Myosin in autoinhibited 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 states close to the thick filament backbone. It remains elusive whether these myosin heads in the state(s) can be recruited in response to physiological stimuli when required to boost cardiac output.

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.

Myosin in autoinhibited state(s), stabilized by mavacamten, can be recruited via inotropic effectors.

Mavacamten is a novel, FDA-approved, small molecule therapeutic designed to regulate cardiac function by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin towards ordered states close to the thick filament backbone. It remains unresolved whether mavacamten permanently sequesters these myosin heads in the state(s) or whether these heads can be recruited in response to physiological stimuli when required to boost cardiac output.

The Impact of Mavacamten on the Pathophysiology of Hypertrophic Cardiomyopathy: A Narrative Review.

Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This diversity and heterogeneity have added to the complexity of modeling the pathophysiological pathways that contribute to the disease burden. The development of novel therapeutic approaches targeting precise mechanisms within the underlying biology of HCM provides a tool to model and test these pathways.

Direct Interstitial Decongestion in an Animal Model of Acute-on-Chronic Ischemic Heart Failure.

Removal of excess fluid in acute decompensated heart failure (ADHF) targets the intravascular space, whereas most fluid resides in the interstitial space. The authors evaluated an approach to interstitial decongestion using a device to enhance lymph flow. The device was deployed in sheep with induced heart failure (HF) and acute volume overload to create a low-pressure zone at the thoracic duct outlet.

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

[Figure: see text].

Acute Effects of Pimobendan on Cardiac Function in Dogs With Tachycardia Induced Dilated Cardiomyopathy: A Randomized, Placebo-Controlled, Crossover Study.

Pimobendan provides a significant survival benefit in dogs with cardiac disease, including degenerative mitral valve disease and dilated cardiomyopathy (DCM). Its positive inotropic effect is well-known, however, it has complex effects and the mechanisms behind the survival benefit are not fully characterized. Secondary hemodynamic effects may decrease mitral regurgitation (MR) in DCM, and the benefits of pimobendan may extend to improved cardiac relaxation and improved atrial function.

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).

Intravenous Infusion of the Novel HNO Donor BMS-986231 Is Associated With Beneficial Inotropic, Lusitropic, and Vasodilatory Properties in 2 Canine Models of Heart Failure.

The effects of the nitroxyl donor BMS-986231 on hemodynamics, left ventricular (LV) function, and pro-arrhythmic potential were assessed using canine heart failure models. BMS-986231 significantly (p < 0.05) increased LV end-systolic elastance, pre-load-recruitable stroke work, ejection fraction, stroke volume, cardiac output, ratio of early-to-late filling time integrals, and early mitral valve inflow velocity deceleration time.

CXL-1020, a Novel Nitroxyl (HNO) Prodrug, Is More Effective than Milrinone in Models of Diastolic Dysfunction-A Cardiovascular Therapeutic: An Efficacy and Safety Study in the Rat.

The nitroxyl (HNO) prodrug, CXL-1020, induces vasorelaxation and improves cardiac function in canine models and patients with systolic heart failure (HF). HNO's unique mechanism of action may be applicable to a broader subset of cardiac patients. This study investigated the load-independent safety and efficacy of CXL-1020 in two rodent (rat) models of diastolic heart failure and explored potential drug interactions with common HF background therapies.

Myocardial electrotonic response to submaximal exercise in dogs with healed myocardial infarctions: evidence for β-adrenoceptor mediated enhanced coupling during exercise testing.

Introduction: Autonomic neural activation during cardiac stress testing is an established risk-stratification tool in post-myocardial infarction (MI) patients. However, autonomic activation can also modulate myocardial electrotonic coupling, a known factor to contribute to the genesis of arrhythmias. The present study tested the hypothesis that exercise-induced autonomic neural activation modulates electrotonic coupling (as measured by myocardial electrical impedance, MEI) in post-MI animals shown to be susceptible or resistant to ventricular fibrillation (VF).

