Heart rate-induced modifications of concentric left ventricular hypertrophy: exploration of a novel therapeutic concept

Abstract

Lowering the heart rate is considered to be beneficial in heart failure (HF) with reduced ejection fraction (HFrEF). In a dilated left ventricle (LV), pharmacological heart rate lowering is associated with a reduction in LV chamber size. In patients with HFrEF, this structural change is associated with better survival. HF with preserved ejection fraction (HFpEF) is increasingly prevalent but, so far, without any evidence-based treatment. HFpEF is typically associated with LV concentric remodeling and hypertrophy. The effects of heart rate on this structural phenotype are not known. Analogous with the benefits of a low heart rate on a dilated heart, we hypothesized that increased heart rates could lead to potentially beneficial remodeling of a concentrically hypertrophied LV. This was explored in an established porcine model of concentric LV hypertrophy and fibrosis. Our results suggest that a moderate increase in heart rate can be used to reduce wall thickness, normalize LV chamber volumes, decrease myocardial fibrosis, and improve LV compliance. Our results also indicate that the effects of heart rate can be titrated, are reversible, and do not induce HF. These findings may provide the rationale for a novel therapeutic approach for HFpEF and its antecedent disease substrate.

Pharmacological heart rate lowering in patients with a preserved ejection fraction—review of a failing concept

“…49 It is well established that a sustained increase in HR can induce eccentric LV remodeling in both animal models and patients. 50–54 This process plays a role in many physiological adaptations, e.g. pregnancy and extreme endurance sports, but is clinically most prominent in a form of pathological remodeling commonly known as tachycardia-induced dilated cardiomyopathy.…”

“…49–52 Importantly, simple HR lowering is sufficient to revert the enlarged LV to a normal size and EF. 27,50–54 It can therefore be argued that, in the case of a dilated LV chamber, HR lowering leads to reverse, concentric remodeling that results in LV size reduction which is a component of the observed benefits in dilated cardiomyopathy and HFrEF. In subjects with a normal LV size this mechanism is offset by a larger effect of prolonged LV filling, which increases end-diastolic chamber dimensions, as demonstrated in the atenolol arm of the LIFE study.…”

Novel Göttingen Miniswine Model of Heart Failure With Preserved Ejection Fraction Integrating Multiple Comorbidities

“…Models that use hypertension as the sole driver of HFpEF pathophysiology include those that focus hypertension directly to the myocardium by mechanical manipulations to facilitate pressure overload LV hypertrophy. Devices that constrict the aorta with bands ( 10 , 11 ), cuffs ( 12 , 13 ), and stents ( 14 ), mitral regurgitation valve chordae rupture ( 15 ), and renal artery stenosis combined with ventricular pacing ( 16 ) all result in increased myocardial mass, stiffness, and fibrosis; however, the absence of multiorgan pathogenic effects significantly limits their clinical applicability. In contrast, pharmacological approaches to induce LV hypertrophy in swine through systemic hypertension by vasopressor ( 17 , 18 , 19 ) lack the severity to meaningfully affect cardiac function and fail to demonstrate overt heart failure at rest.…”

An approach towards individualized lower rate settings for pacemakers

“… 12 In contrast, among patients with HFpEF low HRs may be detrimental ( Supplemental Table 1 ) by increasing central arterial pressures and left ventricular end-diastolic pressure, both of which contribute to increased wall stress and chronic adverse remodeling. 6 Atrial pacing above 60 bpm improves cardiac filling pressures, 6 symptoms, and functional capacity in HFpEF patients, 7 and reverses concentric left ventricular hypertrophy in animal models 13 ( Supplemental Table 2 ).…”