Targeted multiple biomarker approach in predicting cardiovascular events in patients with diabetes.

OBJECTIVE: We hypothesised that biomarkers representing different pathophysiological pathways of atherosclerosis namely growth differentiation factor 15 (GDF-15), N-terminal pro B-type natriuretic peptide (NT-proBNP) and high-sensitive troponin T (hs-TnT) could enhance cardiovascular risk prediction in patients with type 2 diabetes mellitus. METHODS: This is a prospective study in 746 patients with type 2 diabetes mellitus, who were followed up for 60 months. The primary endpoint was defined as unplanned hospitalisation for cardiovascular disease or death. The prognostic performance of the biomarkers of interest (GDF-15 in comparison with NT-proBNP and hs-TnT) was evaluated in univariate as well as in stepwise Cox regression models. HRs are presented per standard unit increase. RESULTS: The primary endpoint was registered in 171 patients (22.9%). In univariate Cox regression models, GDF-15 as well as hs-TnT provided significant prognostic information. Even after adjusting for established cardiovascular risk factors, GDF-15, hs-TnT and NT-proBNP remained strong independent predictors of the endpoint (logGDF-15: HR 1.37, p<0.01, CI 1.12 to 1.68; loghs-TnT: HR 1.43, p<0.01, CI 1.13 to 1.1.82; logNT-proBNP: HR 1.45, p<0.01, CI 1.26 to 1.66). The number of elevated markers showed a strong complementarity to predict future long-term risk. Adding hs-TnT and GDF-15 to a zero model already including NT-proBNP led to a net reclassification improvement (NRI) of 33.6% (CI 16.0% to 50.8%, NRI for patients with event: 11.1% CI -4.7% to 26.6%, for patients without event: 22.5% CI 13.6% to 30.5%). CONCLUSIONS: GDF-15 and hs-TnT are strong independent cardiovascular biomarkers augmenting the predictive value of NT-proBNP in patients with diabetes.

Association of nutritional risk index with metabolic biomarkers, appetite-regulatory hormones and inflammatory biomarkers and outcome in patients with chronic heart failure.

AIMS: We aimed to evaluate the association of the nutritional status by using the nutritional risk index (NRI) with metabolic and inflammatory biomarkers, and appetite-regulatory hormones in a cohort of stable patients with heart failure (HF), and to analyse its prognostic value. METHODS AND RESULTS: In this prospective observational cohort study, we included 137 stable chronic HF patients (median age, 60 years; median body mass index, 27 kg/m(2) ) with optimised medical treatment. Baseline NRI of < 113 (n = 45) was associated with a significant increase in the levels of ghrelin (p < 0.001), peptide YY (p = 0.007), pentraxin-3 (p = 0.001), tumour necrosis factor-alpha (p = 0.018), adiponectin (p < 0.0001) and the N-terminal prohormone of brain natriuretic peptide (NT-proBNP; p < 0.0001) compared with those in patients with NRI of ≥ 113. The NRI was found to be correlated with the homoeostasis model assessment of insulin resistance index (r = 0.444; p < 0.0001) and inversely correlated with the NT-proBNP level (r = -0.410; p < 0.0001). The overall mortality rate was 20%. A baseline NRI of < 113 was associated with a higher risk of all-cause mortality (log rank = 0.031). CONCLUSION: We propose that the NRI is a useful and easily applicable tool for the early identification of nutritional depletion in patients with chronic HF as it discriminates metabolic changes prior to the clinical manifestation of body wasting. Furthermore, poor nutritional status, represented as a low NRI, is associated with an increased incidence of death in such cases.

Dose matters! Optimisation of guideline adherence is associated with lower mortality in stable patients with chronic heart failure.

