting Intracellular Intrinsic Factors: Restoring Calcium Homeostasis

Targeting calcium homeostasis to improve lusitropy has been a long-standing goal in treating diastolic heart failure. During cardiac ischemia, an increase in intracellular calcium is proposed to impair myocyte contraction and may alter myocyte recovery following reperfusion. Many of the agents that improve calcium sensitization have demonstrated improvement in lusitropy in animal models and in mechanistic studies.

MCC-135 (Calderet)

MCC-135 is an agent for cardiac diseases, including heart failure or myocardial infarction, that demonstrates improving effects for cardiac diastolic dysfunction and protective effects for cardiac necrosis by enhancing Ca ²⁺ uptake by the sarcoplasmic reticulum and inhibiting the sarcolemmal Na ⁺ /Ca ²⁺ exchange. These effects have been shown mainly in animal models and were thought to reduce calcium overload at the sarcoplasmic reticulum, thereby preserving myocardial function in diastolic heart failure and reducing the incidence of fatal reperfusion arrhythmias in the setting of ischemia. However, published human data on this compound is limited. The Phase II randomized, double-blind, placebo-controlled, parallel-assignment, safety/efficacy MCC-135 GO1 study has been performed in patients with symptomatic diastolic heart failure ; the results of the study have not yet been presented. The future clinical development of MCC-135 for diastolic heart failure is currently unclear.

Ranolazine

Ranolazine has been safe and effective in reducing angina in patients with refractory chronic stable angina (currently approved indication) without any alterations in hemodynamic profiles. Ranolazine also has inhibitory effects on the late sodium channel, which has prompted interest in using ranolazine for treatment of diastolic dysfunction. Animal studies have identified improvements in LV function following ranolazine therapy, and early human studies have shown improvement in diastolic indices following intravenous administration of ranolazine in humans. Through its inhibition of the late sodium current, ranolazine reduces the activity of sodium-calcium exchange (NCX) and lowers intracellular calcium overload. However, such effects have been limited to in vitro and animal studies, ²⁷ and their benefits are yet to be confirmed in humans. Nevertheless, as an approved drug, there is good potential for ranolazine to be developed in the area of diastolic heart failure.

Gene Therapy

Direct gene transfer has yielded some success in experimental models of diastolic heart failure. The concept is straightforward: Overexpression of a gene that encodes a specific protein to enhance or replace an abnormality in calcium handling may improve excitation-contraction coupling and result in improvement in diastolic function. Genes that improve calcium homeostasis, such as Ca ²⁺ -ATPase (SERCA2a) and parvalbumin, phospholamban (S16EPLN), protein phosphatase 1, and NCX, have been prime targets for this type of strategy in animal models. Most of the studies demonstrated hemodynamic improvement of LV relaxation but not necessarily reduction in LV end diastolic pressures. Various other cell therapies, antisense therapies, and other targets, such as Akt and ryanodine receptor-stabilizing proteins (FKBP12.6), have also been reported. However, human data regarding the safety and efficacy of gene therapy remain scarce.

It should be emphasized that not all strategies targeting calcium homeostasis can result in diastolic improvement. One such innovative device therapy modulates intracellular calcium levels using noncontractile repetitive pacing, so-called cardiac contractility modulation. Clinical trials are currently under way to determine its efficacy in improving cardiac performance, but so far there has not been any noticeable improvement in diastology, despite an impressive increase in cardiac contractility in symptomatic patients with impaired cardiac function.

Insulin Sensitizers

Several new diabetic medications have been evaluated in the improvement of diastolic dysfunction in long-term therapy (see Chapter 26 ). The number of studies on this topic is limited. Hyperglycemia has been associated with increased diastolic abnormalities, and metformin has been shown to reduce diastolic dysfunction in diabetic myocardium. Pioglitazone has also been shown to improve diastolic indices in patients with essential hypertension. However, no clinical studies have been performed to specifically examine the role of these agents in improving diastolic indices beyond the setting of diabetes mellitus.

