Development Of Heart Failure In Patients Research Articles

Abstract 4328: Integrated Network and Microarray Analysis to Identify New Biomarkers of Heart Failure after Myocardial Infarction

Purpose : A significant proportion of acute myocardial infarction (MI) patients develop heart failure (HF). Early identification of patients at risk of developing HF after MI would be a major breakthrough. An approach combining the power of biological information networks and the precision of microarray analysis was undertaken to identify new biomarkers of HF. Methods : Since angiogenesis may be related to MI and HF, a protein-protein interaction (PPI) network was constructed by first extracting from the Entrez-Gene database a set of genes relevant to angiogenesis and MI. These genes were used as inputs to retrieve annotated interactions from the Human Protein Reference Database. Potential biomarkers were identified by network analysis. Gene expression profiles of blood cells taken at the time of MI in two groups of 16 patients (high ejection fraction (EF) at 1 month, EF≥45% and low EF at 1 month, EF≤40%) were obtained using oligonucleotide microarrays containing 25,000 genes and compared by Statistical Analysis of Microarrays (SAM). Prediction models based on machine learning were used to classify low and high EF patients. Results : SAM identified 525 genes differentially expressed between patients with high and low EF (fold-change ≥1.3). The PPI network included 556 nodes (proteins) and 686 edges (interactions). A network clustering algorithm identified 53 proteins highly specialized in growth and regulation processes. Out of these, 38 were found differentially expressed by SAM. Further filtering reported 3 genes as the optimal biomarker set: Vascular Endothelial Growth Factor B (VEGFB), Placental Growth Factor (PGF), both pro-angiogenic, and the anti-angiogenic protein Thrombospondin-1 (THBS1). Prediction models reported areas under the receiver operating characteristic curve (AUC) of 0.82 for this biomarker set. Conclusion : The classification performances achieved with the 3 biomarkers stresses the prognostic value of genes involved in angiogenesis. The network-based approach allowed us to identify powerful biomarkers, which could not be identified by applying standard gene expression data analysis only. Therefore, combined network and microarray analysis allows a systematic and less biased approach to biomarker discovery.

Circulating Osteoprotegerin Levels and Long-Term Prognosis in Patients With Acute Coronary Syndromes

This study was designed to assess the association between osteoprotegerin (OPG) levels on admission and long-term prognosis in patients with acute coronary syndromes (ACS). Osteoprotegerin, a member of the tumor necrosis factor receptor superfamily, has pleiotropic effects on bone metabolism, endocrine function, and the immune system. Serum samples for OPG analysis were obtained within 24 h of admission in 897 ACS patients (median age 66 years, 71% men) and related to the incidence of death, heart failure (HF) hospitalizations, myocardial infarction (MI), and stroke. A total of 261 patients died during a median follow-up of 89 months. The baseline OPG concentration was strongly associated with increased long-term mortality (hazard ratio [HR] for HR per 1 SD increase in logarithmically transformed OPG level 1.7 [range 1.5 to 1.9] p < 0.0001) and HF hospitalizations (HR 2.0 [range 1.6 to 2.5]; p < 0.0001) but weaker with recurrent MI (HR 1.3 [range 1.0 to 1.5]; p = 0.02) and not with stroke (HR 1.2 [range 0.9 to 1.6]; p = 0.35). After adjustment for conventional risk markers, including troponin I, C-reactive protein (CRP), B-type natriuretic peptide (BNP), and ejection fraction, the association remained significant for mortality (HR 1.4 [range 1.2 to 1.7]; p < 0.0001) and HF hospitalization (HR 1.6 [range 1.2 to 2.1]; p = 0.0002), but not recurrent MI. By comparison of the area under the receiver-operating characteristics curves, OPG performed similarly to BNP and ejection fraction and significantly better than CRP and troponin I as a predictor of death. Serum OPG is strongly predictive of long-term mortality and HF development in patients with ACS, independent of conventional risk markers.

