Increased Myocardial Stiffness in Patients With High-Risk Left Ventricular Hypertrophy: The Hallmark of Stage-B Heart Failure With Preserved Ejection Fraction

Abstract

Background: Individuals with left ventricular hypertrophy (LVH) and elevated cardiac biomarkers in middle age are at high risk for the development of heart failure with preserved ejection fraction (HFpEF). However, it is unknown what the pathophysiological underpinnings of this high-risk state may be. We tested the hypothesis that patients with LVH and elevated cardiac biomarkers would demonstrate elevated left ventricular (LV) myocardial stiffness in comparison with healthy controls as a key marker for future HFpEF.

Methods: Forty-six patients with LVH (LV septum >11 mm) and elevated cardiac biomarkers (N-terminal pro-B-type natriuretic peptide [>40 pg/mL] or troponin T [>0.6 pg/mL]) were recruited, along with 61 age- and sex-matched (by cohort) healthy controls. To define LV pressure-volume relationships, right heart catheterization and 3-dimensional echocardiography were performed while preload was manipulated using lower body negative pressure and rapid saline infusion.

Results: There were significant differences in body size, blood pressure, and baseline pulmonary capillary wedge pressure between groups (eg, pulmonary capillary wedge pressure: LVH, 13.4±2.7 versus control, 11.7±1.7 mm Hg, P<0.0001). The LV was less distensible in LVH than in controls (smaller volume for the same filling pressure). When preload was expressed as transmural filling pressure (pulmonary capillary wedge pressure - right atrial pressure), LV myocardial stiffness was nearly 30% greater in LVH than in controls (LVH stiffness constant, 0.053±0.027 versus controls, 0.042±0.020, P=0.028).

Conclusions: LV myocardial stiffness in patients with LVH and elevated biomarkers (stage-B HFpEF) is greater than in age- and sex-matched controls and thus appears to represent a transitional state from a normal healthy heart to HFpEF. Although the LV myocardial stiffness of patients with LVH is greater than that of healthy controls at this early stage, further studies are required to clarify whether interventions such as exercise training to improve LV compliance may prevent the full manifestation of the HFpEF syndrome in these high-risk individuals.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT03476785 and NCT02039154.

Keywords: diastole; heart failure; hypertrophy, left ventricular; vascular stiffness; ventricular dysfunction, left.

Figures

Figure 1.. LVH Study Consort Diagram.

LVH, left ventricular hypertrophy; ECG, electrocardiography

Figure 2.. Starling mechanism (SV and PCWP relationship).

LVH, left ventricular hypertrophy group; PCWP, pulmonary capillary wedge pressure, SV was scaled to lean body surface area.

Figure 3.. Preload-recruitable stroke work.

LVH, left ventricular hypertrophy group; LVEDV, left ventricular end-diastolic volume.

Figure 4.. LV transmural stiffness.

LVH, left ventricular hypertrophy group; PCWP, pulmonary capillary wedge pressure; LVEDV was scaled to lean body surface area, Transmural pressure = PCWP — right atrial pressure (RAP).

Figure 5.. Summary diagram of left ventricular end-diastolic pressure-volume relationships between LVH patients and healthy controls.

LV chamber distensibility was lower while PCWP was higher in the LVH group compared to the healthy controls. The pericardial constraint may be the dominant factor regulating the shape of the LV-EDPVR especially at higher pressure range during rapid saline infusion. In the other hand, myocardial compliance is the dominant element affecting the shape of the LV-EDPVR at lower pressure range during lower body negative pressure. In this study, to reduce the effect of pericardial pressure on LV-EDPVR, we calculated the transmural pressure (= PCWP - RAP) as an effective LV distending pressure. Indeed, the LV transmural stiffness slopes in LVH patients appeared to be greater in than healthy control subjects. These findings demonstrated that it is not the pericardium that causes the rise in the LV distending pressure, but myocardial compliance per se during rapid saline infusion. LVH, left ventricular hypertrophy; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; LV-EDPVR, left ventricular end-diastolic pressure and volume relationship; T, LV wall stress; h, wall thickness; P, left ventricular pressure, r, radius; series 1: LVH, series 2: controls.