Heart Rate-Induced Myocardial Ca2+ Retention and Left Ventricular Volume Loss in Patients With Heart Failure With Preserved Ejection Fraction

Abstract

Background Increases in heart rate are thought to result in incomplete left ventricular (LV) relaxation and elevated filling pressures in patients with heart failure with preserved ejection fraction (HFpEF). Experimental studies in isolated human myocardium have suggested that incomplete relaxation is a result of cellular Ca²⁺ overload caused by increased myocardial Na⁺ levels. We tested these heart rate paradigms in patients with HFpEF and referent controls without hypertension. Methods and Results In 22 fully sedated and instrumented patients (12 controls and 10 patients with HFpEF) in sinus rhythm with a preserved ejection fraction (≥50%) we assessed left-sided filling pressures and volumes in sinus rhythm and with atrial pacing (95 beats per minute and 125 beats per minute) before atrial fibrillation ablation. Coronary sinus blood samples and flow measurements were also obtained. Seven women and 15 men were studied (aged 59±10 years, ejection fraction 61%±4%). Patients with HFpEF had a history of hypertension, dyspnea on exertion, concentric LV remodeling and a dilated left atrium, whereas controls did not. Pacing at 125 beats per minute lowered the mean LV end-diastolic pressure in both groups (controls -4.3±4.1 mm Hg versus patients with HFpEF -8.5±6.0 mm Hg, P=0.08). Pacing also reduced LV end-diastolic volumes. The volume loss was about twice as much in the HFpEF group (controls -15%±14% versus patients with HFpEF -32%±11%, P=0.009). Coronary venous [Ca²⁺] increased after pacing at 125 beats per minute in patients with HFpEF but not in controls. [Na⁺] did not change. Conclusions Higher resting heart rates are associated with lower filling pressures in patients with and without HFpEF. Incomplete relaxation and LV filling at high heart rates lead to a reduction in LV volumes that is more pronounced in patients with HFpEF and may be associated with myocardial Ca²⁺ retention.

Keywords: Ca2+ cycling/excitation-contraction coupling; heart failure; hypertension; ion channels/membrane transport; mechanisms.

Figure 1. LA Pressures at Baseline Sinus Rhythm and During Atrial Pacing.

Left atrial (LA) pressures at baseline sinus rhythm and during atrial pacing at 95 beats per minute (bpm) and then 125 bpm in a control patient and in a patient with heart failure with preserved ejection fraction (HFpEF) as demonstrative examples.

Figure 2. LVEDP and Mean LA Pressure at Baseline and During Atrial Pacing.

Left ventricular end‐diastolic pressures (LVEDP) and mean left atrial (LA) pressures in controls and patients with heart failure with preserved ejection fraction (HFpEF). bpm indicates beats per minute.

Figure 3. Arterial BPs at Baseline and During Atrial Pacing.

Arterial blood pressures (BPs) in controls and patients with heart failure with preserved ejection fraction (HFpEF). Systolic BP at baseline heart rate vs 95 beats per minute (bpm) (P=0.02). Diastolic BP at baseline heart rate vs 95 bpm (P=0.003) or 125 bpm (P=0.004).

Figure 4. Left Ventricular End‐Diastolic and End‐Systolic Volume Index at Baseline and During Atrial Pacing.

Left ventricular end‐diastolic volume index (LVEDVI) and left ventricular end‐systolic volume (LVESV) index (LVESVI) in controls and patients with heart failure with preserved ejection fraction (HFpEF). Error bars: (left panels) interquartile ranges, (right panels) SEM. bpm indicates beats per minute.

Figure 5. Left Ventricular M‐Mode Tracing at Baseline and During Atrial Pacing.

Left ventricular M‐mode tracing recorded with the intracardiac ultrasound probe positioned at the right ventricular septum at baseline sinus rhythm, 95beats per minute (bpm), and 125bpm in controls and in patients with heart failure with preserved ejection fraction (HFpEF). SR indicates sarcoplasmic reticulum.

Figure 6. Myocardial Calcium Efflux After Pacing at 125 bpm.

Myocardial calcium efflux after pacing at 125 beats per minute (bpm) in controls and patients with heart failure with preserved ejection fraction (HFpEF)