Myosin in autoinhibited off state(s), stabilized by mavacamten, can be recruited in response to inotropic interventions.

Mavacamten is a FDA-approved small-molecule therapeutic designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin toward ordered off states close to the thick filament backbone. It remains elusive whether these myosin heads in the off state(s) can be recruited in response to physiological stimuli when required to boost cardiac output. We show that cardiac myosins stabilized in these off state(s) by mavacamten are recruitable by 1) Ca2+, 2) increased chronotropy [heart rate (HR)], 3) stretch, and 4) ß-adrenergic (ß-AR) stimulation, all known physiological inotropic interventions. At the molecular level, we show that Ca2+ increases myosin ATPase activity by shifting mavacamten-stabilized myosin heads from the inactive super-relaxed state to the active disordered relaxed state. At the myofilament level, both Ca2+ and passive lengthening can shift mavacamten-ordered off myosin heads from positions close to the thick filament backbone to disordered on states closer to the thin filaments. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten-treated cells. This observation was confirmed in vivo in telemetered rats, where left-ventricular dP/dtmax, an index of inotropy, increased with HR in mavacamten-treated animals. Finally, we show that ß-AR stimulation in vivo increases left-ventricular function and stroke volume in the setting of mavacamten. Our data demonstrate that the mavacamten-promoted off states of myosin in the thick filament are at least partially activable, thus preserving cardiac reserve mechanisms.

Mavacamten, a precision medicine for hypertrophic cardiomyopathy: From a motor protein to patients.

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder characterized by left ventricular hypertrophy, hyperdynamic contraction, and impaired relaxation of the heart. These functional derangements arise directly from altered sarcomeric function due to either mutations in genes encoding sarcomere proteins, or other defects such as abnormal energetics. Current treatment options do not directly address this causal biology but focus on surgical and extra-sarcomeric (sarcolemmal) pharmacological symptomatic relief. Mavacamten (formerly known as MYK-461), is a small molecule designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin, the fundamental motor of the sarcomere. This review summarizes the mechanism and translational progress of mavacamten from proteins to patients, describing how the mechanism of action and pharmacological characteristics, involving both systolic and diastolic effects, can directly target pathophysiological derangements within the cardiac sarcomere to improve cardiac structure and function in HCM. Mavacamten was approved by the Food and Drug Administration in April 2022 for the treatment of obstructive HCM and now goes by the commercial name of Camzyos. Full information about the risks, limitations, and side effects can be found at www.accessdata.fda.gov/drugsatfda_docs/label/2022/214998s000lbl.pdf.

The Super-Relaxed State and Length Dependent Activation in Porcine Myocardium.

[Figure: see text].

Effects of danicamtiv, a novel cardiac myosin activator, in heart failure with reduced ejection fraction: experimental data and clinical results from a phase 2a trial.

AIMS: Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction. METHODS AND RESULTS: We studied the effects of danicamtiv on LV and LA function in non-clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double-blind, single- and multiple-dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50-100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment-emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to -1.0%, P < 0.05) and circumferential strain (up to -3.3%, P < 0.01), decreased LA minimal volume index (up to -2.4 mL/m2 , P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo. CONCLUSIONS: Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre-clinical findings of direct activation of LA contractility.

Effects of acute vagal nerve stimulation on the early passive electrical changes induced by myocardial ischaemia in dogs: heart rate-mediated attenuation.

Parasympathetic activity during acute coronary artery occlusion (CAO) can protect against ischaemia-induced malignant arrhythmias; nonetheless, the mechanism mediating this protection remains unclear. During CAO, myocardial electrotonic uncoupling is associated with autonomically mediated immediate (i.e. type 1A) arrhythmias and can modulate pro-arrhythmic dispersion of repolarization. Therefore, the effects of acutely enhanced or decreased cardiac parasympathetic activity on early electrotonic coupling during CAO, as measured by myocardial electrical impedance (MEI), were investigated. Anaesthetized dogs were instrumented for MEI measurements, and left circumflex coronary arterial occlusions were performed in intact (CTRL) and vagotomized (VAG) animals. The CAO was followed by either vagotomy (CTRL) or vagal nerve stimulation (VNS, 10 Hz, 10 V) in the VAG dogs. Vagal nerve stimulation was studied in two additional sets of animals. In one set heart rate (HR) was maintained by pacing (220 beats min(-1)), while in the other set bilateral stellectomy preceded CAO. The MEI increased after CAO in all animals. A larger MEI increase was observed in vagotomized animals (+85 +/- 9 Omega, from 611 +/- 24 Omega, n = 16) when compared with intact control dogs (+43 +/- 5 Omega, from 620 +/- 20 Omega, n = 7). Acute vagotomy during ischaemia abruptly increased HR (from 155 +/- 11 to 193 +/- 15 beats min(-1)) and MEI (+12 +/- 1.1 Omega, from 663 +/- 18 Omega). In contrast, VNS during ischaemia (n = 11) abruptly reduced HR (from 206 +/- 6 to 73 +/- 9 beats min(-1)) and MEI (-16 +/- 2 Omega, from 700 +/- 44 Omega). These effects of VNS were eliminated by pacing but not by bilateral stellectomy. Vagal nerve stimulation during CAO also attenuated ECG-derived indices of ischaemia (e.g. ST segment, 0.22 +/- 0.03 versus 0.15 +/- 0.03 mV) and of rate-corrected repolarization dispersion [terminal portion of T wave (TPEc), 84.5 +/- 4.2 versus 65.8 +/- 5.9 ms; QTc, 340 +/- 8 versus 254 +/- 16 ms]. Vagal nerve stimulation during myocardial ischaemia exerts negative chronotropic effects, limiting early ischaemic electrotonic uncoupling and dispersion of repolarization, possibly via a decreased myocardial metabolic demand.