AIMS: Guidelines have been published for improving management of chronic heart failure (CHF). We examined the association between improved guideline adherence and risk for all-cause death in patients with stable systolic HF. METHODS: Data on ambulatory patients (2006-2010) with CHF and reduced ejection fraction (HF-REF) from the Austrian Heart Failure Registry (HIR Austria) were analysed. One-year clinical data and long-term follow-up data until all-cause death or data censoring were available for 1014 patients (age 65 [55-73], male 75%, NYHA class I 14%, NYHA II 56%, NYHA III/IV 30%). A guideline adherence indicator (GAI [0-100%]) was calculated for each patient at baseline and after 12 ± 3 months that considered indications and contraindications for ACE-I/ARB, beta blockers, and MRA. Patients were considered ΔGAI-positive if GAI improved to or remained at high levels (≥ 80%). ΔGAI50+ positivity was ascribed to patients achieving a dose of ≥ 50% of suggested target dose. RESULTS: Improvements in GAI and GAI50+ were associated with significant improvements in NYHA class and NT-proBNP (1728 [740-3636] to 970 [405-2348]) (p<0.001). Improvements in GAI50+, but not GAI, were independently predictive of lower mortality risk (HR 0.55 [95% CI 0.34-0.87; p=0.01]) after adjustment for a large variety of baseline parameters and hospitalisation for heart failure during follow-up. CONCLUSIONS: Improvement in guideline adherence with particular emphasis on dose escalation is associated with a decrease in long-term mortality in ambulatory HF-REF subjects surviving one year after registration.

Serum uric acid is related to cardiovascular events and correlates with N-terminal pro-B-type natriuretic peptide and albuminuria in patients with diabetes mellitus.

BACKGROUND: Hyperuricemia is a risk factor for cardiovascular events and renal insufficiency. It correlates to intima-media thickness and microalbuminuria. In this study we evaluated uric acid as an independent marker for cardiac events in patients with diabetes. METHODS: In a prospective observational study we recruited 494 patients with diabetes. Patients were then followed for 12.8 months (mean follow-up) and hospitalizations as a result of cardiac events (ischaemic heart disease, arrhythmias, heart failure) were recorded. RESULTS: The median duration of diabetes was 11 ± 10.35 years. Patients were in the mean 60 ± 13 years old and mean HbA(1c) was 62 ± 13 mmol/mol (7.8 ± 3.3%). At baseline, mean uric acid was 321.2 ± 101.1 µmol/l (range 101.1-743.5 µmol/l), median N-terminal pro-B-type natriuretic peptide was 92 ± 412 pg/ml and median urinary albumin to creatinine ratio was 8 ± 361 mg/g; Uric acid significantly correlated to N-terminal pro-B-type natriuretic peptide (r = 0.237, P < 0.001) and urinary albumin:creatinine ratio (r = 0.198, P < 0.001). In a Cox regression model, including age, estimated glomerular filtration rate, gender, systolic blood pressure, smoking and alcohol consumption, uric acid was the best predictor of cardiac events (hazard ratio 1.331, confidence interval 1.095-1.616, P = 0.04). However, uric acid lost its prognostic value when the natural logarithm of N-terminal pro-B-type natriuretic peptide was added to the model. CONCLUSION: Serum uric acid is a predictor of cardiac events and correlates to N-terminal pro-B-type natriuretic peptide and albuminuria, underscoring the importance of uric acid as a cardiovascular risk marker in patients with diabetes.

Macrophage-modulating cytokines predict adverse outcome in heart failure.

Cytokines regulating the mobilisation, recruitment and survival of mononuclear cells may play an important role in progression of heart failure. Therefore, we investigated the role of granulocyte colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1) and macrophage colony stimulating factor (M-CSF) in patients with advanced heart failure. G-CSF, MCP-1 and M-CSF were determined in plasma of 351 patients with advanced heart failure by specific ELISAs. During a median follow up period of 16 months (95% confidence interval [CI]: 15-17 months) 175 patients (50%) experienced the composite endpoint rehospitalisation and all-cause mortality. M-CSF tertiles were associated with a gradually increasing risk with hazard ratios (HR) of 2.2 (95% CI: 1.5-3.2; for trend, p<0.001) for the composite endpoint and 2.6 (95% CI: 1.5-4.6; for trend, p=0.002) for all-cause mortality comparing third and first tertile. These associations remained significant in a multivariable Cox regression model after adjustment for BNP and other known risk factors (p=0.043 and p=0.024). High MCP-1 concentrations were associated with an increased risk of all-cause mortality with an adjusted HR of 1.9 (third vs. first tertile, 95% CI: 1.1-3.3; for trend, p=0.034). In contrast, G-CSF tertiles were not significantly associated with the composite endpoint or all-cause mortality in multivariable Cox regression. In conclusion, the independent and concentration-dependent association of macrophage-modulating cytokines and in particular of M-CSF with adverse outcome in advanced HF patients suggests that these cytokines may play an important pathophysiological role in progression of cardiomyopathy.

