Failing human myocardium is characterized by abnormal relaxation, a deficient sarcoplasmic reticulum (SR) Ca(2+) uptake, and a negative frequency response, which have all been related to a deficiency ...in the SR Ca(2+) ATPase (SERCA2a) pump.
To test the hypothesis that an increase in SERCA2a could improve contractile function in cardiomyocytes, we overexpressed SERCA2a in human ventricular myocytes from 10 patients with end-stage heart failure and examined intracellular Ca(2+) handling and contractile function. Overexpression of SERCA2a resulted in an increase in both protein expression and pump activity and induced a faster contraction velocity (26.7+/-6.7% versus 16.6+/-2.7% shortening per second, P<0.005) and enhanced relaxation velocity (32. 0+/-10.1% versus 15.1+/-2.4%, P<0.005). Diastolic Ca(2+) was decreased in failing cardiomyocytes overexpressing SERCA2a (270+/-26 versus 347+/-30 nmol/L, P<0.005), whereas systolic Ca(2+) was increased (601+/-38 versus 508+/-25 nmol/L, P<0.05). In addition, the frequency response was normalized in cardiomyocytes overexpressing SERCA2a.
These results support the premise that gene-based therapies and targeting of specific pathways in human heart failure may offer a new modality for the treatment of this disease.
Heart failure is a debilitating condition resulting in severe disability and death. In a subset of cases, clustered as idiopathic dilated cardiomyopathy (iDCM), the origin of heart failure is ...unknown. In the brain of patients with dementia, proteinaceous aggregates and abnormal oligomeric assemblies of beta-amyloid impair cell function and lead to cell death.
We have similarly characterized fibrillar and oligomeric assemblies in the hearts of iDCM patients, pointing to abnormal protein aggregation as a determinant of iDCM. We also showed that oligomers alter myocyte Ca(2+) homeostasis. Additionally, we have identified 2 new sequence variants in the presenilin-1 (PSEN1) gene promoter leading to reduced gene and protein expression. We also show that presenilin-1 coimmunoprecipitates with SERCA2a.
On the basis of these findings, we propose that 2 mechanisms may link protein aggregation and cardiac function: oligomer-induced changes on Ca(2+) handling and a direct effect of PSEN1 sequence variants on excitation-contraction coupling protein function.
Abstract Background Mimicking ST-segment elevation myocardial infarction upon presentation, acute nonrheumatic streptococcal myocarditis is a treatable etiology of myocarditis which has only been ...infrequently reported. Methods Patients were identified through a retrospective query of electronic medical records over a 17-year period (January 1994 to December 2010). We describe a case series of acute nonrheumatic streptococcal myocarditis complicating pharyngitis in young adults. Results Nine patients were identified; 89% were male, patients had an average age of 28.6 years, and 56% and 22% had confirmed group A and group G streptococcus, respectively. Latency from pharyngitis to chest pain averaged 3.1 ± 1.1 days. No patients met the revised Jones criteria for acute rheumatic fever. All 9 patients (100%) presented with ST-segment elevations on electrocardiography and elevated cardiac biomarkers. Average peak creatine kinase was 934 U/L (normal < 400 U/L), creatine kinase-MB was 82 ng/mL (normal < 6.9 ng/mL), and troponin T was 2.30 ng/mL (normal < 0.03 ng/mL). Six patients underwent coronary angiography, which revealed no obstructive culprit lesions. Cardiac magnetic resonance imaging confirmed myocarditis in 3 patients and was used to document resolution in follow-up for 2 patients. All patients had a complete clinical recovery. Conclusions Acute nonrheumatic streptococcal myocarditis is an under-recognized and treatable cause of ST-segment elevation and chest pain in young adults with a history of recent pharyngitis. Etiopathology extends beyond Lancefield group A streptococcus and includes group G streptococcal infection. Cardiac magnetic resonance may be useful in confirming the diagnosis and documenting the resolution.
The 6-min walk test (6'WT) is a simple measure of functional capacity and predicts survival in patients with moderate heart failure (HF).
To assess the role of the 6'WT in the evaluation of patients ...with advanced HF, 45 patients (age 49±8 years, mean±SD; New York Heart Association class 3.3±0.6; left ventricular ejection fraction 0.20±0.06; right ventricular ejection fraction 0.31±0.11) underwent symptom-limited cardiopulmonary exercise testing and the 6'WT during cardiac transplant evaluation.