Acute and chronic effects of cardiac resynchronization in patients developing heart failure with long-term pacemaker therapy for acquired complete atrioventricular block

We assessed the effects of cardiac re-synchronization therapy (CRT) in patients who developed otherwise unexplained heart failure (HF) during right ventricular apical (RVA)-pacing for acquired complete atrioventricular block (CAVB). Eighteen consecutive CAVB patients with HF during RVA-pacing were assessed with haemodynamic studies immediately and 12 months after CRT-upgrade. Ten patients had idiopathic CAVB and 13 showed normal left ventricular (LV) function at RVA-pacemaker implantation. HF developed after 81 +/- 10 months. RVA-pacing duration correlated (r = 0.49, P < 0.05) with LV ejection fraction (LVEF) deterioration. Biventricular- (BiV) and LV-pacing acutely improved the systolic function comparably, but only BiV improved diastolic function. One-year post-CRT-initiation, New York Heart Association classification improved 35 +/- 3% (P < 0.05) and the number of hospitalizations decreased 85 +/- 3% (P < 0.0001). CRT decreased LV end-diastolic diameter (LVEDd) 7 +/- 2% (P < 0.01) and increased LVEF by 23 +/- 7% (P < 0.01). The CRT-induced reduction in LVEDd tended to be greater in patients with RVA-pacing for < 5 years vs. > 5 years (7.7 +/- 2.5 vs. 3.6 +/- 1.0 mm, P = 0.08). CRT-upgrade improves the cardiac function and symptoms in CAVB patients with HF progression related to RVA-pacing. Because adverse LV-remodelling may be partly irreversible, consideration should be given to BiV- and LV-pacing upgrade as soon as possible after the indications appear, and prospective studies of the optimal timing of CRT-upgrade may be useful.

552 Right ventricular involvement and its prognostic value for heart failure development in patients with isolated extreme obesity

552 Right ventricular involvement and its prognostic value for heart failure development in patients with isolated extreme obesity

Update in Adult Congenital Cardiac Surgery

The number of grown-up patients with congenital heart disease (GUCH) is constantly increasing and will equal the number of children requiring surgery for congenital heart disease (CHD). Specialized centers dealing with the medical and paramedical problems of these patients are required. GUCH patients can be divided into the following groups: (1) patients with minor cardiac malformations presenting at adult age for first treatment; (2) patients presenting for correction as adults because they are either naturally balanced or were surgically palliated; (3) patients presenting for expected reoperations after correction in childhood; (4) patients requiring repair of residual defects after correction; (5) patients developing heart failure after correction or palliation of CHD requiring thoracic transplantation; and (6) patients developing acquired heart disease in addition to CHD. Special aspects of malformations frequently occurring in GUCH patients are discussed in detail. Acquired heart disease in this patient population is expected to increase in the coming decades as survivors of CHD grow old.

493: Re-transplantation for heart failure with preserved systolic function

Purpose: Re-transplantation has been considered for heart transplant patients with severe systolic dysfunction mainly due to underlying cardiac allograft vasculopathy (CAV) or severe rejection. However, some patients develop heart failure symptoms (shortness of breath, low cardiac output, fatigue, etc.) with preserved systolic function (defined as left ventricular ejection fraction (LVEF) >/= 40%). Similar to restrictive cardiomyopathic patients, these patients have symptoms refractory to medical therapy, which severely reduces their quality of life, necessitating re-transplantation.