Dose-Dependent Hemodynamic, Biochemical, and Tissue Oxygen Effects of OC99 following Severe Oxygen Debt Produced by Hemorrhagic Shock in Dogs.

We determined the dose-dependent effects of OC99, a novel, stabilized hemoglobin-based oxygen-carrier, on hemodynamics, systemic and pulmonary artery pressures, surrogates of tissue oxygen debt (arterial lactate 7.2 ± 0.1 mM/L and arterial base excess -17.

Cardiac function after acute support with direct mechanical ventricular actuation in chronic heart failure.

Direct mechanical ventricular actuation (DMVA) exerts direct cardiac compression/decompression and does not require blood contact. The safety and effects of DMVA support in chronically dysfunctional beating hearts in vivo have not been established. This study evaluated hemodynamics and load-independent systolic/diastolic cardiac function before/after acute support (2 hours) using DMVA in small hearts with induced chronic failure.

Reduction of early reperfusion injury with the mitochondria-targeting peptide bendavia.

We recently showed that Bendavia, a novel mitochondria-targeting peptide, reduced infarction and no-reflow across several experimental models. The purpose of this study was to determine the therapeutic timing and mechanism of action that underlie Bendavia's cytoprotective property. In rabbits exposed to in vivo ischemia/reperfusion (30/180 min), Bendavia administered 20 minutes prior to reperfusion (0.

Evaluation of oscillometric and vascular access port arterial blood pressure measurement techniques versus implanted telemetry in anesthetized cats.

Objective: To compare the use of a semi-invasive vascular access port (VAP) device or noninvasive oscillometry versus invasive telemetry for blood pressure measurements in cats.

Animals: 6 healthy cats.

Procedures: 30 days before the study, all cats received an implanted telemeter and a VAP device.

Effects of perzinfotel, butorphanol tartrate, and a butorphanol-perzinfotel combination on the minimum alveolar concentration of isoflurane in cats.

Objective: To determine the effects of perzinfotel, butorphanol, and their combination on the minimal alveolar concentration (MAC) of isoflurane in cats.

Animals: 7 healthy sexually intact cats (4 males and 3 females), aged 12 to 17 months and weighing 2.8 to 4.

Effects of perzinfotel on the minimum alveolar concentration of isoflurane in dogs when administered as a preanesthetic via various routes or in combination with butorphanol.

Objective: To determine the anesthetic-sparing effects of perzinfotel when administered as a preanesthetic via IV, IM, or SC routes or IM in combination with butorphanol.

Animals: 6 healthy sexually intact Beagles (4 males and 2 females; age, 18.5 to 31 months; body weight, 9.

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.

Electrotonic remodeling following myocardial infarction in dogs susceptible and resistant to sudden cardiac death.

Passive electrical remodeling following myocardial infarction (MI) is well established. These changes can alter electrotonic loading and trigger the remodeling of repolarization currents, a potential mechanism for ventricular fibrillation (VF). However, little is known about the role of passive electrical markers as tools to identify VF susceptibility post-MI.

Assessment of cardiac function during axial-flow left ventricular assist device support using a left ventricular pressure-derived relationship: comparison with pre-load recruitable stroke work.

Background: In this study we evaluate load-independent ventricular function during left ventricular assist device (LVAD) support based solely on telemetered measurements of left ventricular (LV) pressure, which has not been reported previously.

Methods: Adult sheep underwent placement of an axial-flow LVAD, a telemetered LV pressure manometer and instruments for pressure-volume analysis. In unsedated sheep, the simultaneous determination of both stroke work/end-diastolic volume (SW/EDP [PRSW]; slope: M(W)) and LV triple-product (TP = LVSP .

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.

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.

Early time course of myocardial electrical impedance during acute coronary artery occlusion in pigs, dogs, and humans.

Changes in myocardial electrical impedance (MEI) and physiological end points have been correlated during acute ischemia. However, the importance of MEI's early time course is not clear. This study evaluates such significance, by comparing the temporal behavior of MEI during acute total occlusion of the left anterior descending coronary artery in anesthetized humans, dogs, and pigs.