The cardiokine secreted Frizzled-related protein 3, a modulator of Wnt signalling, in clinical and experimental heart failure.

OBJECTIVES: Experimental studies have shown involvement of Wnt signalling in heart failure (HF). We hypothesized that secreted frizzled-related protein 3 (sFRP3), a modulator of Wnt signalling, is related to the progression of HF. DESIGN: Circulating sFRP3 was measured in 153 HF patients and compared with 25 healthy controls. The association of sFRP3 with mortality was evaluated in 1202 patients (GISSI-HF trial). sFRP3 mRNA expression was assessed in failing human and murine left ventricles (LV), and cellular localization was determined after fractioning of myocardial tissue. In vitro studies were carried out in cardiac fibroblasts subjected to cyclic mechanical stretch. RESULTS: (i) Heart failure patients had significantly raised serum sFRP3 levels compared with controls, (ii) during a median follow-up of 47 months, 315 patients died in the GISSI-HF substudy. In univariable Cox regression, tertiles of baseline sFRP3 concentration were significantly associated with all-cause and cardiovascular mortality. After adjustment for demographic and clinical variables, but not for CRP and NT-proBNP, the associations with mortality remained significant for the third tertile (all-cause, HR 1.45, P = 0.011; cardiovascular, HR 1.66, P = 0.003), (iii) sFRP3 mRNA expression was increased in failing human LV, with a decline following LV assist device therapy. LV from post-MI mice showed an increased sFRP3 mRNA level, particularly in cardiac fibroblasts, and (iv) mechanical stretch enhanced sFRP3 expression and release in myocardial fibroblasts. CONCLUSION: There is an association between increased sFRP3 expression and adverse outcome in HF, suggesting that the failing myocardium itself contributes to an increase in circulating sFRP3.

Effects on survival of loop diuretic dosing in ambulatory patients with chronic heart failure using a propensity score analysis.

OBJECTIVE: To ascertain whether increasing doses of orally administered furosemide are associated with impaired survival in outpatients with chronic heart failure (CHF) and left ventricular (LV) systolic dysfunction. METHODS: Transthoracic echo-Doppler examination was carried out at baseline in 813 consecutive CHF outpatients with LV ejection fraction ≤ 45%. The total daily dose of furosemide was assessed for each patient. Chronic kidney disease (CKD) was defined by a glomerular filtration rate < 60 ml/min/1.73 m(2). The end-point was all-cause mortality. To control the prognostic effect of furosemide for the propensity of using high doses of the drug, the Cox model was stratified by the propensity score, itself computed from a multivariable logistic model. Mean follow up was 44 months. RESULTS: After stratification for the propensity score, the risk of death increased linearly across quartiles of furosemide dose (HR 1.38, 95% CI 1.14-1.68, p < 0.001). A daily dose of 50 mg was identified as the best threshold value to predict a high risk of death within 3 years with an area under the ROC curve of 0.68 (95% CI 0.64-0.72). Increasing doses of furosemide were associated with an increased risk of death regardless of LV filling pattern, CKD and background therapy with ACE-inhibitors or beta-blockers. CONCLUSIONS: In outpatients with CHF, after stratification for the propensity score, the risk of death increased linearly across quartiles of furosemide daily dose. A threshold furosemide dose of 50 mg was related with the worse outcome.

Prognostic significance of serum uric acid in outpatients with chronic heart failure is complex and related to body mass index: data from the IN-CHF Registry.

BACKGROUND AND AIMS: In the field of cardiovascular diseases, elevated levels of serum uric acid (UA) reflect a marked activation of the xanthine oxidase pathway with increase in free radicals production; it is often associated with an inflammatory state, oxygen consumption and endothelial dysfunction. All these associations have been also confirmed in heart failure (HF) but the pathophysiological role of UA in this setting is not well understood. The aim of this study was to evaluate the prognostic role of UA in outpatients enrolled in the Italian Registry of Congestive Heart Failure (IN-CHF). METHODS AND RESULTS: All patients met the European Society of Cardiology (ESC) criteria for diagnosis of HF. We considered patients with complete clinical data and UA level available at the baseline and at 1-year follow-up. The study population was composed of 877 patients aged 63 ± 12 years. One-year mortality was 10.8% and dead patients had a higher level of UA than survivors (7.1 mg dl⁻¹ vs 6.6 mg dl⁻¹, p < 0.0207). In multivariable full model of analysis, UA did not result in an independent predictor of death in overall population, but only in patients with low body mass index (BMI) (≤22 kg m⁻²) (hazard ratio (HR): 2.38, 95% confidence interval (CI) 1.36-4.18). In this subgroup, a statistically significant gradual relationship between UA and survival was detected starting from values higher than 8 mg dl⁻¹. CONCLUSION: Elevated level of UA is not an independent predictor of mortality in chronic HF, but it markedly worsens outcome if associated with low level of BMI. This association is likely an indicator of chronic inflammatory and catabolic state.

A cost-utility analysis of increasing percutaneous coronary intervention use in elderly patients with acute coronary syndromes in six European countries.

