James O. Mudd

Tackling heart failure in the twenty-first century

Heart failure, or congestive heart failure, is a condition in which the heart cannot supply the bodys tissues with enough blood. The result is a cascade of changes that lead to severe fatigue, breathlessness and, ultimately, death. In the past quarter century, much progress has been made in understanding the molecular and cellular processes that contribute to heart failure, leading to the development of effective therapies. Despite this, chronic heart failure remains a major cause of illness and death. And because the condition becomes more common with increasing age, the number of affected individuals is rising with the rapidly ageing global population. New treatments that target disease mechanisms at the cellular and whole-organ level are needed to halt and reverse the devastating consequences of this disease.

An abnormal Ca2+ response in mutant sarcomere protein–mediated familial hypertrophic cardiomyopathy

Dominant-negative sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), a disease characterized by left-ventricular hypertrophy, angina, and dyspnea that can result in sudden death. We report here that a murine model of FHC bearing a cardiac myosin heavy-chain gene missense mutation (αMHC403/+), when treated with calcineurin inhibitors or a K+-channel agonist, developed accentuated hypertrophy, worsened histopathology, and was at risk for early death. Despite distinct pharmacologic targets, each agent augmented diastolic Ca2+ concentrations in wild-type cardiac myocytes; αMHC403/+ myocytes failed to respond. Pretreatment with a Ca2+-channel antagonist abrogated diastolic Ca2+ changes in wild-type myocytes and prevented the exaggerated hypertrophic response of treated αMHC403/+ mice. We conclude that FHC-causing sarcomere protein gene mutations cause abnormal Ca2+ responses that initiate a hypertrophic response. These data define an important Ca2+-dependent step in the pathway by which mutant sarcomere proteins trigger myocyte growth and remodel the heart, provide definitive evidence that environment influences progression of FHC, and suggest a rational therapeutic approach to this prevalent human disease.

Fusion of Aortic Valve Commissures in Patients Supported by a Continuous Axial Flow Left Ventricular Assist Device

BACKGROUND Left ventricular assist devices (LVADs) are an important therapy for selected individuals with advanced heart failure unable to wait for a suitable donor for transplantation. Pulsatile LVADs are associated with commissural fusion of the aortic valve, yet little is known about this association with newer generation continuous axial flow LVADs. METHODS We retrospectively reviewed pathologic samples from 9 patients enrolled in the HeartMate II Bridge to Transplantation Trial. Echocardiograms at 1, 6 and 12 months after device placement were evaluated for aortic valve opening and aortic insufficiency. At the time of transplantation, explanted hearts were examined for gross pathologic valvular abnormalities and histologic analysis. RESULTS All but 1 explant had evidence of commissural fusion of the native aortic valve leaflets. Over time there was a decreasing prevalence of aortic valve opening and an increasing prevalence of mild to moderate aortic insufficiency independent of pump speed. All patients had improvements in their functional status and were successfully bridged to orthotopic heart transplantation. CONCLUSIONS Commissural fusion of the native aortic valve leaflets occurs frequently with an increasing prevalence of aortic insufficiency during continuous flow LVAD support. With the potential broader use of non-pulsatile LVADs and the prospect of using LVADs as means to assist in myocardial recovery, special attention should be given to evaluating aortic valve function during LVAD support.

Comparison of Two Murine Models of Familial Hypertrophic Cardiomyopathy

Abstract— Although sarcomere protein gene mutations cause familial hypertrophic cardiomyopathy (FHC), individuals bearing a mutant cardiac myosin binding protein C (MyBP-C) gene usually have a better prognosis than individuals bearing &bgr;-cardiac myosin heavy chain (MHC) gene mutations. Heterozygous mice bearing a cardiac MHC missense mutation (&agr;MHC403/+ or a cardiac MyBP-C mutation (MyBP-Ct/+) were constructed as murine FHC models using homologous recombination in embryonic stem cells. We have compared cardiac structure and function of these mouse strains by several methods to further define mechanisms that determine the severity of FHC. Both strains demonstrated progressive left ventricular (LV) hypertrophy; however, by age 30 weeks, &agr;MHC403/+ mice demonstrated considerably more LV hypertrophy than MyBP-Ct/+ mice. In older heterozygous mice, hypertrophy continued to be more severe in the &agr;MHC403/+ mice than in the MyBP-Ct/+ mice. Consistent with this finding, hearts from 50-week-old &agr;MHC403/+ mice demonstrated increased expression of molecular markers of cardiac hypertrophy, but MyBP-Ct/+ hearts did not demonstrate expression of these molecular markers until the mice were >125 weeks old. Electrophysiological evaluation indicated that MyBP-Ct/+ mice are not as likely to have inducible ventricular tachycardia as &agr;MHC403/+ mice. In addition, cardiac function of &agr;MHC403/+ mice is significantly impaired before the development of LV hypertrophy, whereas cardiac function of MyBP-Ct/+ mice is not impaired even after the development of cardiac hypertrophy. Because these murine FHC models mimic their human counterparts, we propose that similar murine models will be useful for predicting the clinical consequences of other FHC-causing mutations. These data suggest that both electrophysiological and cardiac function studies may enable more definitive risk stratification in FHC patients.

