Guy A. MacGowan

Circulating Interleukin-6 in Severe Heart Failure

In a group of patients with New York Heart Association class IV heart failure, significant relations between interleukin-6 and tumor necrosis factor-alpha, and between levels of both interleukin-6 and tumor necrosis factor-alpha and plasma levels of norepinephrine were observed. The present study also demonstrates that in patients with heart failure, elevated levels of tumor necrosis factor-alpha and interleukin-6 may be present even without cachexia.

Intravenous immune globulin in the therapy of peripartum cardiomyopathy

OBJECTIVES We sought to evaluate the effect of therapy with intravenous immune globulin on recovery of left ventricular function in women presenting with peripartum cardiomyopathy. BACKGROUND Peripartum cardiomyopathy is a rare complication of pregnancy that results in significant morbidity and mortality in women of childbearing age. Intravenous immune globulin has been reported to improve left ventricular systolic function in patients with acute dilated cardiomyopathy and myocarditis, but its effectiveness in peripartum cardiomyopathy is unknown. METHODS In this retrospective study, we compared the clinical outcomes of six women with peripartum cardiomyopathy treated with intravenous immune globulin (2 g/kg) with those of 11 recent historical control subjects. All women in the study were referred between 1991 and 1998 with class II to IV heart failure and a left ventricular ejection fraction of <0.40. Left ventricular ejection was reassessed during early follow-up (6.1+/-2.9 months). RESULTS The two groups did not differ in terms of baseline left ventricular ejection fraction, left ventricular end-diastolic diameter, months to presentation, age or multiparity. The improvement in left ventricular ejection fraction in patients treated with immune globulin was significantly greater than in the conventionally treated group (increase of 26+/-8 ejection fraction units vs. 13+/-13, p = 0.042). CONCLUSIONS In this small retrospective study of women with peripartum cardiomyopathy, patients treated with immune globulin had a greater improvement in ejection fraction during early follow-up than patients treated conventionally. Given the poor prognosis of women with peripartum cardiomyopathy who do not improve, this therapy merits further study.

Manganese-enhanced MRI of mouse heart during changes in inotropy†

Recently the dual properties of manganese ion (Mn2+) as an MRI contrast agent and a calcium analogue to enter excitable cells has been used to mark specific cells in brain and as a potential intracellular cardiac contrast agent. Here the hypothesis that in vivo manganese‐enhanced MRI (MEMRI) can detect changes in inotropy in the mouse heart has been tested. T1‐weighted images were acquired every minute during an experimental time course of 75 min. Varying doses of Mn2+ (3.3–14.0 nmoles/min/g BW) were infused during control and altered inotropy with dobutamine (positive inotropy due to increased calcium influx) and the calcium channel blocker diltiazem (negative inotropy). Infusion of MnCl2 led to a significant increase in signal enhancement in mouse heart that saturated above 3.3 ± 0.1 nmoles/min/g BW Mn2+ infusion. At the highest Mn2+ dose infused there was a 41–47% increase in signal intensity with no alteration in cardiac function as measured by MRI‐determined ejection fractions. Dobutamine increased both the steady‐state level of enhancement and the rate of MRI signal enhancement. Diltiazem decreased both the steady‐state level of enhancement and the rate of MRI signal enhancement. These results are consistent with the model that Mn2+‐induced enhancement of cardiac signal is indicative of the rate of calcium influx into the heart. Thus, the simultaneous measurement of global function and calcium influx using MEMRI may provide a useful method of evaluating in vivo responses to inotropic therapy. Magn Reson Med 46:884–890, 2001. Published 2001 Wiley‐Liss, Inc.

Effect of the Asp298 Variant of Endothelial Nitric Oxide Synthase on Survival for Patients With Congestive Heart Failure

