Prospective randomized controlled trial of the safety and feasibility of a novel mesenchymal precursor cell therapy in hypoplastic left heart syndrome.

Objective: To assess the safety and feasibility of low-dose, novel, allogenic mesenchymal precursor cell (MPC) therapy as an adjunct to left ventricular (LV) recruitment for patients with hypoplastic left heart syndrome (HLHS) and borderline left ventricles. MPC injections into the hypoplastic left ventricle may stimulate neovascularization and beneficial LV remodeling and may improve the likelihood of achieving biventricular (BiV) or 1.5 ventricle (1.

Randomized Trial of Targeted Transendocardial Mesenchymal Precursor Cell Therapy in Patients With Heart Failure.

Background: Mesenchymal precursor cells (MPCs) are allogeneic, immunoselected cells with anti-inflammatory properties that could improve outcomes in heart failure with reduced ejection fraction (HFrEF).

Objectives: This study assessed the efficacy and safety of MPCs in patients with high-risk HFrEF.

Methods: This randomized, double-blind, multicenter study evaluated a single transendocardial administration procedure of MPCs or sham-control in 565 intention-to-treat patients with HFrEF on guideline-directed therapies.

Remestemcel-L Therapy for COVID-19-Associated Multisystem Inflammatory Syndrome in Children.

Multisystem inflammatory syndrome in children (MIS-C) is a serious postinfectious immune dysregulation associated with coronavirus disease 2019 that may present with severe and life-threatening cardiovascular dysfunction, hemodynamic instability, shock, and multisystem organ failure. Optimal treatment is unknown. Current standard of care consists of nonspecific anti-inflammatory and antithrombotic therapies.

Phase 3 DREAM-HF Trial of Mesenchymal Precursor Cells in Chronic Heart Failure.

Advanced heart failure (HF) is a progressive disease characterized by recurrent hospitalizations and high risk of mortality. Indeed, outcomes in late stages of HF approximate those seen in patients with various aggressive malignancies. Clinical trials assessing beneficial outcomes of new treatments in patients with cancer have used innovative approaches to measure impact on total disease burden or surrogates to assess treatment efficacy.

Eicosapentaenoic Acid as a Potential Therapeutic Approach to Reduce Cardiovascular Risk in Patients with End-Stage Renal Disease on Hemodialysis: A Review.

Background: Patients with end-stage renal disease on hemodialysis have excess cardiovascular disease (CVD) burden with substantially increased CV event rates compared with the general population.

Summary: Traditional interventions that, according to standard clinical guidelines, reduce CV risk such as antihypertensive therapy, diet, exercise, and statins are not similarly effective in the hemodialysis population. This raises the question of whether additional risk factors, such as enhanced inflammation and oxidative stress, may drive the increased CVD burden in hemodialysis patients.

Optimizing Cholesterol Treatment in Patients With Muscle Complaints.

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.

Biologic plausibility, cellular effects, and molecular mechanisms of eicosapentaenoic acid (EPA) in atherosclerosis.

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.

A Phase II Dose-Escalation Study of Allogeneic Mesenchymal Precursor Cells in Patients With Ischemic or Nonischemic Heart Failure.

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).

Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial.

Background: SERCA2a deficiency is commonly seen in advanced heart failure (HF). This study is designed to investigate safety and biological effects of enzyme replacement using gene transfer in patients with advanced HF.

Methods And Results: A total of 9 patients with advanced HF (New York Heart Association [NYHA] Class III/IV, ejection fraction [EF] < or = 30%, maximal oxygen uptake [VO2 max] <16 mL.

Design of a phase 1/2 trial of intracoronary administration of AAV1/SERCA2a in patients with heart failure.

Background: Heart failure (HF) remains a major cause of morbidity and mortality in North America. With an aging population and an unmet clinical need by current pharmacologic and device-related therapeutic strategies, novel treatment options for HF are being explored. One such promising strategy is gene therapy to target underlying molecular anomalies in the dysfunctional cardiomyocyte.

Noninvasive method for determination of arterial compliance using Doppler echocardiography and subclavian pulse tracings. Validation and clinical application of a physiological model of the circulation.

Background: The Poiseuillian model of the arterial system currently applied in clinical physiology does not explain how arterial pressure is maintained during diastole after cessation of pulsatile aortic inflow. Arterial pressure-flow relations can be more accurately described by models that incorporate arterial viscoelastic properties such as arterial compliance. Continuous pressure and flow measurements are needed to evaluate these properties.

Cardiovascular consequences of correction of the anemia of renal failure with erythropoietin.