Outcome after device implantation in chronic heart failure is dependent on concomitant medical treatment.

BACKGROUND: Device implantation in chronic heart failure (CHF) for cardiac resynchronization therapy (CRT) with or without implantable cardioverter/defibrillator (ICD) is an established treatment option for symptomatic patients under medical baseline therapy. Although recommended, the need for optimization of medical therapy was never proven. As in 'the real world', medical therapy is not always up-titrated to the desirable dosages; this provides the opportunity to evaluate the impact of optimizing medical therapy in patients who had received a device therapy with proven effectiveness. MATERIALS AND METHODS: This observational cohort study retrospectively assessed the 'real life'-effect of CRT compared with that of CRT/ICD therapy and the impact of concomitant pharmacotherapy on outcome. Outcome of patients with guideline recommended renin-angiotensin system inhibitor and ss-blocker dosages was compared with that of patients who failed to reach the desired dosages. Mean follow-up for the 205 CHF (95 CRT and 110 CRT/ICD) patients was 16.8 + or - 12.4 months. RESULTS: In the total study cohort, 83 (41%) reached the combined primary endpoint of all-cause death or cardiac hospitalization [CRT group: 25 (26%), CRT/ICD group: 58 (52.7%), P < 0.001]. Multiple cox regression analysis revealed non-optimized medical therapy at follow-up [HR = 2.080 (1.166-3.710), P = 0.013] and CRT/ICD vs. CRT [HR = 2.504 (1.550-4.045), P < 0.001] as significant predictors of the primary endpoint. CONCLUSION: Our data stress the importance of professional monitoring and titration of pharmacotherapy not only in medically treated CHF patients but also in patients under device therapy by a heart failure unit or a specialized cardiologist.

Interactions of glucose metabolism and chronic heart failure.

BACKGROUND: We evaluated insulin sensitivity and beta cell function in patients with chronic heart failure (CHF), and investigated a possible correlation of these metabolic parameters with specific biomarkers of heart failure. Additionally, we investigated the effects of two angiotensin receptor blockers (ARBs), namely telmisartan and candesartan, that were administered over a 5 month treatment period, as additional therapy to standard care. METHODS AND RESULTS: The study group consisted of 94 CHF patients. Insulin sensitivity (OGIS index) and insulin secretion parameters were investigated by frequently sampled oral glucose tolerance tests and consecutive mathematical modelling. In total, 94.6 % of patients had clinically overt diabetes, impaired glucose tolerance or insulin resistance at the time of enrolment HbA1c was found to correlate to NT-proBNP, MR-proADM, CT-proET-1, and MR-proANP, but not to Copeptin. NT-proBNP correlated inversely to OGIS. None of the metabolic parameters were altered significantly after candesartan or telmisartan treatment in either the patient or standard care group. CONCLUSION: Insulin sensitivity and insulin secretion are impaired in CHF and biomarkers of heart failure and atherosclerotic disease correlate to glucose metabolism.