AIMS: Percutaneous coronary intervention reduces mortality in acute coronary syndrome patients but the cost-utility of increasing its use in elderly acute coronary syndrome patients is unknown. METHODS: We assessed the efficiency of increased percutaneous coronary intervention use compared to current practice in patients aged ≥75 years admitted for acute coronary syndrome in France, Germany, Greece, Italy, Portugal and Spain with a semi-Markov state transition model. In-hospital mortality reduction estimates by percutaneous coronary intervention use and costs were derived from the EUROpean Treatment & Reduction of Acute Coronary Syndromes cost analysis EU project (n = 28,600). Risk of recurrence and out-of-hospital all-cause mortality were obtained from the Information System for the Development of Research in Primary Care (SIDIAP) database from North-Eastern Spain (n = 55,564). In-hospital mortality was modelled using stratified propensity score analysis. The 8-year acute coronary syndrome recurrence risk and out-of-hospital mortality were estimated with a multistate survival model. The scenarios analysed were to increase percutaneous coronary intervention use among patients with the highest, moderate and lowest probability of receiving percutaneous coronary intervention based on the propensity score analysis. RESULTS: France, Greece and Portugal showed similar total costs/1000 individuals (7.29-11.05 m €); while in Germany, Italy and Spain, costs were higher (13.53-22.57 m €). Incremental cost-utility ratios of providing percutaneous coronary intervention to all patients ranged from 2262.8 €/quality adjusted life year gained for German males to 6324.3 €/quality adjusted life year gained for Italian females. Increasing percutaneous coronary intervention use was cost-effective at a willingness-to-pay threshold of 10,000 €/quality adjusted life year gained for all scenarios in the six countries, in males and females. CONCLUSION: Compared to current clinical practice, broadening percutaneous coronary intervention use in elderly acute coronary syndrome patients would be cost-effective across different healthcare systems in Europe, regardless of the selected strategy.

Real-time three-dimensional echocardiography permits quantification of left ventricular mechanical dyssynchrony and predicts acute response to cardiac resynchronization therapy.

OBJECTIVE: To evaluate the value of real-time three-dimensional echocardiography (RT3DE) to predict acute response to cardiac resynchronization therapy (CRT). METHODS: Sixty consecutive heart failure patients scheduled for CRT were included. RT3DE was performed before and within 48 hours after pacemaker implantation to calculate both left ventricular (LV) volumes and LV dyssynchrony. LV dyssynchrony was defined as the standard deviation of the time taken to reach the minimum systolic volume for 16 LV segments (referred to as the systolic dyssynchrony index, SDI). Patients were subsequently divided into acute responders or nonresponders, based on a reduction > or = 15% in LV end-systolic volume immediately after CRT. RESULTS: Four patients (7%) were excluded from further analysis because of either suboptimal apical acquisitions or significant translation artifacts. Out of the remaining 56 patients, 35 patients (63%) were classified as acute responders. Baseline characteristics were similar between responders and nonresponders, except for the SDI, which was larger in responders. Moreover, responders demonstrated a significant reduction of SDI immediately after CRT (from 9.7 +/- 4.1% to 3.6 +/- 1.8%, P < 0.0001), whereas SDI did not change in nonresponders (3.4 +/- 1.8% vs 3.1 +/- 1.1%, NS). ROC curve analysis revealed that a cut-off value for SDI of 5.6% yielded a sensitivity of 88% with a specificity of 86% to predict acute echocardiographic response to CRT (AUC 0.96). CONCLUSION: RT3DE is highly predictive for acute response to CRT (sensitivity 88% and specificity 86%). In addition, RT3DE allows assessment of changes in LV volumes and LV ejection fraction before and after CRT implantation.

The tailored medical therapy in patients with advanced heart failure referred for cardiac transplantation.

INTRODUCTION: Optimal pharmacologic management of heart transplant (HT) candidates is required prior to evaluation so as to obtain a reliable prognostic stratification and to address the donor shortage. The aim of this study was to determine whether a tailored medical approach was effectively achieved before HT waiting list enrollment. MATERIALS AND METHODS: This study concerned 40 consecutive patients referred for HT evaluation who underwent a clinical assessment, including hemodynamic, echocardiographic, and brain natriuretic peptide determinations. Medical therapy was optimized according to the clinical assessment to improve neurohormonal and hemodynamic profiles. We analyzed the distribution of the different drugs between the first and the following evaluation to demonstrate whether a significant improvement of medical therapy could be achieved in advanced chronic heart failure (ACHF). RESULTS: The mean age was 53 years, including 93% males. The etiology of disease was ischemic in 40% and idiopathic in 45%. The mean left ventricular ejection fraction was 23%, mean values of hemodynamic data were cardiac index (CI) 2+/-0.6 L/min/m(2), mean pulmonary arterial pressure (mPAP) 30+/-10 mm Hg, wedge pressure (PWP) 23+/-8 mm Hg; mean BNP was 618 pg/mL. Median follow-up was 397 days; 82% of candidates underwent HT waiting-list enrollment. The medical treatment was modified as follows: beta-blockers were introduced or uptitrated in 32%, angiotensin receptor blockers (ARB) were introduced in 7.5%, spironolactone was started in 42%, nitrates were introduced in 20%, and diuretics were uptitrated in 35% of patients. CONCLUSION: In patients with ACHF referred for HT, a further effort in the assessment of the medical treatment is strongly recommended.

