Abstract
Up-regulation of Ca2+ entry through Ca2+ channels by high rates of beating is involved in the frequency-dependent regulation of contractility: this process is crucial in adaptation to exercise and stress and is universally known as force-frequency relation (FFR). Disturbances in calcium handling play a central role in the disturbed contractile function in myocardial failure. Measurements of twitch tension in isolated left-ventricular strips from explanted cardiomyopathic hearts compared with non-failing hearts show flat or biphasic FFR, while it is up-sloping in normal hearts. Starting in 2003 we introduced the FFR measurement in the stress echo lab using the end-systolic pressure (ESP)/End-systolic volume index (ESVi) ratio (the Suga index) at increasing heart rates. We studied a total of 2,031 patients reported in peer-reviewed journals: 483 during exercise, 34 with pacing, 850 with dobutamine and 664 during dipyridamole stress echo. We demonstrated the feasibility of FFR in the stress echo lab, the clinical usefulness of FFR for diagnosing latent contractile dysfunction in apparently normal hearts, and residual contractile reserve in dilated idiopathic and ischemic cardiomyopathy. In 400 patients with left ventricular dysfunction (ejection fraction 30 ± 9%) with negative stress echocardiography results, event-free survival was higher (p < 0.001) in patients with ΔESPVR (the difference between peak and rest end-systolic pressure-volume ratio, ESPVR) ≥ 0.4 mmHg/mL/m2. The prognostic stratification of patients was better with FFR, beyond the standard LV ejection fraction evaluation, also in the particular settings of severe mitral regurgitation or diabetics without stress-induced ischemia. In the particular setting of selection of heart transplant donors, the stress echo FFR was able to correctly select 34 marginal donor hearts efficiently transplanted in emergency recipients. Starting in 2007, we introduced an operator-independent cutaneous sensor to monitor the FFR: the force is quantified as the sensed pre-ejection myocardial vibration amplitude. We demonstrated that the sensor-derived force changes at increasing heart rates are highly related with both max dP/dt in animal models, and with the stress echo FFR in 220 humans, opening a new window for pervasive cardiac heart failure monitoring in telemedicine systems.
Highlights
The assessment of left ventricular contractility is an old dream for the cardiologist, but until recently it has been a methodological nightmare
Ca2+ ions enter through the calcium channel that opens in response to the wave of depolarization that travels along the sarcolemma
There is a change in the gene expression from the normal adult pattern to that of fetal life with an inversion of the normal positive slope of the force-frequency relation [2]: systolic calcium release and diastolic calcium reuptake process is lowered at the basal state, and instead of accelerating for increasing heart rates, slows down [3] (Additional files 1, 2, 3, 4, 5)
Summary
The assessment of left ventricular contractility (usually obtained in the daily routine through gross proxies such as ejection fraction and regional wall motion) is an old dream for the cardiologist, but until recently it has been a methodological nightmare. Ten years ago ΔESPVR (or simpler PVR, pressure-volume relation) was introduced in the stress echo lab as a measure of the heart rate-dependent changes in contractility [6], associated or not with adrenergic stimulation [7,8] (Figure 2). From upper to lower rows: systolic blood pressure (SP) by cuff sphygmomanometer (first row); LV end-systolic volumes (ESV) calculated with the biplane Simpson method (second row); heart rate increase (b.p. m.) during dobutamine infusion (third row); in the lowest row, the force-frequency relation built off-line with the values recorded at baseline (second column), and at different steps (third, fourth, fifth columns) up to peak exercise (seventh column). These processes may include interstitial fibrosis, microvascular disease and cardiac autonomic neuropathy; Table 1 The spectrum of diagnostic applications of contractility in the stress echo lab Author, year Stress Pts (n)
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