Correspondence

Cardiac contractility modulation signals improve exercise intolerance and maladaptive regulation of cardiac key proteins for systolic and diastolic function in HFpEF

In heart failure with reduced ejection fraction and heart failure with preserved ejection fraction, profound cellular and molecular changes have recently been documented in the failing myocardium. These changes include altered calcium handling and metabolic efficiency of the cardiac myocyte, reactivation of the fetal gene program, changes in the electrophysiological properties of the heart, and accumulation of collagen (fibrosis) at the interstitial level. Cardiac contractility modulation therapy is an innovative device-based therapy currently approved for heart failure with reduced ejection fraction in patients with narrow QRS complex and under investigation for the treatment of heart failure with preserved ejection fraction. This therapy is based on the delivery of high-voltage biphasic electrical signals to the septal wall of the right ventricle during the absolute refractory period of the myocardium. At the cellular level, in patients with heart failure with reduced ejection fraction, cardiac contractility modulation therapy has been shown to restore calcium handling and improve the metabolic status of cardiac myocytes, reverse the heart failure–associated fetal gene program, and reduce the extent of interstitial fibrosis. This review summarizes the preclinical literature on the use of cardiac contractility modulation therapy in heart failure with reduced and preserved ejection fraction, correlating the molecular and electrophysiological effects with the clinical benefits demonstrated by this therapy.

Cardiac contractility modulation (also known as CCM) is a novel device therapy that delivers nonexcitatory electric stimulation to cardiac myocytes during the absolute refractory period, and it has been shown to improve functional status and clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF). CCM therapy is currently recommended for a subset of patients with advanced HFrEF who are not candidates for cardiac resynchronization therapy. A growing body of evidence demonstrates the benefit of CCM therapy in patients with HFrEF and with ejection fraction at the upper end of the spectrum and in patients with HF and with mildly reduced ejection fraction (HFmrEF). Experimental studies have also observed reversal of pathological biomolecular intracellular changes with CCM therapy in HF with preserved ejection fraction (HFpEF), indicating the potential for clinically meaningful benefits of CCM therapy in these patients. In this review, we sought to discuss the basis of CCM therapy and its potential for management of patients with HF with higher ejection fractions.

The treatment of diastolic heart failure (HF), also known as heart failure with preserved systolic function (HFpEF), has been challenging, partly because there is a lack of consensus regarding the definition of the disease entity as well as a paucity of large-scale clinical trials to demonstrate effective therapeutic strategies. Diastolic and systolic HF may have certain similar pathophysiologic processes in common, but there are also distinct differences in myocardial structure and function. Most treatment strategies for diastolic HF strive to alleviate signs and symptoms or prevent exacerbating factors rather than alter the underlying pathophysiologic abnormalities (e.g., improving active relaxation or reducing passive stiffness). Several lines of new investigations have identified regression of left ventricular hypertrophy as a potential target of therapy, while others hope to improve outcomes in patients with features of diastolic HF via novel targets. Some of these drugs have already been approved for other indications, and improvement in diastolic dysfunction is considered an ancillary property that may have potential for further clinical development. This chapter summarizes the ongoing efforts to develop future therapies targeting extrinsic or intrinsic factors in diastolic HF.

Diastolic heart failure (DHF) is caused by inadequate dilatation of the left ventricle during diastole, while the ejection fraction may be preserved or reduced. It is estimated that 40%–50% of patients with heart failure present with DHF. These patients are characterized by high mortality rates and frequent hospitalizations, similar to those found in patients with systolic heart failure. Currently available medical treatment includes modification of risk factors such as blood pressure control and pharmacotherapy. Despite these therapies, the overall prognosis of DHF remains poor. This chapter reviews current methods and novel approaches for treating patients with DHF.