G. William Dec

Idiopathic Dilated Cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) is a primary myocardial disease of unknown cause characterized by left ventricular or biventricular dilatation and impaired myocardial contractility1. Depend...

Preserved right ventricular ejection fraction predicts exercise capacity and survival in advanced heart failure

OBJECTIVES This study was undertaken to determine which exercise and radionuclide ventriculographic variables predict prognosis in advanced heart failure. BACKGROUND Although cardiopulmonary exercise testing is frequently used to predict prognosis in patients with advanced heart failure, little is known about the prognostic significance of ventriculographic variables. METHODS The results of maximal symptom-limited cardiopulmonary exercise testing and first-pass radionuclide ventriculography in patients with advanced heart failure referred for evaluation for cardiac transplantation were analyzed. RESULTS Sixty-seven patients with advanced heart failure (mean [+/- SD]; age 51 +/- 10 years, New York Heart Association functional classes III (58%) and IV (18%); mean left ventricular ejection fraction 0.22 +/- 0.07) underwent simultaneous upright bicycle ergometric cardiopulmonary exercise testing and first-pass rest/exercise radionuclide ventriculography. Mean peak oxygen consumption (VO2) was 11.8 +/- 4.2 ml/kg per min, and mean peak age- and gender-adjusted percent predicted oxygen consumption (%VO2) was 38 +/- 11.9%. Univariate predictors of overall survival included right ventricular ejection fraction > or = 0.35 at rest and > or = 0.35 at exercise and %VO2 > or = 45% (all p < 0.05). In a multivariate proportional hazards survival model, right ventricular ejection fraction > or = 0.35 at exercise (p < 0.01) and %VO2 > or = 45% (p = 0.01) were selected as independent predictors of overall survival. Univariate predictors of event-free survival included right ventricular ejection fraction > or = 0.35 at rest (p = 0.01) and > or = 0.35 at exercise (p < 0.01), functional class II (p < 0.05) and %VO2 > or = 45% (p = 0.05). Right ventricular ejection fraction > or = 0.35 at exercise (p = 0.01) was the only independent predictor of event-free survival in a multivariate proportional hazards model. Cardiac index at rest, VO2, left ventricular ejection fraction at rest, and exercise-related increase or decrease > 0.05 in left or right ventricular ejection fraction were not predictive of overall or event-free survival in any univariate or multivariate analysis. CONCLUSIONS 1) Right ventricular ejection fraction > or = 0.35 at rest and exercise is a more potent predictor of survival in advanced heart failure than VO2 or %VO2; 2) %VO2 rather than VO2 predicts survival in advanced heart failure; 3) neither %VO2 nor VO2 predicts survival to the combined end point of death or admission for inotropic or mechanical support in patients with advanced heart failure.

Active myocarditis in the spectrum of acute dilated cardiomyopathies: clinical features, histologic correlates, and clinical outcome

We studied the clinical features and course (average follow-up time, 18 months) of 27 patients with acute dilated cardiomyopathy (symptoms for less than 6 months) who were referred for endomyocardial biopsy. Almost 40 per cent of the patients subsequently had a rise in left ventricular ejection fraction (on average, from 0.21 to 0.41) and substantial improvement in heart failure; the remainder died or had chronic dilated cardiomyopathy. Biopsy revealed myocarditis in 18 patients, and this finding was especially common (89 per cent) in patients who had been ill for less than four weeks. But the biopsy specimen was negative in four patients whose clinical features and later course were diagnostic of myocarditis. Nine patients received immunosuppressive drugs, and four improved--a rate that did not differ from the rate of spontaneous improvement. Neither the histologic features of the biopsy specimen nor the clinical features at presentation were clearly correlated with subsequent improvement, whether or not immunosuppressive drugs were given. We conclude that many cases of unexplained dilated cardiomyopathy result from myocarditis. Definitive histologic confirmation depends on the duration of illness. The efficacy of immunosuppressive treatment must still be established.

Restoration of Contractile Function in Isolated Cardiomyocytes From Failing Human Hearts by Gene Transfer of SERCA2a

BACKGROUND 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. METHODS AND RESULTS 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. CONCLUSIONS 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.