While there are limited peroxisome proliferator-activated receptors-gamma (PPARγ) in the myocardium, abundant receptors for another “sensitizer,” glucagon-like peptide 1 (GLP-1), may indicate potential direct metabolic effects on the myocardium. Short-term infusion of GLP-1 in diabetic patients with no history of heart failure has also resulted in improvement in invasive hemodynamic measurements of diastolic dysfunction ; mechanistic human trials are currently ongoing in patients with advanced systolic heart failure, and an injectable form of GLP-1 is currently approved for glycemic control in patients with diabetes mellitus.

Fatty Acid Oxidation Inhibitor

Improving cardiac metabolism can also be achieved by reducing fatty acid oxidation, thereby restoring the balance of glucose and fatty acid utilization in the failing heart. Both perhexiline and oxfenicine inhibit fatty acid oxidation and reduce the rise in diastolic tension during ischemia. Several existing drugs, such as trimetazidine and perhexiline, have been tested in patients with heart failure in the setting of impaired LVEF, and echocardiographic indices of diastolic dysfunction (E/A ratio, diastolic strain, or strain rate) improved in parallel with alterations in phosphocreatine/ATP ratios. While there have been some safety concerns with renal and hepatic drug toxicities for perhexiline, trimetazidine has been widely used in Europe for treating angina.

Copper Chelating Therapy (Trientine)

Another intriguing concept that has emerged over the past few years is the role of copper metabolism in the development of diabetic cardiomyopathy. Cooper et al. published several key papers illustrating the efficacy of trientine, a copper chelating agent for Wilson’s disease, in reversing LV remodeling (predominantly regression of hypertrophy) without lowering blood sugar. It was also shown to substantially improve cardiomyocyte structure and to reverse elevation in LV collagen and β-1 integrin. These data are believed to implicate accumulation of elevated loosely bound copper in the mechanism of diabetic cardiomyopathy and to support the use of selective copper chelation in the treatment of this condition. This hypothesis is now being tested in a new formulation of trientine (under the name Laszarin™, Protemix Inc). Early-phase reports of oral treatment with trientine show elevations in copper excretion in humans with type 2 diabetes, and following 6 months of treatment, it caused elevated LV mass to decline significantly toward normal. To date, trientine has been well tolerated by patients in clinical trials, and it has a long safety profile in the treatment of Wilson’s disease. A Phase IIb clinical trial of trientine administration in patients with diabetic heart failure with a quality of life (exercise tolerance) outcome is currently under way. Larger clinical trials are in the planning stages. Nevertheless, our understanding of why copper chelation may work is rudimentary; it is unclear whether it will work outside the setting of diabetes mellitus, and whether structural changes may directly translate into clinical benefits.

Statins and Coenzyme Q10

Statins have been widely used to treat hypercholesterolemia. Interestingly, their anti-inflammatory and pleiotropic effects have been considered as potential treatments in the setting of diastolic heart failure (see Chapter 32 ). Treatment with statins in non-heart failure patients has been associated with reduction in markers of oxidative and nitrosative stress. Fukuta et al. conducted an exploratory study of statin therapy in patients with diastolic heart failure. This study evaluated 137 patients with heart failure and preserved LV function. Use of statin therapy was associated with an improvement in survival and a relative risk of death of 0.22. In contrast, treatment with an ACE inhibitor, aldosterone receptor blocker, beta blocker, or calcium channel blocker had no significant effect on survival.

Propensity analysis confirmed that statin therapy was associated with improved survival and a trend toward improved survival without cardiovascular hospitalization. Interpretation of these results must take into consideration that this was not a randomized clinical trial. Nevertheless, other prospective studies have identified potential benefits of statin use on LV remodeling. There have been several plausible explanations for the potential benefits of statins in this population, including prevention of hypertrophy and fibrosis, providing ancillary anti-inflammatory and antioxidative effects, and of progression of coronary ischemia. With broad use of statins in the at-risk population (particularly in diabetic patients), large-scale exploration of efficacy with statin therapy in this setting will be challenging. It will be interesting to see if the ongoing clinical trials using rosuvastatin have any effects on diastolic remodeling or mortality benefits.