Lack of association of tumor necrosis factor-α polymorphisms with Chagas disease in Brazilian patients

One third of Trypanosoma cruzi-infected individuals develop chronic Chagas disease cardiomyopathy (CCC) while the majority remains asymptomatic (ASY). About 30% of CCC patients develop heart failure due to end-stage inflammatory dilated cardiomyopathy. Increased production of tumor necrosis factor (TNF)-α has been described in all clinical forms of Chagas disease, and the highest levels are detected in CCC patients with severe ventricular dysfunction. Genetic susceptibility may play a role in the clinical outcome of Chagas disease. We investigated TNF as a candidate gene for susceptibility to development and/or progression of CCC. We analyzed the TNFa microsatellite and the −308 TNF promoter polymorphisms, in 166 CCC compared to 80 ASY geographically and age-matched patients in an association study. To analyze the association of TNF polymorphisms with progression of the cardiomyopathy, CCC patients were also grouped in three categories according to degree of left ventricular (LV) dysfunction into severe ( n = 57), mild to moderate ( n = 21) and absent ( n = 88). Our results show no significant differences either between CCC and ASY patients, or among CCC patients according to severity of cardiomyopathy with respect to TNFa or −308 TNF promoter polymorphisms. These results indicate that TNF polymorphisms are associated neither to CCC development nor to progression to more severe forms of cardiomyopathy in Brazilian Chagas disease patients.

TNF gene polymorphisms are associated with reduced survival in severe Chagas' disease cardiomyopathy patients

Chronic Chagas' disease cardiomyopathy (CCC) is the most important clinical outcome of infection by the parasite Trypanosoma cruzi, affecting 18 million individuals in Latin America. One-third of CCC patients develop heart failure due to end-stage dilated cardiomyopathy, and their survival is reduced by 50% compared to patients with other cardiomyopathies. Genetic susceptibility may play a role in the differential survival of severe CCC patients. Given the role of TNF-α in the progression of heart failure, and the increased TNF-α plasma and heart tissue levels observed in these patients, we chose TNF as a candidate gene for increased mortality in severe CCC patients. We typed the TNFa microsatellite and the −308 TNF promoter polymorphism and then analyzed the survival curves of 42 patients with severe ventricular dysfunction (left ventricular ejection fraction ≤ 40%) according to the presence of the TNF2 promoter allele or the TNFa2 microsatellite allele, both previously associated with high TNF-α production. Multivariate regression analysis (Cox proportional hazards model) revealed the TNF genotype and age of onset of severe CCC as independent predictors of mortality in severe CCC. We showed that patients positive for TNF2 or TNFa2 alleles display a significantly shorter survival time compared to those carrying other alleles; the median survival times were 2.9 and 8 months, respectively (HR adj = 2.28, p = 0.020). We have identified for the first time a genetic factor related to reduced survival in severe Chagas' disease cardiomyopathy. The association of TNF genotype with earlier death in CCC should be taken into account when planning therapeutic intervention.

Myocardial T2* in Patients with Cardiac Failure Secondary to Iron Overload.

Introduction: Myocardial iron overload is a well established cause of heart failure in a number of haematological disorders and is the leading cause of death in β-thalassaemia major (TM). Once overt heart failure develops prognosis is very poor and it would therefore be desirable to identify patients at risk, prior to the development of symptomatic heart failure. Myocardial iron can now be rapidly and reproducibly assessed using a validated cardiac magnetic resonance (CMR) T2* technique. Left ventricular ejection fraction has been demonstrated to relate to myocardial T2* (normal >20ms), and accordingly iron overloaded patients with symptomatic heart failure are likely to have a low T2* but there are no reports of the myocardial T2* level in newly presenting patients with heart failure and the threshold for increased risk is also unknown.Purpose: To establish the distribution of myocardial T2* values in patients presenting with symptomatic heart failure secondary to iron overload.Methods: Database records of CMR T2* assessments over a 5 year period were reviewed to identify iron overloaded patients presenting with heart failure.Results: 28 patients (median age 29y, 11–79) with iron overload and documented heart failure were identified. 22 patients had thalassaemia major, 3 hereditary haemochromatosis, and 3 had miscellaneous transfusion dependent anaemias. The mean myocardial T2* in all groups was 6.8+/− 2.2ms reflecting severe iron loading by clinical criteria. See figure 1. Myocardial T2* values were similar between sub-groups as follows: TM patients 6.7+/− 2.4ms, haemochromatosis 7.7ms (6.7–7.4ms), miscellaneous 6.8ms (4.8–9.1ms).Conclusion: In this database review, the patients developing heart failure secondary to iron overload all had abnormal myocardial T2*, and overall 89% of heart failure patients had values less than 10ms, which reflects severe myocardial iron loading. This data suggests a myocardial T2* <10ms should be considered a threshold for risk of heart failure (with its attendant high mortality) and such patients should be treated aggressively with increased iron chelation. It also suggests that clinical heart failure occurs nearly exclusively in patients with severe myocardial iron loading. [Display omitted]

