Chronic activation of the Anrep effect in regulating myocardial contractility in patients with obstructive hypertrophic cardiomyopathy

Background: 

Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, marked by left ventricular (LV) hypertrophy, hyperdynamic systole, and diastolic dysfunction. HCM patients often present with symptoms from LV outflow tract obstruction (LVOTO), which elevates afterload and increases the risk of heart failure. The Anrep effect, an adaptation enhancing LV contractility in response to raised afterload, is hypothesized to influence HCM pathophysiology.

We explored the manifestation of the Anrep effect and its reversibility in obstructive HCM (HOCM) patients undergoing alcohol septal ablation (ASA) to relieve LVOTO.

Using non-invasive, echocardiography-supported volume measurements and (non-invasive) blood pressure measurements via an arm cuff, pressure-volume (PV) diagrams were reconstructed from 27 HOCM patients pre- and 3 months post-ASA. Key measurements included LV end-systolic pressure (LVESP) and effective arterial elastance (Ea) as afterload indicators, and contractility indices such as end-systolic elastance (Ees), and the duration of systole (SET). Stroke work (SW), potential energy (PE), and total PV area (PVA) quantified mechanical work and efficiency (SW/PVA).

Three months post-ASA, patients exhibited a significant reduction in afterload, evidenced by a decrease in the left ventricular outflow tract gradient (63 ± 38  vs. 17 ± 12 mmHg; p<0.001) and effective arterial elastance (Ea) (from 2.7 ± 0.9 vs  2.2 ± 0.7 mmHg/ml; p = 0.02).  Ees, (3.6±1.7 vs. 2.2±0.7 mmHg/ml; p=0.006), SET (389±42 vs. 360±32 ms; p<0.0001), SW, PE, and PVA were all also significantly reduced, indicating decreases in contractility, systolic period and mechanical work. Consequently, mechanical efficiency was improved while stroke volume remained unchanged post-procedure (71±19 vs. 67±19ml; p= 0.31). The triadic pattern of reduced afterload, contractility, and SET is characteristic of the Anrep effect. Other explanations for the reduced contractility, such as decreased adrenergic drive, were ruled out, as this would have likely increased systolic duration or changed heart rate after afterload reduction. The nearly unchanged heart rate also excludes the involvement of the Bowditch effect. The Frank-Starling mechanism was also deemed unlikely, as preload does not influence Ees, a specific marker of contractility. Lastly, the Gregg effect, which suggests a change in contractility due to coronary flow, is unlikely in the blood-perfused heart.

The Anrep effect is a compensatory yet energetically costly cardiac response to maintain stroke volume against high afterload, which manifests through enhanced contractility and prolonged systolic duration. The present study supports that the Anrep effect is activated in HOCM and chronically reverses by ASA. Beyond HOCM, these findings may be relevant to other diseases with elevated afterload.