The issues are further complicated by the phenomenon known as “statin cardiomyopathy.” In some studies diastolic parameters have become more impaired following statin therapy and can be improved by coenzyme (Co) Q10 administration. Indeed, CoQ10 has been widely used as a nutriceutical agent due to its antioxidant effects. Claims have been made that CoQ10 may possess some effects on improving diastolic dysfunction in small clinical studies, but no definitive evidence for diastolic improvement is available.

Thyroid Hormone Analog

The connection between thyroid hormone and the cardiovascular system has been well recognized. In hyperthyroidism, cardiac contractility and cardiac output are enhanced and systemic vascular resistance is decreased, whereas the opposite is true in hypothyroidism. Furthermore, significant correlations were found between pulse-wave tissue Doppler imaging parameters and serum-free T3 and T4 and concentrations of thyroid-stimulating hormone in both subclinical hypothyroid and in euthyroid patients. Treatment with thyroid hormones and their analogs may restore diminished expression of sarcoplasmic reticulum proteins, including GLUT-4 and SERCA2. A recently developed T3 analog, 3,5-diiodothyropropionic acid (DITPA), has been shown to improve diastolic indices, but current ongoing Phase II heart failure studies have been limited to those with chronic systolic heart failure.

Advanced Glycation End-Product Crosslink Breakers

Advanced glycation end-products (AGEs) are permanent carbohydrate structures that form when carbohydrates bind to proteins, lipids, and DNA (see Chapter 30 ). Many proteins, including the structural proteins collagen and elastin, play an integral role in the architecture of tissues and organs and in the maintenance of cardiovascular elasticity and vascular wall integrity. By irreversibly crosslinking collagen molecules in the setting of aging or diabetes, AGEs may increase the tensile strength of the collagen and also may make it less susceptible to degradation by MMPs. The formation of AGE “crosslink” therefore leads to increased stiffness, and abnormal protein accumulation may cause further complications of aging and diabetes. AGEs are also known to induce oxidative stress, in which reactive molecules provoke the underlying component of inflammation.

Pharmacologic intervention with alagebrium, the prototype AGE crosslink breaker, directly targets the biochemical pathway leading to myocardial and vascular stiffness. Removal of the AGEs by cleavage of the abnormal crosslinking bonds has been associated with diminished inflammatory and sclerotic signaling pathways. These pathways are responsible for the deposition of abnormal amounts of matrix proteins that physically stiffen tissues. The presence of AGE crosslinks also renders tissues and organs less susceptible to normal turnover, thus enhancing the presence of these abnormal bonds on various molecules. Importantly, alagebrium does not disrupt the natural carbohydrate modification to proteins, intramolecular crosslinking, or peptide bonds that are responsible for maintaining the normal integrity of the collagen chain. Thus, normal structure and function are preserved, while abnormal crosslinking is reduced. Preliminary studies have indicated that alagebrium can partially reverse some of the constellation of functional deficits and structural abnormalities of diastolic dysfunction and may be able to modify some aspects of chronic heart failure. Most importantly, alagebrium modifies the underlying disease pathology rather than treating the symptoms of disease.

Distensibility Improvement and Remodeling in Diastolic Heart Failure (DIAMOND), a Phase IIa clinical study, was conducted to evaluate the potential effects of alagebrium in patients with diastolic heart failure. In this open-label study, 23 patients (New York Heart Association [NYHA] classes II-III, LVEF >50%, age ≥60 years) received 210 mg of alagebrium twice daily for 16 weeks in addition to their current medications. Patients who received alagebrium had a statistically significant reduction in LV mass, as well as a marked improvement in the initial phase of LV diastolic filling and better quality of life in the absence of blood pressure reduction. The results from the parallel, open-label Patients with Impaired Ejection Fraction and Diastolic Dysfunction: Efficacy and Safety Trial of Alagebrium (PEDESTAL) study on patients with systolic heart failure and diastolic dysfunction were presented at the 2005 American Heart Association scientific sessions and showed trends consistent with the DIAMOND study results. However, recent safety concerns have emerged regarding liver toxicity in male rats treated with alagebrium, and the clinical development of this drug class in hypertension and erectile dysfunction has been discontinued. Nevertheless, if the benefits outweigh the risks, this novel approach will be highly promising.