Functional Capacity Impairment in Patients with Coronary Artery Disease: Prevalence, Risk Factors and Prognosis

Background: Some patients developing heart failure and functional capacity impairment have no history of myocardial infarction (MI), and stable angina pectoris is their principal clinical manifestation of coronary artery disease (CAD). The present study was aimed to evaluate the outcome of CAD-related functional capacity impairment in patients with and without a history of MI over a 7.7-year follow-up. Methods: The study sample comprised 14,283 coronary patients aged 45–74 years, screened for participation in the Bezafibrate Infarction Prevention study. The presence of NYHA functional class II was defined as mild functional capacity impairment and the presence of NYHA functional class III–IV was defined as advanced functional capacity impairment. Results: The patients were divided in two groups: (1) those with a history of MI, 10,307 patients, who formed three subgroups: NYHA I 7,551 patients (73.3%); NYHA II 2,176 patients (21.1%); NYHA III + IV 580 patients (5.6%), and (2) those without a history of MI, 3,976 patients, who also formed three subgroups: NYHA I 2,744 patients (69.0%); NYHA 981 patients (24.7%); NYHA III + IV 251 patients (6.3%). Multivariate analysis identified a history of MI as a consistent predictor of increased all-cause and cardiac mortality for patients with NYHA I, II and III + IV subgroups with escalating significance for patients with advanced functional capacity impairment: hazard ratios of 1.55 (95% CI 1.36–1.75), 1.56 (95% CI 1.30–1.86) and 1.72 (95% CI 1.24–2.40) for all-cause and 1.93 (95% CI 1.60–2.33), 1.73 (95% 1.35–2.20) and 3.22 (95% CI 1.87–5.54) for cardiac mortality, respectively. Conclusions: The prevalence of low functional capacity is similar among coronary patients with and without a history of MI, but their long-term survival differs substantially in favor of the latter. Therefore, two different types of CAD-related advanced functional capacity impairments (post-MI and non-post-MI) can be distinguished.

Prevention and management of chronic heart failure in patients at risk

The prevalence and incidence of chronic heart failure (HF) have now reached epidemic proportions. However, the issue of the prevention of HF has been raised only recently. New US guidelines have introduced a new classification system that includes 4 categories: patients at risk, patients with asymptomatic left ventricular dysfunction, patients with symptomatic HF, and those with refractory HF. Because coronary artery disease is the major cause of HF, its risk factors are also those of HF. Hypertension favors the development of HF through accelerated atherosclerosis and increased left ventricular wall stress and hypertrophy. Left ventricular hypertrophy is also a powerful risk factor for HF, independent of blood pressure. Angiotensin-converting enzyme (ACE) inhibitors, β-blockers, and diuretics are the antihypertensive agents that have been associated with favorable effects in patients with overt HF. Therefore, they may be preferred in the prevention of this syndrome. Diabetes is the most frequent noncardiac comorbidity of HF and is independently associated with an increased risk. Normalization of glycemic and glycosylated hemoglobin levels is a desirable goal of treatment. However, no direct evidence exists in the prevention of HF. A greater control of the other risk factors (eg, hypertension, hyperlipidemia) is, on the other hand, particularly important. β-Blockers and ACE inhibitors have both been shown to have favorable effects across all spectrums of severity of HF. The ACE inhibitor ramipril has also been shown to prevent the development of HF in patients at risk without left ventricular dysfunction. The role of antiplatelet agents, warfarin, and statins is clear in the prevention of the coronary artery disease. However, it has not been adequately assessed in patients with HF and awaits the results of ongoing trials.

