Impaired endothelial-dependent vasodilation has been demonstrated in two animal models of congestive heart failure and in the coronary circulation of patients with idiopathic dilated cardiomyopathy. To determine whether this impairment contributes to the abnormal peripheral vasomotor tone in patients with congestive heart failure, the local vascular response to intraarterial infusions of graded concentrations (10(-8) M to 10(-5) M) of acetylcholine (an endothelial-dependent vasodilator) and nitroglycerin (a direct-acting vasodilator) was studied in the superficial femoral artery of 19 patients with congestive heart failure (New York Heart Association classes I to IV) and 6 age-matched normal control subjects. The local vascular response was determined from the arterial blood flow velocity pattern obtained by transcutaneous Doppler ultrasonography. Acetylcholine, 10(-5) M, induced a pattern characteristic of vasodilation in all six normal subjects; mean blood flow velocity for the group significantly increased from 11.9 +/- 2.7 to 44.8 +/- 20.9 cm/s (p less than 0.05). In contrast, the same dose of acetylcholine induced a blood flow velocity pattern characteristic of vasodilation in only 4 of the 19 patients with congestive heart failure. Group mean blood flow velocity did not change significantly. Nitroglycerin, 10(-7) M, induced vasodilation in all 6 normal subjects but in only 1 of 19 patients. Nitroglycerin, 10(-5) M, was administered to 10 patients; all 10 demonstrated a pattern characteristic of vasodilation. Thus, acetylcholine-mediated endothelial-dependent vasodilation appears to be impaired in the peripheral vasculature of patients with congestive heart failure. Both endothelial dysfunction and abnormal vascular smooth muscle responsiveness may contribute to abnormal peripheral vasomotor tone.

Left ventricular (LV) diastolic pressure-volume (P-V) relations arise from a complex interplay of active decay of force (i.e., relaxation), passive elastic myocardial properties, and time-varying inflow across the mitral orifice. This study was designed to quantify the passive properties of the intact ventricle and the effects of elastic recoil by separating filling from relaxation with a method of LV volume clamping with a remote-controlled mitral valve. Eleven open-chest fentanyl-anesthetized dogs were instrumented with aortic and mitral flow probes, LV and left atrium micromanometers, and a remote-controlled mitral valve. We prevented complete (end-systolic volume clamping) or partial filling at different times in diastole. The ventricle thus relaxed completely at different volumes, and we generated P-V coordinates for the passive ventricle that included negative, as well as positive, values of pressure. We then estimated ventricular volumes from ventricular weight in eight dogs, using regression equations based on data in the literature, to determine the equilibrium volume (V0), that is, volume at zero transmural pressure, in the working ventricle. We abandoned the traditional exponential approach and characterized by the P-V relation with a logarithmic approach that included maximum LV volume (Vm), minimum volume (Vd), and stiffness parameters (Sp and Sn) for the positive (p) and negative (n) phases: Pp = -Sp In[(Vm - V)/(Vm - V0)] and Pn = Sn In[(V - Vd)/(V0 - Vd)]. With this formulation, the chamber compliance, dP/dV, is normalized by the LV operating volume, and Sp and Sn are size-independent chamber stiffness parameters with the units of stress. In eight ventricles with LV weight = 131 +/- 20 g, Vm = 116 +/- 18 ml, V0 = 37 +/- 6 ml, and Vd = 13 +/- 2 ml, stiffness Sp = 14.6 mm Hg and Sn = 5.1 mm Hg were determined from the slopes of the log-linearized equations. Also, the duration of LV relaxation is increased by the process of ventricular filling (161 +/- 31 msec, filling versus 108 +/- 36 msec, nonfilling, measured from dP/dtmin, p less than 0.0001). We conclude that volume clamping is a useful method of studying restoring forces and that the logarithmic approach is conceptually and quantitatively useful in characterizing the passive properties of the intact ventricle.

Background: Surgical aortic valve replacement (SAVR) represents a class I indication in symptomatic patients with severe aortic stenosis (AS). However, indications for early SAVR in asymptomatic patients with severe AS and normal left ventricular function remain debated. Methods: The Aortic Valve replAcemenT versus conservative treatment in Asymptomatic seveRe aortic stenosis (AVATAR) trial is an investigator-initiated international prospective randomized controlled trial that evaluated the safety and efficacy of early SAVR in the treatment of asymptomatic patients with severe AS, according to common criteria (valve area ≤1 cm 2 with aortic jet velocity >4 m/s or a mean trans-aortic gradient ≥40 mm Hg), and with normal LV function. Negative exercise testing was mandatory for inclusion. The primary hypothesis was that early SAVR would reduce the primary composite endpoint of all-cause death, acute myocardial infarction, stroke or unplanned hospitalization for heart failure, as compared to a conservative strategy according to guidelines. The trial was designed as event-driven to reach a minimum of 35 prespecified events. The study was performed in 9 centers in 7 European countries. Results: Between June 2015 and September 2020, 157 patients (mean age 67 years, 57 % men) were randomly allocated to early surgery (n=78) or conservative treatment (n=79). Follow-up was completed in May 2021. Overall median follow-up was 32 months: 28 months in the early surgery group and 35 months in the conservative treatment group. There was a total of 39 events, 13 in early surgery and 26 in conservative treatment group. In the early surgery group, 72 patients (92.3 %) underwent SAVR with operative mortality of 1.4 %. In an intention-to-treat analysis, patients randomized to early surgery had a significantly lower incidence of primary composite endpoint than those in the conservative arm (HR 0.46, 95 % CI 0.23-0.90, p=0.02). There was no statistical difference in secondary endpoints, including all-cause mortality, first heart failure hospitalizations, major bleeding or thromboembolic complications, but trends were consistent with the primary outcome. Conclusions: In asymptomatic patients with severe AS, early surgery reduced a primary composite of all-cause death, acute myocardial infarction, stroke or unplanned hospitalization for heart failure compared with conservative treatment. This randomized trial provides preliminary support for early SAVR once AS becomes severe, regardless of symptoms.

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LV unloading not only altered interventricular septal geometry but also reduced septal systolic thickening and output, all of which may contribute to impaired RV contractility during mechanical LV support.