Background—Significant variation exists within the endothelial nitric oxide synthase (NOS3) gene that may influence cardiovascular risk. The Asp298 variant of NOS3 has a shorter half-life in endothelial cells. Given the importance of nitric oxide in the heart failure syndrome, we evaluated the effect of this variant on event-free survival in a population with systolic dysfunction. Methods and Results—Four hundred sixty-nine patients (72% male, 49% ischemic; mean age, 56±12 years) with systolic dysfunction (left ventricular ejection fraction ≤0.45) were enrolled in a study of Genetic Risk Assessment of Cardiac Events (GRACE). The polymorphism in exon 7 of NOS3, a G-T transition at position 894 that results in a Glu to Asp amino acid substitution for codon 298, was genotyped and subjects were followed prospectively to the end point of death or heart transplantation. Event-free survival was compared on the basis of the presence (group 1, n=266) or absence (group 2, n=203) of the Asp298 variant. Event-free survival was significantly poorer in patients with the Asp298 variant (percent event-free survival group 1 at 1/2/3 years=78/65/54; group 2=82/72/64, P =0.03). In subset analysis, the adverse impact of the Asp298 variant was primarily in patients with nonischemic cardiomyopathy (group 1=82/73/63; group 2=87/79/71, P =0.03) and was not apparent among patients with ischemic heart disease (group 1=75/59/47; group 2=74/62/54, P =0.71). Conclusions—For patients with heart failure caused by systolic function, the Asp298 variant of NOS3 is associated with poorer event-free survival, particularly in patients with nonischemic cardiomyopathy.

Cardiac structure and function are altered in adults with non-alcoholic fatty liver disease

BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is associated with a twofold greater risk of developing cardiovascular disease. Despite this, little is known about the effect of NAFLD upon cardiac function, limiting our ability to identify therapeutic strategies. This study aimed to address this by defining the effect of NAFLD on cardiac function, structure, and metabolism. METHODS Nineteen adults with NAFLD were age-, sex-, and BMI-matched to healthy controls without liver or metabolic disease. Cardiac structure and function were assessed using high-resolution cardiac MRI and tagging at 3.0 T. High-energy phosphate metabolism was assessed using (31)P-magnetic resonance spectroscopy to measure the PCr/ATP ratio. RESULTS Adults with NAFLD had significantly thicker left ventricular walls at systole (14 ± 3 vs. 12 ± 2 mm; p <0.01) and diastole (8 ± 1 vs. 7 ± 1 mm; p <0.01) than those without fatty liver and showed decreased longitudinal shortening (14 ± 3 vs. 17 ± 3%; p <0.01). The eccentricity ratio was significantly higher in the NAFLD group (1.1 ± 0.2 vs. 0.9 ± 0.2 g/ml; p <0.01) indicating concentric remodelling. Peak whole wall strain was higher in the NAFLD group (19 ± 2 vs. 17 ± 3%; p <0.01), as was peak endocardial strain (28 ± 4 vs. 22 ± 5%; p <0.01). Cardiac metabolism, measured by PCr/ATP ratio, was not altered in NAFLD (1.8 ± 0.3 vs. 1.9 ± 0.3; p=0.36). CONCLUSIONS Significant changes in cardiac structure and function are evident in adults with NAFLD in the apparent absence of metabolic changes or overt cardiac disease. Clinicians should continue to explore therapies to improve cardiac function as a means to modify the excess risk of cardiovascular disease associated with NAFLD.

Exercise-Related Ventilatory Abnormalities and Survival in Congestive Heart Failure

This retrospective study of 104 New York Heart Association class 1 to 4 heart failure patients undergoing exercise stress testing with gas exchange analysis demonstrated that the ventilatory equivalent for carbon dioxide at anaerobic threshold is useful in determining prognosis in patients with severe congestive heart failure, particularly when used in combination with peak exercise oxygen consumption. A ventilatory equivalent for carbon dioxide >50 and peak oxygen consumption < or =15.0 ml/kg/min defines a very high-risk patient group who should be prioritized for transplantation.

Effects of afterload on regional left ventricular torsion

OBJECTIVE To determine if left ventricular torsion, as measured by magnetic resonance tissue tagging, is afterload dependent in a canine isolated heart model in which neurohumoral responses are absent, and preload is constant. METHODS In ten isolated, blood perfused, ejecting, canine hearts, three afterloads were studied, while keeping preload constant: low afterload, high afterload (stroke volume reduced by approx. 50% of low afterload), and isovolumic loading (infinite afterload). RESULTS There were significant effects of afterload on both torsion (P < 0.05) and circumferential shortening (P < 0.0005). Between low and high afterloads, at the anterior region of the endocardium only, where torsion was maximal, there was a significant reduction in torsion (15.1 +/- 2.2 degrees to 7.8 +/- 1.8 degrees, P < 0.05). Between high afterload and isovolumic loading there was no significant change in torsion (7.8 +/- 1.8 degrees to 6.2 +/- 1.5 degrees, P = NS). Circumferential shortening at the anterior endocardium was significantly reduced both between low and high afterload (-0.19 +/- 0.02 to -0.11 +/- 0.02, P < 0.0005), and also between high afterload and isovolumic loading (-0.11 +/- 0.02 to 0.00 +/- 0.02, P < 0.05). Plots of strains with respect to end-systolic volume demonstrated a reduction in both torsion and shortening with afterload-induced increases in end-systolic volume. Torsion, but not circumferential shortening, persisted at isovolumic loading. CONCLUSIONS Maximal regional torsion of the left ventricle is afterload dependent. The afterload response of torsion appears related to the effects of afterload on end-systolic volume.