Right ventricular dysfunction and risk of heart failure and mortality after myocardial infarction

ObjectivesThe aim of this study was to determine the prognostic value of right ventricular (RV) function in patients after a myocardial infarction (MI). BackgroundRight ventricular function has been shown to predict exercise capacity, autonomic imbalance and survival in patients with advanced heart failure (HF). MethodsTwo-dimensional echocardiograms were obtained in 416 patients with left ventricular (LV) dysfunction (ejection fraction [LVEF] ≤40%) from the Survival And Ventricular Enlargement (SAVE) echocardiographic substudy (mean 11.1 ± 3.2 days post infarction). Right ventricular function from the apical four-chamber view, assessed as the percent change in the cavity area from end diastole to end systole (fractional area change [FAC]), was related to clinical outcome. ResultsRight ventricular function correlated only weakly with the LVEF (r = 0.12, p = 0.013). On univariate analyses, the RV FAC was a predictor of mortality, cardiovascular mortality and HF (p < 0.0001 for all) but not recurrent MI. After adjusting for age, gender, diabetes mellitus, hypertension, previous MI, LVEF, infarct size, cigarette smoking and treatment assignment, RV function remained an independent predictor of total mortality, cardiovascular mortality and HF. Each 5% decrease in the RV FAC was associated with a 16% increased odds of cardiovascular mortality (95% confidence interval 4.3% to 29.2%; p = 0.006). ConclusionsRight ventricular function is an independent predictor of death and the development of HF in patients with LV dysfunction after MI.

Prognosis after Myocardial Infarction

A group of 102 patients (66 males, age 62 +/- 11 years) surviving an acute myocardial infarction was followed for 6 to 48 months. Survival was analyzed by the method of Kaplan Meier and Cox analysis was used to identify prognostic factors. Thirteen patients died during follow up: 3 had sudden death, 3 a stroke, 3 died from heart failure, 3 had reinfarction and cardiogenic shock and 1 died from cholangitis. Most deaths occurred in the first few months of follow up. Survival was 92% at 6 months, 90% at 1 year, 88% at 2 years and 86% at 3 years after infarction. Single variable analysis disclosed a 2 to 3 fold late mortality risk associated to the presence of age over 60 years, old myocardial infarction, hypertension, diabetes mellitus and ventricular tachycardia or fibrillation during the acute phase. Greater than 3 fold risk was seen for patients developing heart failure or shock during myocardial infarction. Heart failure was the only statistically significant risk factor identified by multivariate analysis.

The effect of early converting enzyme inhibition on neurohumoral activation in acute myocardial infarction

The effect of early converting enzyme inhibition with enalapril on the extent of neurohumoral activation in acute myocardial infarction was evaluated in a randomized, placebo-controlled double blind fashion. Plasma levels of atrial natriuretic factor and noradrenaline on day 1, i.e. prior to randomization ( n = 99), and on days 3 ( n = 145) and 30 ( n = 69) following myocardial infarction were determined. Enalapril did not significantly affect neurohumoral activation on day 3 (enalapril vs. placebo (mean (S.E.M.); atrial natriuretic factor: 35.3 (3.0) vs. 37.2 (2.9) pmol/l; noradrenaline: 2.82 (0.20) vs. 3.70 (1.02) nmol/l) or at 1 month (atrial natriuretic factor: 33.1 (3.0) vs. 32.4 (3.9) pmol/l; noradrenaline; 2.77 (0.25) vs. 2.82 (0.28) nmol/l). However, in myocardial infarction patients developing heart failure, a significant attenuation of the day 3 atrial natriuretic factor, but not of the noradrenaline response, was seen (atrial natriuretic factor: 47.0 (7.7) vs. 59.0 (6.4) pmol/l, P < 0.05; noradrenaline: 3.37 (0.42) vs. 6.59 (3.26) nmol/l, P = ns). In conclusion, enalapril did not significantly reduce neurohumoral activation in acute myocardial infarction, possibly because the activation in most patients is modest and confined to the early convalescent phase. However, in patients with myocardial infarction and heart failure enalapril therapy was associated with a reduction in early plasma atrial natriuretic factor levels, compatible with decreased cardiac filling pressures.