Vacuum-assisted apical suction devices induce passive electrical changes consistent with myocardial ischemia during off-pump coronary artery bypass graft surgery.

OBJECTIVE: Off-pump coronary artery bypass graft surgery is common therapy to completely revascularize diseased hearts. In order to graft posterior arteries in this procedure, the heart must be lifted from the chest cavity and manipulated to expose the surgical field using an apical suction device. This suction device may cause unwanted myocardial ischemia. METHODS: In this observational study, we measured myocardial electrical impedance, a parameter that responds to myocardial ischemia, as well as ST-segment changes during off-pump coronary artery bypass graft surgery in 12 patients with two-vessel coronary artery disease undergoing revascularisation of the left anterior descending and the posterior descending coronary arteries. During the posterior descending artery revascularisation phase of the procedure the apical suction device was oriented over the electrodes used to measure myocardial electrical impedance, thus allowing us the opportunity to assess myocardial ischemia in this region of the heart. RESULTS: In these 12 patients, myocardial electrical impedance progressively increased under the suction device during posterior coronary artery revascularisation, suggesting that myocardial ischemia developed in this region of the myocardium. ST-segment changes were negligible while the heart was vertically displaced (and the suction device attached), but increased immediately when the heart was returned to the neutral anatomical position. CONCLUSION: Our data suggest that the apical suction device may cause ischemia while the heart is vertically displaced and electrically disconnected from the body. Under these conditions, ST-segment changes may not detect myocardial ischemia. Myocardial electrical impedance has the potential to reliably detect intraoperative myocardial ischemia under these circumstances.

Correlation of autologous skeletal myoblast survival with changes in left ventricular remodeling in dilated ischemic heart failure.

OBJECTIVES: The effect of autologous skeletal myoblast transplantation has not been rigorously studied in the setting of end-stage ischemic heart failure free of concomitant coronary revascularization. The aims of the present study were to determine autologous skeletal myoblast survival and its effects on left ventricular function and remodeling in sheep with dilated ischemic heart failure. METHODS: Ischemic heart failure (left ventricular ejection fraction, 30% +/- 2%; left ventricular end-systolic volume index, 82 +/- 9 mL/m2) was created in sheep (n = 11) with serial left circumflex coronary artery microembolizations. Instruments were inserted for the long-term determination of left ventricular global and regional dimensions, hemodynamics, and pressure-volume analysis after autologous skeletal myoblast transplantation (approximately 3.0 x 10(8) myoblasts; heart failure plus autologous skeletal myoblast group, n = 5) or without (heart failure-control group, n = 6). Measurements were performed in conscious animals. RESULTS: Autologous skeletal myoblast-derived skeletal muscle was found in all injected animals at 6 weeks. In ischemic heart failure, autologous skeletal myoblast cardiomyoplasty failed to improve systolic (left ventricular ejection fraction, 29% +/- 4%; dP/dT(max), 2863 +/- 152 mm Hg/s; end-systolic elastance, 1.6 +/- 0.22) or diastolic (left ventricular end-diastolic pressure, 21 +/- 2 mm Hg; time constant of relaxation (Tau), 34 +/- 4 ms; dP/dT(min), -1880 +/- 68 mm Hg/s) function. There was, however, attenuation in the left ventricular dilatation after autologous skeletal myoblast transplantation (change in end-systolic volume index, 14% +/- 4% vs 32% +/- 6%; P < .05). The effects of autologous skeletal myoblast-derived skeletal muscle were exclusive to the left ventricular short-axis dimension and dependent on autologous skeletal myoblast survival (R2 = 0.59, P = .006, n = 11). CONCLUSIONS: Autologous skeletal cardiomyoplasty was able to attenuate left ventricular remodeling in sheep with end-stage ischemic heart failure.