Left Ventricular and Myocardial Function in Mice Expressing Constitutively Pseudophosphorylated Cardiac Troponin I

Rationale: Protein kinase (PK)C-induced phosphorylation of cardiac troponin (cTn)I has been shown to regulate cardiac contraction. Objective: Characterize functional effects of increased PKC-induced cTnI phosphorylation and identify underlying mechanisms using a transgenic mouse model (cTnIPKC-P) expressing mutant cTnI (S43E, S45E, T144E). Methods and Results: Two-dimensional gel analysis showed 7.2±0.5% replacement of endogenous cTnI with the mutant form. Experiments included: mechanical measurements (perfused isolated hearts, isolated papillary muscles, and skinned fiber preparations), biochemical and molecular biological measurements, and a mathematical model–based analysis for integrative interpretation. Compared to wild-type mice, cTnIPKC-P mice exhibited negative inotropy in isolated hearts (14% decrease in peak developed pressure), papillary muscles (53% decrease in maximum developed force), and skinned fibers (14% decrease in maximally activated force, Fmax). Additionally, cTnIPKC-P mice exhibited slowed relaxation in both isolated hearts and intact papillary muscles. The cTnIPKC-P mice showed no differences in calcium sensitivity, cooperativity, steady-state force-MgATPase relationship, calcium transient (amplitude and relaxation), or baseline phosphorylation of other myofilamental proteins. The model-based analysis revealed that experimental observations in cTnIPKC-P mice could be reproduced by 2 simultaneous perturbations: a decrease in the rate of cross-bridge formation and an increase in calcium-independent persistence of the myofilament active state. Conclusions: A modest increase in PKC-induced cTnI phosphorylation (≈7%) can significantly alter cardiac muscle contraction: negative inotropy via decreased cross-bridge formation and negative lusitropy via persistence of myofilament active state. Based on our data and data from the literature we speculate that effects of PKC-mediated cTnI phosphorylation are site-specific (S43/S45 versus T144).

Left ventricular torsion, energetics, and diastolic function in normal human aging

This study determined, for the first time, whether the effects of normal aging on systolic and diastolic left ventricular function in subjects without cardiovascular disease are related to underlying energetic defects. Cardiac magnetic resonance imaging with tissue tagging and (31)P spectroscopy was used to determine global structure, function, myocardial strains, and the phosphocreatine-to-ATP ratio (PCr/ATP) in 49 healthy subjects aged 20-69 yr. The three major abnormalities that developed with increasing age were the early filling percentage (EFP, the left ventricular volume increase from end systole to mid-diastole divided by stroke volume × 100), which decreased with age, indicating impaired early diastolic filling (r = -0.72, P < 0.0001), the torsion-to-shortening ratio (TSR, measure of subepicardial torsion exerting mechanical advantage over subendocardial shortening), which increased with age indicating relative subendocardial dysfunction (r = 0.44, P < 0.02), and the PCr/ATP (decreased with increasing age, r = -0.52, P < 0.003). EFP and TSR were strongly correlated (r = -0.63, P < 0.0001), although they were not related to PCr/ATP [EFP vs. PCr/ATP: r = 0.34, not significant (NS) and TSR vs. PCr/ATP: r = -0.3, P = NS]. In normal aging, changes in EFP and TSR likely share the same pathophysiology, although it is unlikely that energetics have a major role in the functional effects of aging.

Contrasting effects of steroids and angiotensin-converting-enzyme inhibitors in a mouse model of dystrophin-deficient cardiomyopathy

Duchenne muscular dystrophy (DMD) is associated with progressive cardiomyopathy. Oral corticosteroids are the gold standard for the treatment of skeletal muscle weakness; however, the effects of steroids on cardiac function have not been prospectively studied. In addition, the early role of ACE‐inhibitors (ACE‐I) is controversial. We aimed to determine the effects of steroids and ACE‐I on development of left ventricular dysfunction in the mdx mouse, a model for dystrophin‐deficient cardiomyopathy.