Matrix Metalloproteinase Inhibitors

Collagen deposition leading to increased stiffness can result from alterations in the balance of promoters and inhibitors of MMPs. However, this concept of inhibiting MMPs to reduce collagen deposition suffers from the problem of using a therapeutic target that has widespread effects that extend beyond the failing myocardium. Recent results from the Prevention of Myocardial Infarction Early Remodeling (PREMIER) study showed that the prototype MMP inhibitor, PG-116800, did not show significant benefits in preventing LV remodeling over placebo following myocardial infarction. This inhibitor has yet to be tested in the setting of diastolic heart failure. Several other drugs are also being considered to target MMPs and tissue inhibitors of metalloproteinases (TIMPs) in this population; but until a more specific target can be identified, this strategy remains largely theoretical.

Cardiac Resynchronization Therapy

As in many other areas in cardiology, innovative device therapies have emerged. One of them is cardiac resynchronization therapy (CRT), for patients with systolic heart failure with dyssynchrony (see Chapter 29 ). When properly optimized, CRT has been shown to improve systolic as well as diastolic dysfunction. We still have very limited experience regarding the role of dyssynchrony in pure diastolic heart failure, and the significance of dyssynchrony (especially diastolic dyssynchrony) in patients with preserved systolic function remains unclear. While studies to date have limited CRT to patients with systolic heart failure, patients with atrial fibrillation who may be dependent on cardiac pacing have been shown to benefit in the Post Atrioventricular Nodal Ablation Evaluation (PAVE) LV-based cardiac stimulation trial. Furthermore, regional wall thickness and diastolic indices appear to improve following CRT, especially in non-ischemic cardiomyopathy.

Implantable Hemodynamic Monitoring Devices

One strategy to improve care for patients with diastolic heart failure targets improved monitoring of diastolic parameters to guide therapy. Since the common end result of passive stiffness and abnormal relaxation is elevated LV end diastolic pressure, proactive intracardiac hemodynamic monitoring is a theoretical solution to guide optimal drug therapy. Over the past two decades, implantable hemodynamic monitoring (IHM) devices have undergone significant refinements, and the recent multicenter Chronicle Offers Management to Patients with Advanced Signs and Symptoms of Heart Failure (COMPASS-HF) safety study, utilizing the Chronicle device (Medtronic Inc.), resulted in significant reduction in heart failure hospitalizations and mortality in patients with NYHA class III heart failure (approximately 30% of the study population had preserved cardiac function). Several other hemodynamic monitoring devices are currently undergoing early clinical development, and it is likely that IHM devices will guide drug management in selected patients with diastolic heart failure.

Novel Mechanical Assist Devices

Mechanical assist devices have focused on improving forward flow by providing either pulsatile or nonpulsatile pumps as “replacements” for myocardial function. However, currently available mechanical devices are invasive and focus mainly on salvaging patients with end-stage systolic dysfunction. Most of these strategies are highly invasive, with potential complications that can be extensive and devastating, which has limited their broad adoption.

Two devices specifically designed to enhance diastolic filling are now in preclinical phases of testing. Although these devices require invasive surgical implantation through a simple off-pump closed-heart procedure, preclinical data have been promising. The ImCardia (CorAssist Cardiovascular Inc.) is an elastic, self-expanding device with a special silicon lattice material attached to the external surface of the left ventricle. The ImCardia harnesses the heart’s systolic energy during recoil from systole in order to reduce diastolic intracardiac pressure. The device operates without the need for an external source of energy. In contrast, the Levram Physiological Cardiac Assist Device (PCAD) (Levram Medical Systems) utilizes a single blood displacement chamber and a single cannula. The cannula is inserted into the failing ventricle cavity via the LV apex and is connected to a blood displacement actuator. Instead of the traditional “rerouting” concept of ventricular assist devices, the Levram PCAD utilizes the residual power of the cardiac muscle and works with its dynamics in a synchronized manner, thereby providing direct add-on mechanical pumping assistance during systole and diastole. Both studies will begin human feasibility trials in the near future, but the concept for surgical interdiction is still in early development, largely due to its invasive nature.