Myocarditis Current Trends in Diagnosis and Treatment

Myocarditis is clinically and pathologically defined as “inflammation of the myocardium.” Despite its rather clear-cut definition, the classification, diagnosis, and treatment of myocarditis continue to prompt considerable debate. The more routine use of endomyocardial biopsy has helped to better define the natural history of human myocarditis and to clarify clinicopathological correlations. Clinical presentations of the disease range from nonspecific systemic symptoms (fever, myalgias, palpitations, or exertional dyspnea) to fulminant hemodynamic collapse and sudden death. The extreme diversity of clinical manifestations has made the true incidence of myocarditis difficult to determine. Recent prospective postmortem data have implicated myocarditis in sudden cardiac death of young adults at rates of 8.6% to 12%.1,2 Furthermore, it has been identified as a cause of dilated cardiomyopathy in 9% of cases in a large prospective series.3 Recent molecular techniques have facilitated new insights into inflammatory autoimmune processes that affect the myocardium and ultimately result in acute or chronic dilated cardiomyopathy. Despite the well-established morbidity and mortality associated with myocarditis,4–7 clinical practice guidelines with regard to its evaluation and treatment are lacking.8 The wide variety of etiologies implicated in myocarditis and its heterogeneous clinical presentations5,7,9 have impeded patient identification and consensus on the most appropriate diagnostic criteria. The Dallas pathological criteria, published in 1986, served as the first attempt to develop standardized diagnostic guidelines for the histopathological classification of myocarditis.10 Active myocarditis is characterized by an inflammatory cellular infiltrate with evidence of myocyte necrosis (Figure 1), whereas borderline myocarditis demonstrates an inflammatory cellular infiltrate without evidence of myocyte injury (Figure 2). The inflammatory infiltrate should be further described as lymphocytic, eosinophilic, or granulomatous (Figure 3). The amount of inflammation may be mild, moderate, or severe, and its distribution may be focal, confluent, or diffuse, respectively. A retrospective study of 112 consecutive …

Controlled Trial of Intravenous Immune Globulin in Recent-Onset Dilated Cardiomyopathy

BackgroundThis prospective placebo-controlled trial was designed to determine whether intravenous immune globulin (IVIG) improves left ventricular ejection fraction (LVEF) in adults with recent onset of idiopathic dilated cardiomyopathy or myocarditis. Methods and ResultsSixty-two patients (37 men, 25 women; mean age ±SD 43.0±12.3 years) with recent onset (≤6 months of symptoms) of dilated cardiomyopathy and LVEF ≤0.40 were randomized to 2 g/kg IVIG or placebo. All underwent an endomyocardial biopsy before randomization, which revealed cellular inflammation in 16%. The primary outcome was change in LVEF at 6 and 12 months after randomization. Overall, LVEF improved from 0.25±0.08 to 0.41±0.17 at 6 months (P <0.001) and 0.42±0.14 (P <0.001 versus baseline) at 12 months. The increase was virtually identical in patients receiving IVIG and those given placebo (6 months: IVIG 0.14±0.12, placebo 0.14±0.14; 12 months: IVIG 0.16±0.12, placebo 0.15±0.16). Overall, 31 (56%) of 55 patients at 1 year had an increase in LVEF ≥0.10 from study entry, and 20 (36%) of 56 normalized their ejection fraction (≥0.50). The transplant-free survival rate was 92% at 1 year and 88% at 2 years. ConclusionsThese results suggest that for patients with recent-onset dilated cardiomyopathy, IVIG does not augment the improvement in LVEF. However, in this overall cohort, LVEF improved significantly during follow-up, and the short-term prognosis remains favorable.

Consensus Conference Report Maximizing Use of Organs Recovered From the Cadaver Donor: Cardiac Recommendations: March 28–29, 2001, Crystal City, Va

The shortage of available donor hearts continues to limit cardiac transplantation. For this reason, strict criteria have limited the number of patients placed on the US waiting list to ≈6000 to 8000 per year. Because the number of available donor hearts has not increased beyond ≈2500 per year, the transplant waiting list mortality rate remains substantial. Suboptimal and variable utilization of donor hearts has compounded the problem in the United States. In 1999, the average donor yield from 55 US regions was 39%, ranging from 19% to 62%. This report provides the detailed cardiac recommendations from the conference on “Maximizing Use of Organs Recovered From the Cadaver Donor” held March 28 to 29, 2001, in Crystal City, Va. The specific objective of the report is to provide recommendations to improve the evaluation and successful utilization of potential cardiac donors. The report describes the accuracy of current techniques such as echocardiography in the assessment of donor heart function before recove...The shortage of available donor hearts continues to limit cardiac transplantation. For this reason, strict criteria have limited the number of patients placed on the US waiting list to 6000 to 8000 per year. Because the number of available donor hearts has not increased beyond 2500 per year, the transplant waiting list mortality rate remains substantial. Suboptimal and variable utilization of donor hearts has compounded the problem in the United States. In 1999, the average donor yield from 55 US regions was 39%, ranging from 19% to 62%. This report provides the detailed cardiac recommendations from the conference on “Maximizing Use of Organs Recovered From the Cadaver Donor” held March 28 to 29, 2001, in Crystal City, Va. The specific objective of the report is to provide recommendations to improve the evaluation and successful utilization of potential cardiac donors. The report describes the accuracy of current techniques such as echocardiography in the assessment of donor heart function before recovery and the impact of these data on donor yield. The rationale for and specific details of a donor-management pathway that uses pulmonary artery catheterization and hormonal resuscitation are provided. Administrative recommendations such as enhanced communication strategies among transplant centers and organ-procurement organizations, financial incentives for organ recovery, and expansion of donor database fields for research are also described. (Circulation. 2002;106:836-841.)