Echo Doppler parameters predict response to cardiac resynchronization therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) has been shown to reduce heart failure related morbidity and mortality. However, approximately 30% of patients do not respond to CRT. We investigated the usefulness of Echo Doppler parameters to predict reverse remodelling, functional improvement and mortality following CRT. MATERIALS AND METHODS: Our population consists of 200 consecutive heart failure patients evaluated for ventricular dyssynchrony by echocardiography between February 1999 and May 2007 who subsequently received CRT. Patients were reassessed for signs of reverse remodelling after a mean follow-up of 10 months. Information on vital status was obtained from local registration authorities. RESULTS: Three parameters significantly predicted reverse remodelling in the logistic regression analysis: the Q-to-E-wave-delay (QED) at a cutoff of 550 ms (odds ratio 4.5, P-value 0.001), the interventricular mechanical delay (IVMD) at a cutoff of 60 ms (odds ratio 2.4, P-value 0.02), and the aortic electromechanical delay (A-EMD) at a cutoff of 140 ms (odds ratio 2.9, P-value 0.004). Furthermore, the QED and the IVMD also predicted all-cause mortality (hazard ratio 0.36, P-value 0.02 and 0.21, P-value 0.004, respectively). Adjustment for confounders did not alter the results. CONCLUSIONS: The QED and IVMD predict reverse remodelling and survival following CRT. These parameters are easy to obtain, provide valuable prognostic information, and should thus be measured in CRT candidates evaluated by echocardiography.

Copeptin, a fragment of the vasopressin precursor, as a novel predictor of outcome in heart failure.

BACKGROUND: Natriuretic peptides, particularly brain natriuretic peptide (BNP), are elevated in heart failure and therefore considered to be excellent predictors of outcome. Vasopressin is also known to be related to the severity of heart disease. Copeptin--an inactive fragment of the vasopressin precursor--has not been previously investigated in the context of heart failure. MATERIALS AND METHODS: We prospectively studied 268 patients with advanced heart failure after they had been discharged from the hospital. We investigated the ability of BNP and copeptin to predict death, re-hospitalization due to heart failure, and a combination of the two endpoints. RESULTS: Over a mean follow-up period of 15.8 months (up to 24 months), 83 patients died, 122 patients experienced worsening of heart failure, and 145 patients achieved the combined endpoint. Univariate predictors of death were copeptin, BNP, age and impaired kidney function. In multivariate analysis, copeptin (chi(2) = 16, P < 0.0001) and age (chi(2) = 4, P < 0.05) were independent predictors. Univariate predictors of re-hospitalization due to heart failure were copeptin, BNP, age and impaired kidney function. Furthermore, in multivariate analysis BNP (chi(2) = 18, P < 0.0001), age (chi(2) = 11.8, P < 0.001) and copeptin (chi(2) = 4.2, P < 0.05) were found to be independent predictors. CONCLUSION: Our study is the first to show that copeptin is an excellent predictor of outcome in advanced heart failure patients. Its value is superior to that of BNP in predicting death and a combined endpoint, although BNP is still suitable for predicting chronic heart failure (CHF) re-hospitalization. Our data imply that vasopressin antagonism might be a new target to improve outcome in this population.

Non-invasive beat-to-beat cardiac output monitoring by an improved method of transthoracic bioimpedance measurement.

The report describes a method of impedance cardiography using an improved estimate of thoracic volume. The formulas and their implementation in hardware and software are explained and new shortband electrodes are described which generate a good homogeneous thoracic field. Examples of stroke volume and cardiac output curves underline the capabilities of the monitoring system "Task Force Monitor". In several experiments, results are compared to thermodilution as well as to BioZ measurements: the new method excels in comparison with thermodilution and is comparable to the BioZ device. Compared to traditional electrodes, the new shortband electrodes are shown to provide better reproducibility.

Neurohormonal risk stratification for sudden death and death owing to progressive heart failure in chronic heart failure.

