The velocity of circumferential fiber shortening (Vcf) is an index of myocardial performance which, although sensitive to contractile state, has limited usefulness because of its dependence on left ventricular loading conditions. This study investigated the degree and velocity of left ventricular fiber shortening as it relates to wall stress in an attempt to develop an index of contractility that is independent of preload and heart rate while incorporating afterload. Studies were performed in 78 normal subjects using M-mode echocardiography, phonocardiography and indirect carotid pulse tracings under baseline conditions. In addition, studies were performed on 25 subjects during afterload augmentation with methoxamine, 8 subjects before and during afterload challenge after increased preload with dextran and 7 subjects with enhanced left ventricular contractility with dobutamine. The relation of end-systolic stress to the velocity of fiber shortening and to the rate-corrected velocity of shortening (corrected by normalization to an RR interval of 1) was inversely linear with correlation coefficients of -0.72 and -0.84, respectively. Alterations in afterload, preload or a combination of the two did not significantly affect the end-systolic wall stress/rate-corrected velocity of shortening relation, whereas during inotropic stimulation, the values were higher, with 94% of the data points above the normal range. Age did not appear to affect the range of normal values for this index. In contrast, the end-systolic wall stress/fractional shortening relation was not independent of preload status, responding in a manner similar to that seen with a positive inotropic intervention. Thus, the velocity of circumferential fiber shortening normalized for heart rate is inversely related to end-systolic wall stress in a linear fashion. Accurate quantitation can be performed by noninvasive means and a range of normal values determined. This index is a sensitive measure of contractile state that is independent of preload, normalized for heart rate and incorporates afterload. In contrast, the end-systolic wall stress/fractional shortening relation is dependent on end-diastolic fiber length in the range of physiologically relevant changes in preload.

Rationale: Allogeneic mesenchymal precursor cells (MPCs) have been effective in large animal models of ischemic and nonischemic heart failure (HF). Objective: To evaluate the feasibility and safety of 3 doses (25, 75, or 150 million cells) of immunoselected allogeneic MPCs in chronic HF patients in a phase 2 trial. Methods and Results: We sequentially allocated 60 patients to a dosing cohort (20 per dose group) and randomized them to transendocardial MPC injections (n=15) or mock procedures (n=5). The primary objective was safety, including antibody testing. Secondary efficacy end points included major adverse cardiac events (MACE; cardiac death, myocardial infarction, or revascularization), left ventricular imaging, and other clinical-event surrogates. Safety and MACE were evaluated for up to 3 years. MPC injections were feasible and safe. Adverse events were similar across groups. No clinically symptomatic immune responses were noted. MACE was seen in 15 patients: 10 of 45 (22%) MPC-treated and 5 of 15 (33%) control patients. We found no differences between MPC-treated and control patients in survival probability, MACE-free probability, and all-cause mortality. We conducted a post hoc analysis of HF-related MACE (HF hospitalization, successfully resuscitated cardiac death, or cardiac death) and events were significantly reduced in the 150 million MPC group (0/15) versus control (5/15; 33%), 25 million MPC group (3/15; 20%), and 75 million MPC group (6/15; 40%); the 150 million MPC group differed significantly from all groups according to Kaplan–Meier statistics >3 years ( P =0.025 for 150 million MPC group versus control). Conclusions: Transendocardial injections of allogeneic MPCs were feasible and safe in chronic HF patients. High-dose allogeneic MPCs may provide benefits in this population.

Residual cardiovascular (CV) risk remains in dyslipidemic patients despite intensive statin therapy, underscoring the need for additional intervention. Eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acid, is incorporated into membrane phospholipids and atherosclerotic plaques and exerts beneficial effects on the pathophysiologic cascade from onset of plaque formation through rupture. Specific salutary actions have been reported relating to endothelial function, oxidative stress, foam cell formation, inflammation, plaque formation/progression, platelet aggregation, thrombus formation, and plaque rupture. EPA also improves atherogenic dyslipidemia characterized by reduction of triglycerides without raising low-density lipoprotein cholesterol. Other beneficial effects of EPA include vasodilation, resulting in blood pressure reductions, as well as improved membrane fluidity. EPA's effects are at least additive to those of statins when given as adjunctive therapy. In this review, we present data supporting the biologic plausibility of EPA as an anti-atherosclerotic agent with potential clinical benefit for prevention of CV events, as well as its cellular effects and molecular mechanisms of action. REDUCE-IT is an ongoing, randomized, controlled study evaluating whether the high-purity ethyl ester of EPA (icosapent ethyl) at 4 g/day combined with statin therapy is superior to statin therapy alone for reducing CV events in high-risk patients with mixed dyslipidemia. The results from this study are expected to clarify the role of EPA as adjunctive therapy to a statin for reduction of residual CV risk.

Statins are highly effective for preventing cardiovascular events by reducing low-density lipoprotein cholesterol (LDL-C). However, many patients taking statins report muscle-related symptoms that prevent the use of guideline recommended doses. Patients with reported intolerance to statins have a high risk of cardiovascular events. Clinical strategies that optimize cardiovascular risk reduction through LDL-C lowering need to be applied in patients experiencing intolerable side effects that they attribute to statins. In this paper, the authors review definitions of statin intolerance, propose algorithms to better define statin intolerance, and describe approaches to optimize cardiovascular risk reduction among individuals reporting statin-associated muscle symptoms.

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