The purpose of this study was to define the physiologic responses of the heart and peripheral circulation to chronic anemia using noninvasive measurements while eliminating confounding biochemical, pharmacologic and physiologic variables. Stable chronic hemodialysis patients were studied at the University Hospital based chronic dialysis unit and echocardiography laboratory before and after therapy with human recombinant erythropoietin (rHuEPO). Subjects included maintenance hemodialysis patients free of left ventricular regional wall motion abnormalities discernible by echocardiography, rhythm disturbance, significant valvular or ischemic heart disease.

Noninvasive assessment of the direct action of oral nifedipine and nicardipine on left ventricular contractile state in patients with systemic hypertension: importance of reflex sympathetic responses.

Objectives: This study was designed to noninvasively assess the direct action of calcium channel blockers on left ventricular contractility in humans and to establish a framework for determining the importance of reflex sympathetic responses to any pharmacologic intervention.

Background: Assessment of left ventricular contractility in patients taking calcium channel blockers by using traditional indexes of systolic performance is difficult because of the after-load-reducing and reflex sympathetic effects of the drugs.

Methods: Fifteen hypertensive patients (mean blood pressure 127 +/- 15 mm Hg) were studied with Doppler echocardiography and calibrated subclavian pulse tracings while receiving placebo and 1 week after randomization to treatment with oral nifedipine (20 mg three times daily; n = 7) or nicardipine (30 mg three times daily; n = 8).

Effects of simultaneous alterations in preload and afterload on measurements of left ventricular contractility in patients with dilated cardiomyopathy: comparisons of ejection phase, isovolumetric and end-systolic force-velocity indexes.

Objectives: The study was designed to critically evaluate the clinical utility of ejection phase and nonejection phase indexes of contractile state in patients with severe left ventricular dysfunction.

Background: Ejection phase indexes of left ventricular systolic performance are unable to differentiate contractility changes from alterations in loading conditions. Isovolumetric and end-systolic force-velocity indexes have been proposed as alternative measurements of contractile state that are load independent.

A time-course study of the effects of pentobarbital, fentanyl, and morphine chloralose on myocardial mechanics.

Cardiovascular physiological studies in anesthetized animals may be confounded by the hemodynamic actions of the anesthetic agents themselves. To identify an anesthetic regimen that does not significantly influence cardiovascular physiology, the hemodynamic responses of 28 dogs were studied. Animals were equally divided among groups with 1) no anesthesia (i.

Influence of histamine receptors on basal left ventricular contractile tone in humans: assessment using the H2 receptor antagonist famotidine and the beta-adrenoceptor antagonist esmolol as pharmacologic probes.

Histamine has a positive inotropic action in humans. Recent controversial data have suggested that histamine2 (H2) receptor blockade depresses overall left ventricular systolic performance in healthy volunteers. To explore the possibility that H2 receptors positively influence basal left ventricular contractile tone, 10 normal subjects were studied by using imaging and Doppler echocardiography and calibrated subclavian pulse data in a blinded, randomized, two-period crossover trial with measurements obtained at the end of each 7-day period.

Parathyroid hormone and myocardial performance in dialysis patients.

Whether parathyroid hormone (PTH) has a clinically important effect on myocardial performance is unclear. Previous investigations of cardiac function before and after parathyroidectomy have failed to control for ionized calcium, other biochemical parameters, or heart rate and cardiovascular loading conditions. We performed load- and rate-independent measurements of myocardial contractility in seven stable hemodialysis patients before and after surgical parathyroidectomy under identical conditions of blood ionized calcium (Ca2+), electrolytes, pH, PO2, and hematocrit.

Pulsus paradoxus: a definition revisited.

Pulsus paradoxus is associated with many clinical conditions and is defined as a greater than 10 mm Hg end-inspiratory decrease in systolic blood pressure. Kussmaul's original definition of pulsus paradoxus is presented, along with an explanation of his choice of the term "pulsus paradoxus." A case of pulsus paradoxus is graphically described using simultaneous two-dimensional targeted M-mode, Doppler echocardiographic, and high-fidelity pressure recordings.

Left ventricular mechanics in preeclampsia.

Increased systemic vascular resistance and contracted blood volume are characteristic findings in preeclampsia. These alterations in cardiovascular hemodynamics can adversely affect ejection phase indices of left ventricular performance making it difficult to separate abnormalities resulting from changes in load from those caused by depressed myocardial contractility. To address this issue the contractility-sensitive, load-independent relationship between left ventricular end-systolic wall stress and rate-corrected velocity of fiber shortening was assessed in 10 nulliparous patients with preeclampsia.

Doppler and electromagnetic comparisons of instantaneous aortic flow characteristics in primates.

Assessment of the pulsatile mechanical behavior of the coupled left ventricle and the peripheral arterial circulation requires accurate estimation of instantaneous aortic flow. Before the availability of Doppler technologies, this could only be achieved by invasive techniques. The purpose of this study was to assess the accuracy of Doppler-based measurement of instantaneous aortic blood flow and waveform morphology throughout ventricular ejection when compared with an established invasive method.