Control of in vivo left ventricular [correction] contraction/relaxation kinetics by myosin binding protein C: protein kinase A phosphorylation dependent and independent regulation.

Background— Cardiac myosin binding protein-C (cMyBP-C) is a thick-filament protein whose presence and phosphorylation by protein kinase A (PKA) regulates cross-bridge formation and kinetics in isolated myocardium. We tested the influence of cMyBP-C and its PKA-phosphorylation on contraction/relaxation kinetics in intact hearts and revealed its essential role in several classic properties of cardiac function. Methods and Results— Comprehensive in situ cardiac pressure–volume analysis was performed in mice harboring a truncation mutation of cMyBP-C (cMyBP-C(t/t)) that resulted in nondetectable protein versus hearts re-expressing solely wild-type (cMyBP-CWT:(t/t)) or mutated protein in which known PKA-phosphorylation sites were constitutively suppressed (cMyBP-CAllP-:(t/t)). Hearts lacking cMyBP-C had faster early systolic activation, which then terminated prematurely, limiting ejection. Systole remained short at faster heart rates; thus, cMyBP-C(t/t) hearts displayed minimal rate-dependent decline in diastolic time and cardiac preload. Furthermore, prolongation of pressure relaxation by afterload was markedly blunted in cMyBP-C(t/t) hearts. All 3 properties were similarly restored to normal in cMyBP-CWT:(t/t) and cMyBP-CAllP-:(t/t) hearts, which supports independence of PKA-phosphorylation. However, the dependence of peak rate of pressure rise on preload was specifically depressed in cMyBP-CAllP-:(t/t) hearts, whereas cMyBP-C(t/t) and cMyBP-CAllP-:(t/t) hearts had similar blunted adrenergic and rate-dependent contractile reserve, which supports linkage of these behaviors to PKA-cMyBP-C modification. Conclusions— cMyBP-C is essential for major properties of cardiac function, including sustaining systole during ejection, the heart-rate dependence of the diastolic time period, and relaxation delay from increased arterial afterload. These are independent of its phosphorylation by PKA, which more specifically modulates early pressure rise rate and adrenergic/heart rate reserve.

Pulmonary Arterial Hypertension: MR Imaging-derived First-Pass Bolus Kinetic Parameters Are Biomarkers for Pulmonary Hemodynamics, Cardiac Function, and Ventricular Remodeling

PURPOSE To prospectively compare contrast material-enhanced (CE) magnetic resonance (MR) imaging-derived right-to-left ventricle pulmonary transit time (PTT), left ventricular (LV) full width at half maximum (FWHM), and LV time to peak (TTP) between patients with pulmonary arterial hypertension (PAH) and healthy volunteers and to correlate these measurements with survival markers in patients with PAH. MATERIALS AND METHODS This HIPAA-compliant study received institutional review board approval. Written informed consent was obtained from all participants. Forty-three patients (32 with PAH [29 women; median age, 55.4 years], 11 with scleroderma but not PAH [seven women; median age, 58.9 years]) underwent right-sided heart catheterization and 3-T CE cardiac MR imaging. Eighteen age- and sex-matched healthy control subjects (12 women; median age, 51.7 years) underwent only CE MR imaging. A short-axis saturation-recovery gradient-echo section was acquired in the basal third of both ventricles, and right-to-left-ventricle PTT, LV FWHM, and LV TTP were calculated. Statistical analysis included Kruskal-Wallis test, Wilcoxon rank sum test, Spearman correlation coefficient, multiple linear regression analysis, and Lin correlation coefficient analysis. RESULTS Patients had significantly longer PTT (median, 8.2 seconds; 25th-75th percentile, 6.9-9.9 seconds), FWHM (median, 8.2 seconds; 25th-75th percentile, 5.7-11.4 seconds), and TTP (median, 4.8 seconds; 25th-75th percentile, 3.9-6.5 seconds) than did control subjects (median, 6.4 seconds; 25th-75th percentile, 5.7-7.1 seconds; median, 5.2 seconds; 25th-75th percentile, 4.1-6.1 seconds; median, 3.2 seconds; 25th-75th percentile, 2.8-3.8 seconds, respectively; P < .01 for each) and subjects with scleroderma but not PAH (median, 6.5 seconds; 25th-75th percentile, 5.6-7.0 seconds; median, 5.0 seconds; 25th-75th percentile, 4.0-7.3 seconds; median, 3.6 seconds; 25th-75th percentile, 2.7-4.0 seconds, respectively; P < .02 for each). PTT, LV FWHM, and LV TTP correlated with pulmonary vascular resistance index (P < .01), right ventricular stroke volume index (P ≤ .01), and pulmonary artery capacitance (P ≤ .02). In multiple linear regression models, PTT, FWHM, and TTP were associated with mean pulmonary arterial pressure and cardiac index. CONCLUSION CE MR-derived PTT, LV FWHM, and LV TTP are noninvasive compound markers of pulmonary hemodynamics and cardiac function in patients with PAH. Their predictive value for patient outcome warrants further investigation.