BACKGROUND: This study tested various neurohormones for prediction of heart failure death (death owing to progressive deterioration of ventricular function; HFD). Moreover, B-type natriuretic peptide (BNP) as a predictor of sudden death (SD; as reported previously) and the best predictor of HFD were combined for a simple risk stratification model. DESIGN: BNP, the N-terminal fragment of BNP (N-BNP), and of the atrial natriuretic peptide (N-ANP) and big endothelin levels were obtained from 452 patients with a left ventricular ejection fraction 130 pg mL(-1) and N-ANP < 6300 fmol mL(-1) (Group B, n = 177; 18%; P = 0.0001) and patients with BNP > 130 pg mL(-1) and N-ANP > 6300 fmol mL(-1) (Group C, n = 50; 19%; P = 0.0001). Analyzing 293 survivors and 31 patients with HFD, fewer patients died in Group A (n = 109; 0%; P = 0.0001) and Group B (n = 153; 6%; P = 0.0001) as compared with patients of Group C (n = 62; 34%). CONCLUSION: Prognostic power of neurohormones depends on the mode of death. The combined determination of BNP and N-ANP identifies patients with minimal risk of death, elevated SD but low HFD risk as well as elevated SD and HFD risk.

Natriuretic peptides and the prevalence of congestive heart failure in patients with pacemakers.

AIM: The aim of the study was to investigate the diagnostic potential of natriuretic cardiac peptide measurement in the context of left ventricular dysfunction and comorbidities in a pacemaker population. MATERIAL AND METHODS: Ninety-five consecutive patients with pacemakers were included in the study. All patients underwent echocardiography and were asked to complete the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Brain natriuretic peptide (BNP), N-terminal proatrial natriuretic peptide (N-ANP) and atrial natriuretic peptide levels in plasma were measured. RESULTS: Twenty-six percent of patients had reduced systolic left ventricular function; only 16 patients had a history of congestive heart failure. BNP was abnormally elevated in 64%, N-BNP in 72% and N-ANP in 96% of patients. Both BNP (r = 0.30; P < 0.01) and N-ANP (r = 0.39; P < 0.0005) correlated with MLHFQ. The strongest correlation was found between N-ANP and the ejection fraction (r = 0.6; P < 0.0001). Patients were stratified in a high-risk group and a low risk-group according to their N-ANP (N-ANP > 5000 fmol L(-1); n = 63 and N-ANP < 5000 fmol L(-1), n = 32) and BNP levels (BNP > 400 pg mL(-1); n = 17 and BNP < 400 pg mL(-1), n = 78). N-ANP was correlated with hypertension (P < 0.003) and atrial fibrillation (P < 0.03), and BNP with mitral insufficiency (P < 0.002). CONCLUSIONS: Cardiac natriuretic peptides are markedly elevated in the majority of patients with pacemakers. The prognostic significance of BNP and N-ANP in left ventricular dysfunction warrants close follow-up schedules.

Prediction of outcome by neurohumoral activation, the six-minute walk test and the Minnesota Living with Heart Failure Questionnaire in an outpatient cohort with congestive heart failure.

AIMS: To compare the precursor of atrial and brain natriuretic peptide (N-ANP, N-BNP), brain natriuretic peptide (BNP), big endothelin-1, the 6-min walk test and the Minnesota Living with Heart Failure Questionnaire (LHFQ) with regard to short-term outcome in an ambulatory heart failure population. METHODS AND RESULTS: Ninety-six individuals (left ventricular ejection fraction of 26+/-10%) were included in the study. Within 1 day blood samples of N-ANP, N-BNP, BNP and big endothelin-1 were obtained, and the 6-min walk test and LHFQ were measured. The predictive power of these variables - including renin-angiotensin system antagonist therapy - in respect of 1-year event-free survival were calculated with a Cox regression analysis. All investigated variables had the power to predict outcome in a univariate analysis. Multivariate analysis revealed that N-ANP (chi-square=58 P<0.0001), BNP (chi-square=8 P<0.01), the LHFQ (chi-square=6 P<0.02) and the renin-angiotensin system antagonist (chi-square=4 P<0.05), are independent predictors. CONCLUSION: We conclude that, in an open clinical cohort of patients with large differences in the progression of the disease, N-ANP, BNP and LHFQ are the most reliable predictors of worsening heart failure in the short term. However, the dosage of the ACE inhibitor influenced short-term survival in this population.