Mean 6'WT distance ambulated was 310±100 m and peak oxygen uptake (peak V˙o2) was 12.2±4.5 mL/kg/min. There was a significant correlation between 6'WT distance ambulated and peak V˙o2 (r=0.64, p<0.001). Multivariate analysis of patient characteristics, resting hemodynamics, and 6'WT results identified the distance ambulated during the 6'WT as the strongest predictor of peak V˙o2 (p<0.001). 6'WT distance ambulated less than 300 m predicted an increased likelihood of death or pretransplant hospital admission for continuous inotropic or mechanical support within 6 months (p=0.04), but did not predict long-term overall or event-free survival with a mean follow-up of 62 weeks. Peak V˙o2 was the best predictor of long-term overall and event-free survival.
In patients with advanced HF evaluated for cardiac transplantation, distance ambulated during the 6'WT predicts (1) peak V˙o2 and (2) short-term event-free survival.
The goal of this study was to determine the prognostic value of clinical data available at presentation and histology in cardiac sarcoidosis (CS) and idiopathic giant cell myocarditis (IGCM).
The ...prognosis of patients with nonischemic cardiomyopathy is partly dependent on the histologic diagnosis. Survival in IGCM is poor. The prognosis of a histologically related entity, cardiac sarcoidosis (CS), is less well established, and the prognostic value of the distinction between CS and IGCM on endomyocardial biopsy (EMB) is unknown.
We identified 115 patients from the Multicenter IGCM Registry with CS (n = 42) and IGCM (n = 73). We compared the clinical data for these two groups using Cox proportional-hazards models to assess the association between histologic diagnosis and survival. In order to determine whether histologic features could reliably differentiate these two entities, two cardiac pathologists semiquantitatively graded the inflammatory infiltrate components and compared the results between groups.
Black race was more frequent in the CS group (31% vs. 4%, p < 0.0001). Syncope and atrioventricular block were also more frequently observed in CS than IGCM (31% vs. 5%, p = 0.0002 and 50% vs. 15%, p < 0.0001, respectively). Left-sided heart failure was more common in IGCM (40% vs. 64%, p = 0.013). In CS patients diagnosed by EMB, the five-year transplant-free survival after diagnosis was 69.8% versus 21.9% for IGCM (p < 0.0001, log-rank test). In multivariate models, presentation with heart failure predicted IGCM, and presentation with heart block or more than nine weeks of symptoms predicted CS. Eosinophils, myocyte damage, and foci of lymphocytic myocarditis were more frequent in IGCM, while granulomas and fibrosis were more frequent in CS.
Transplant-free survival is better for patients with CS than for IGCM diagnosed by EMB. Presentation with heart failure predicted IGCM, and presentation with heart block or more than nine weeks of symptoms predicted CS.
In patients with pulmonary hypertension (PH) secondary to congestive heart failure, inhaled nitric oxide (NO) increases pulmonary vascular smooth-muscle intracellular cyclic guanosine monophosphate ...(cGMP) concentration, thereby decreasing pulmonary vascular resistance (PVR) and increasing cardiac index (CI). However, these beneficial effects of inhaled NO are limited in magnitude and duration, at least in part due to cGMP hydrolysis by the type 5 isoform of phosphodiesterase (PDE5). The goal of this study was to determine the acute pulmonary and systemic hemodynamic effects of the selective PDE5 inhibitor, sildenafil, administered alone or in combination with inhaled NO in patients with congestive heart failure and PH.
Single center, case series, pharmacohemodynamic study.
Cardiac catheterization laboratory of a tertiary care academic teaching hospital.
We studied 11 patients with left ventricular systolic dysfunction due to coronary artery disease or idiopathic dilated cardiomyopathy who had PH.
We administered oral sildenafil (50 mg), inhaled NO (80 ppm), and the combination of sildenafil and inhaled NO during right-heart and micromanometer left-heart catheterization.
Sildenafil administered alone decreased mean pulmonary artery pressure by 12 +/- 5%, PVR by 12 +/- 5%, systemic vascular resistance (SVR) by 13 +/- 6%, and pulmonary capillary wedge pressure by 12 +/- 7%, and increased CI by 14 +/- 5% (all p < 0.05) +/- SEM. The combination of inhaled NO and sildenafil decreased PVR by 50 +/- 4%, decreased SVR by 24 +/- 3%, and increased CI by 30 +/- 4% (all p < 0.01). These effects were greater than those observed with either agent alone (p < 0.05). In addition, sildenafil prolonged the pulmonary vasodilator effect of inhaled NO. Administration of sildenafil alone or in combination with inhaled NO did not change systemic arterial pressure or indexes of myocardial systolic or diastolic function.
PDE5 inhibition with sildenafil improves cardiac output by balanced pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled NO in patients with chronic congestive heart failure and PH.
A 53-year-old man presented with shock and ventricular tachycardia. Cardiac MRI revealed an ejection fraction of 43%, with septal hypokinesis, myocardial edema, and late gadolinium enhancement of the ...subendocardium. Diagnostic tests were performed.
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