Control of In Vivo Contraction/Relaxation Kinetics by Myosin Binding Protein C Protein Kinase A Phosphorylation–Dependent and –Independent Regulation

Background— Cardiac myosin binding protein-C (cMyBP-C) is a thick-filament protein whose presence and phosphorylation by protein kinase A (PKA) regulates cross-bridge formation and kinetics in isolated myocardium. We tested the influence of cMyBP-C and its PKA-phosphorylation on contraction/relaxation kinetics in intact hearts and revealed its essential role in several classic properties of cardiac function. Methods and Results— Comprehensive in situ cardiac pressure–volume analysis was performed in mice harboring a truncation mutation of cMyBP-C (cMyBP-C(t/t)) that resulted in nondetectable protein versus hearts re-expressing solely wild-type (cMyBP-CWT:(t/t)) or mutated protein in which known PKA-phosphorylation sites were constitutively suppressed (cMyBP-CAllP-:(t/t)). Hearts lacking cMyBP-C had faster early systolic activation, which then terminated prematurely, limiting ejection. Systole remained short at faster heart rates; thus, cMyBP-C(t/t) hearts displayed minimal rate-dependent decline in diastolic time and cardiac preload. Furthermore, prolongation of pressure relaxation by afterload was markedly blunted in cMyBP-C(t/t) hearts. All 3 properties were similarly restored to normal in cMyBP-CWT:(t/t) and cMyBP-CAllP-:(t/t) hearts, which supports independence of PKA-phosphorylation. However, the dependence of peak rate of pressure rise on preload was specifically depressed in cMyBP-CAllP-:(t/t) hearts, whereas cMyBP-C(t/t) and cMyBP-CAllP-:(t/t) hearts had similar blunted adrenergic and rate-dependent contractile reserve, which supports linkage of these behaviors to PKA-cMyBP-C modification. Conclusions— cMyBP-C is essential for major properties of cardiac function, including sustaining systole during ejection, the heart-rate dependence of the diastolic time period, and relaxation delay from increased arterial afterload. These are independent of its phosphorylation by PKA, which more specifically modulates early pressure rise rate and adrenergic/heart rate reserve.

Prognostic value of left ventricular apical tissue removed for HeartMate II left ventricular assist device placement

BACKGROUND With the increasing use of left ventricular assist devices, the left ventricular apical core has become a more frequently encountered surgical pathology tissue. We investigated the prognostic value of this cardiac tissue in short-term patient mortality. Previous studies have shown that the degree of cardiac fibrosis correlates with improvements in ejection fraction and the likelihood of weaning from an assist device. METHODS Left ventricular apical core tissues from 29 sequential subjects who received a HeartMate II continuous axial flow left ventricular assist device were studied retrospectively to determine whether interstitial fibrosis, replacement fibrosis (scar), the presence of mural thrombus, or other histopathologic findings were associated with hemodynamic changes or mortality in this population. Patients received left ventricular assist devices as bridges to transplantation or as destination therapy. Interstitial fibrosis was determined by observer scoring and digital scoring methods. Before and after left ventricular assist device procedure, right heart catheterizations were reviewed for clinical cardiac data. RESULTS The presence of replacement fibrosis in the apical core tissue significantly correlated with decreased improvement in pulmonary capillary wedge pressure after left ventricular assist device placement (P=.02). Ten subjects died over the course of this study. No specimen variables, including scar, interstitial fibrosis, and the presence of mural thrombosis, correlated with patient mortality. CONCLUSIONS Pathologic findings in left ventricular apical cores have little prognostic utility in guiding patient management as related to overall 1-year mortality, but may indicate patients who are more likely to positively remodel their hearts.