Long-term effect of atenolol on ejection fraction, symptoms, and exercise variables in patients with advanced left ventricular dysfunction.

AIMS: We recently reported a beneficial clinical effect of atenolol, a beta(1) selective adrenergic antagonist, in 100 ambulatory heart failure patients with low left ventricular ejection fraction (LVEF,

Survival benefit of the implantable cardioverter-defibrillator in patients on the waiting list for cardiac transplantation.

BACKGROUND: The implantable cardioverter-defibrillator (ICD) effectively reduces sudden cardiac death in patients with severe LV dysfunction. Effect of ICD therapy on total mortality in patients on the waiting list for cardiac transplantation is still uncertain. METHODS AND RESULTS: We retrospectively analyzed 854 unselected consecutive patients (ICD therapy, n=102; 11.9%) on the waiting list for cardiac transplantation between January 1992 and March 2000. Actuarial 12-month total mortality rate on the waiting list was 24.2%; sudden cardiac death was the predominant mode of death (66.7% of total deaths). Kaplan-Meier analysis revealed improved survival for ICD (total mortality, 13.2%) compared with non-ICD (total mortality, 25.8%) patients (log rank, P=0.03). No event of sudden death occurred in ICD patients, whereas in non-ICD patients, 12-month sudden death rate was 20.1% (P=0.0001). Nonsudden death rates did not differ between ICD and non-ICD patients (P=0.16). A Cox proportional hazards model demonstrated that absence of an ICD was a powerful independent predictor of total mortality (P=0.02; relative risk, 2.22; 95% confidence interval, 1.16 to 4.17) and sudden cardiac death (P<0.0001; infinite relative risk) on the waiting list. CONCLUSIONS: ICD therapy, because it prevents sudden cardiac death, significantly improves survival on the waiting list for cardiac transplantation. The present study supports the use of ICDs as a bridge to transplantation in patients who are at risk of sudden cardiac death. Prospective randomized trials are needed to evaluate the potential benefit of prophylactic ICD therapy as a bridge to transplantation in all patients on cardiac transplant waiting lists.

Prognostic evaluation of neurohumoral plasma levels before and during beta-blocker therapy in advanced left ventricular dysfunction.

OBJECTIVES: The study assessed the relative predictive potency of neurohumoral factors in patients with advanced left ventricular (LV) dysfunction during neurohumoral blocking therapy. BACKGROUND: The course of heart failure is characterized by progressive LV deterioration associated with an increase in cardiac (natriuretic peptides) and predominantly extracardiac (norepinephrine, big endothelin [big ET]) hormone plasma levels. METHODS: Plasma hormones were measured at baseline and months 3, 6, 12 and 24 in 91 patients with heart failure (left ventricular ejection fraction [LVEF] <25%) receiving 40 mg enalapril/day and double-blind atenolol (50 to 100 mg/day) or placebo. After the double-blind study phase, patients were followed up to four years. Stepwise multivariate regression analyses were performed with 10 variables (age, etiology, LVEF, symptom class, atenolol/placebo, norepinephrine, big ET, log aminoterminal atrial natriuretic peptide, log aminoterminal B-type natriuretic peptide [N-BNP] and log B-type natriuretic peptide [BNP]). During the study, the last values prior to patient death were used, and in survivors the last hormone level, New York Heart Association class and LVEF at month 24 were used. RESULTS: Thirty-one patients died from a cardiovascular cause during follow-up. At baseline, log BNP plasma level (x2 = 13.9, p = 0.0002), treatment allocation (x2 = 9.5, p = 0.002) and LVEF (x2 = 5.6, p = 0.017) were independently related to mortality. During the study, log BNP plasma level (x2 = 21.3, p = 0.0001) remained the strongest predictive marker, with LVEF (x2 = 11.2, p = 0.0008) log N-BNP plasma level (x2 = 8.9, p = 0.0027) and treatment allocation (x2 = 6.4, p = 0.0109) providing additional independent information. CONCLUSIONS: In patients with advanced LV dysfunction receiving high-dose angiotensin-converting enzyme inhibitors and beta-blocker therapy BNP and N-BNP plasma levels are both independently related to mortality. This observation highlights the importance of these hormones and implies that they will likely emerge as a very useful blood test for detection of the progression of heart failure, even in the face of neurohumoral blocking therapy.