RBM20 , a gene for hereditary cardiomyopathy, regulates titin splicing

Alternative splicing has a major role in cardiac adaptive responses, as exemplified by the isoform switch of the sarcomeric protein titin, which adjusts ventricular filling. By positional cloning using a previously characterized rat strain with altered titin mRNA splicing, we identified a loss-of-function mutation in the gene encoding RNA binding motif protein 20 (Rbm20) as the underlying cause of pathological titin isoform expression. The phenotype of Rbm20-deficient rats resembled the pathology seen in individuals with dilated cardiomyopathy caused by RBM20 mutations. Deep sequencing of the human and rat cardiac transcriptome revealed an RBM20-dependent regulation of alternative splicing. In addition to titin (TTN), we identified a set of 30 genes with conserved splicing regulation between humans and rats. This network is enriched for genes that have previously been linked to cardiomyopathy, ion homeostasis and sarcomere biology. Our studies emphasize the key role of post-transcriptional regulation in cardiac function and provide mechanistic insights into the pathogenesis of human heart failure.

Socioeconomic status as an independent risk factor for hospital readmission for heart failure

The management of heart failure is characterized by high rates of hospital admission as well as rehospitalization after inpatient treatment of this disorder, whereas skillful medical care may reduce the risk of hospital admission. The purpose of this study was to examine the relation between income (as a measure of socioeconomic status) and the frequency of hospital readmission among a large and diverse group of persons treated for heart failure. We analyzed administrative discharge data from 236 nonfederal acute-care hospitals in New York State, involving 41,776 African-American or Caucasian hospital survivors with International Classification of Diseases, Ninth Revision, Clinical Modification codes for heart failure in the principal diagnosis position between January 1 and December 31, 1995. Household income was derived from postal ZIP codes and census data. We found that patients residing in lower income neighborhoods were more often women or African-Americans, had more comorbid illness, had higher use of Medicaid insurance, and were more often admitted to rural hospitals. There was a stepwise decrease in the crude frequency of readmission from the lowest quartile of income (23.2%) to the highest (20.0%) (p <0.0001 for Mantel-Haenszel chi-square test for trend across all quartiles; p <0.0001 for comparison between quartiles 1 and 4). After adjustment for baseline differences and process of care, income remained a significant predictor, with an increase in the risk of readmission noted in association with lower levels of income (adjusted odds ratio for quartile 1:4 comparison, 1.18; 95% confidence interval, 1.10 to 1.26, p <0.0001). We conclude that lower income patients hospitalized for treatment of heart failure in New York differ from higher income patients in important clinical and demographic comparisons. Even after adjustment for these fundamental differences and other potential confounding factors, lower income is a positive predictor of readmission risk.

Hemodynamic effects of inhaled nitric oxide in heart failure.

OBJECTIVES This study was performed to assess the utility of inhaled nitric oxide as a selective pulmonary vasodilator in patients with severe chronic heart failure and to compare its hemodynamic effects with those of nitroprusside, a nonselective vasodilator. BACKGROUND Preoperative pulmonary vascular resistance is a predictor of right heart failure after heart transplantation. Non-selective vasodilators administered preoperatively to assess the reversibility of pulmonary vasoconstriction cause systemic hypotension, limiting their utility. METHODS Systemic and pulmonary hemodynamic measurement were made at baseline, during oxygen inhalation and with the addition of graded doses of inhaled nitric oxide or intravenous nitroprusside in 16 patients with New York Heart Association class III or IV heart failure referred for heart transplantation. RESULTS Pulmonary vascular resistance decreased to a greater extent with 80 ppm nitric oxide (mean +/- SEM 256 +/- 41 to 139 +/- 14 dynes.s.cm-5) than with the maximally tolerated dose of nitroprusside (264 +/- 49 to 169 +/- 30 dynes.s.cm-5, p < 0.05, nitric oxide vs. nitroprusside). Pulmonary capillary wedge pressure increased with 80 ppm nitric oxide (26 +/- 2 to 32 +/- 2 mm Hg, p < 0.05). Mean arterial pressure did not change with nitric oxide but decreased with nitroprusside. Seven of the 16 patients, including 1 patient who did not have an adequate decrease in pulmonary vascular resistance with nitroprusside but did with nitric oxide, have undergone successful heart transplantation. CONCLUSIONS Inhaled nitric oxide is a selective pulmonary vasodilator in patients with pulmonary hypertension due to left heart failure and may identify patients with reversible pulmonary vasoconstriction in whom agents such as nitroprusside cause systemic hypotension. Inhaled nitric oxide causes an increase in left ventricular filling pressure by an unknown mechanism.