Der Einfluß des neueren Phosphodiesterase-Inhibitors Enoximon bei Patienten mit einer akuten katecholaminrefraktären Herzinsuffizienz während Operationen am offenen Herzen

19 patients in whom cardiopulmonary bypass (cpb) was performed during different types of cardiac operations, developed myocardial failure which remained refractory to inotropic support with increasing doses of adrenaline, dopamine and dobutamine, so that it was impossible to discontinue cpb. After changing the therapeutic approach to a new regime consisting of adrenaline, dopamine and enoximone, low-output syndrome (LCOS) could be successfully reversed in 12 of the 19 patients. In the 7 remaining patients blood pressure dropped in a clinically relevant way under treatment with enoximone. 5 of these patients needed intraaortic balloon pumping (IABP) inspite of the application of enoximone, before cpb could be successfully discontinued. In three patients receiving enoximone, persisting ventricular tachyarrhythmia appeared under treatment, and disappeared after discontinuation of the drug. One patient needed IABP and left heart bypass by means of the centrifugal pump before cpb could be duly discontinued. One patient died intraoperatively due to untreatable right ventricular failure and inability to discontinue cpb. It is concluded that enoximone represents a useful drug in a significant number of patients developing heart failure refractory to inotropic support, on emerging from cpb during cardiac surgery.

Pericarditis and perimyocarditis associated with active Mycoplasma pneumoniae infection.

In 13 patients an association existed from 1970-73 between Mycoplasma pneumoniae infection and acute pericarditis (in eight) or perimyocarditis (in five). In 12 patients the association was moderately probable, with a fourfold rise in complement-fixing antibody titers between acute and convalescent phase sera being noted. In the last patient, a lesser-order association was found using only convalsecent phase serum. The presence of influenza, herpes simplex, Coxsackie B, or adenovirus was excluded by serologic testing. Acute illness was variable, with four patients developing heart failure. Long-term evaluation (mean, 47 months) found eight patients asymptomatic and three symptomatic. Two patients died. Residual effects of the Mycoplasma infection seemed at least partially responsible in one compromised patient and in one who died. Mycoplasma infection should be considered in the presence of acute cardiovascular decompensation, especially when preceded by upper respiratory infection, and added to the possible causes of idiopathic cardiomyopathy.

EXPERIMENTAL HEART FAILURE IN DOGS.

The mortality rate in patients developing heart failure and shock following a myocardial infarction is as high as 60% to 90%. Mechanical support of the heart by assisted circulation has been suggested as treatment in such cases. In order to compare the various techniques of assisted circulation, it is desirable to create experimental heart failure in animals. Ideally, the failure should be comparable to that developing clinically following a myocardial infarct. Previous studies have indicated that this is difficult to duplicate in experimental animals. 3-11 As early as 1862, Panum 12 produced myocardial damage by injecting crude suspensions of oil, tallow, and lamp black into the root of the aorta in dogs. Samuelson, 13 in 1881, produced a myocardial infarct by ligating the anterior descending branch of the left coronary artery. The same year Conheim and Von Schulthess-Rechberg 14 noted that such ligations rarely produced significant hemodynamic changes unless associated