Cross-cultural adaptation of the Minnesota Living with Heart Failure Questionnaire for German-speaking patients.

We performed a cross-cultural adaptation of the "Minnesota Living with Heart Failure Questionnaire" (LHFQ) for use in German-speaking chronic heart failure patients. The instrument was translated and back translated, pre-tested and reviewed by a committee. The German version was tested in 114 patients with chronic heart failure. Reliability was assessed by a test-retest procedure and Cronbach's coefficient alpha of internal consistency (0.94). To assess concurrent validity, we compared the LHFQ sum scores with the New York Heart Association classification rating (r = 0.53; p < 0.0001), the 6-minute walk (r = -0.39; p < 0.0001), the left ventricular ejection fraction (r = -0.24; p = 0.011) and big-endothelin (r = 0.27; p = 0.004). Construct validity on the LHFQ scores in comparison with the Medical Outcomes Study SF-36 Health Survey (MOS SF-36) was significant (-0.41 to -0.74; all p < 0.0001). The reliability and validity of the German version of the LHFQ was proved; the questionnaire can be recommended for use in future clinical trials.

Angiogenesis stimulation in explanted hearts from patients pre-treated with intravenous prostaglandin E(1).

BACKGROUND: Prostaglandin E(1) (PGE(1)) is a potent vasodilator and induces angiogenesis in animal tissues. Previous clinical studies demonstrated that PGE(1) improves hemodynamic parameters in patients with heart failure listed for heart transplantation (HTX). Therefore, we designed a retrospective immunohistochemistry study to investigate various markers of angiogenesis using hearts explanted from PGE(1)-treated patients with idiopathic dilated cardiomyopathy (IDCM). METHODS AND RESULTS: We investigated neovascularization in 18 hearts explanted from patients with IDCM: 9 patients received treatment with chronic infusions of PGE(1) for end-stage heart failure before HTX, whereas the remaining patients with IDCM did not receive PGE(1) and served as controls. We used immunoreactivity against CD34, von Willebrand factor (vWf), vascular endothelial growth factor (VEGF), and MIB-1 (Ki-67) to quantify angiogenesis, and used sirius red staining to determine the degree of fibrosis. Compared with the control group, PGE(1)-treated patients had significantly more CD34-, vWf- and MIB-1-positive cells in the sub-endocardium, myocardium and sub-epicardium (p < 0.01). The degree of fibrosis in the hearts of PGE(1)-treated patients was significantly lower than in control patients (p < 0.05), but we did not see any difference in the percentage of muscle mass. Finally, throughout the ventricles, we found significantly more VEGF-positive capillaries in the PGE(1) group (p < 0.0001). CONCLUSIONS: The data suggest that PGE(1) could be a potent inducer of angiogenesis and the angiogenic factor VEGF, and could cause reduced fibrosis in the failing human heart.

Pathogenesis of heart failure.

Heart failure is a complex clinical syndrome, and only part of this syndrome is based on the mechanical failure of the heart muscle itself to provide sufficient systemic perfusion. Heart failure is accompanied by the activation of various immunologic and neurohumoral mechanisms. These may be intended by nature to be physiologically beneficial, but eventually become deleterious as they provoke ischemic, proarrhythmic, vascular, and structural changes in the myocardium that contribute to the versatile symptoms of the heart failure syndrome. Today's concept of the pathogenesis of heart failure regards heart failure as a dynamic state influenced by at least 2 major mechanisms, namely "neurohumoral" activation and ventricular remodeling. Progressive chronic heart failure can be viewed as a result of the prolonged impact of both pathogenetic mechanisms. This article will describe briefly the features of the neurohumoral forces on the pathogenesis of heart failure, including immunologic forces, which also influence the remodeling process.