Arterial hypertension in patients with atrial fibrillation in Europe: A report from the EURObservational Research Programme pilot survey on atrial fibrillation.

BACKGROUND: Hypertension (HTN) is the most prevalent co-morbidity among atrial fibrillation (AF) patients; the relationship between the two is bidirectional, with an incremental effect on adverse outcomes. PURPOSE: To study clinical features, treatment patterns and 1year outcomes amongst AF patients with HTN in the EURObservational Research Programme Atrial Fibrillation (EORP-AF) Pilot Registry, a prospective multi-national survey conducted by the European Society of Cardiology in 9 European countries. METHODS: Of 3119 enrolled AF patients, 2194 were diagnosed with HTN (AF-HTN) and 909 were normotensive (AF-NT) (16 patients had unknown HTN status). We compared baseline clinical features, management strategy and 1-year outcomes in terms of all-cause death, cardiovascular (CV) death, and any thrombosis-related event (TE: stroke, transient ischemic attack, acute coronary syndrome, coronary intervention, cardiac arrest, peripheral/pulmonary embolism) in AF-HTN vs AF-NT patients. RESULTS: The AF-HTN patients had more prevalent CV risk factors and comorbidities (median CHA2DS2-VASc score (IQR) 4 (3, 5) in AF-HTN, versus 2 (1, 3) in AF-NT; p<0.01). Crude rate of all-cause death and any TE event was higher in AF-HTN (194 (11.2%) versus 60 (8.2%), p=0.02). Kaplan-Meier analysis curves for death by hypertensive status showed no significant differences between the subgroups (log rank test, p=0.22). On logistic regression analysis, HTN did not emerge as an independent risk factor for outcomes (OR 1.08, 95% CI 0.76-1.54). CONCLUSION: AF-HTN patients have a higher prevalence of comorbidities and this conferred a higher risk for a composite endpoint of all-cause death and thromboembolic events. In this cohort HTN did not independently predict all-cause mortality at 1-year.

An update on atrial fibrillation in 2014: From pathophysiology to treatment.

Atrial fibrillation (AF) is the most frequently encountered cardiac arrhythmia. The trigger for initiation of AF is generally an enhanced vulnerability of pulmonary vein cardiomyocyte sleeves to either focal or re-entrant activity. The maintenance of AF is based on a "driver" mechanism in a vulnerable substrate. Cardiac mapping technology is providing further insight into these extremely dynamic processes. AF can lead to electrophysiological and structural remodelling, thereby promoting the condition. The management includes prevention of stroke by oral anticoagulation or left atrial appendage (LAA) occlusion, upstream therapy of concomitant conditions, and symptomatic improvement using rate control and/or rhythm control. Nonpharmacological strategies include electrical cardioversion and catheter ablation. There are substantial geographical variations in the management of AF, though European data indicate that 80% of patients receive adequate anticoagulation and 79% adequate rate control. High rates of morbidity and mortality weigh against perceived difficulties in management. Clinical research and growing experience are helping refine clinical indications and provide better technical approaches. Active research in cardiac electrophysiology is producing new antiarrhythmic agents that are reaching the experimental clinical arena, inhibiting novel ion channels. Future research should give better understanding of the underlying aetiology of AF and identification of drug targets, to help the move toward patient-specific therapy.

Doppler echocardiography reliably predicts pulmonary artery wedge pressure in patients with chronic heart failure with and without mitral regurgitation.

OBJECTIVES: This study was performed to assess whether the combination of multiple echocardiographic and Doppler variables can provide a reliable estimation of pulmonary artery wedge pressure in patients with chronic heart failure. BACKGROUND: In patients with chronic heart failure a high pulmonary artery wedge pressure is associated with poor prognosis, more severe symptoms and low exercise tolerance. Several Doppler echocardiographic indexes have been shown to be related to pulmonary artery wedge pressure, but the dispersion of data has generally not allowed a quantitative assessment of this important variable. METHODS: Simultaneous Doppler echocardiographic examinations and right heart catheterizations were performed in 231 patients with chronic heart failure due to dilated cardiomyopathy. Mitral and pulmonary venous flow velocity variables, left atrial volumes, mitral regurgitation jet area and left ventricular ejection fraction were correlated with pulmonary artery wedge pressure by both single and multilinear regression analysis. The reliability of the obtained multilinear equations was then tested in a separate group of 60 patients. RESULTS: By univariate analysis, the deceleration rate of early diastolic mitral flow and the systolic fraction of pulmonary venous flow showed the strongest correlations (r=0.78 and =-0.76, respectively). Stepwise regression analysis led to two multilinear equations for predicting pulmonary artery wedge pressure in the whole population: the first included only two-dimensional echocardiographic and mitral flow velocity variables (r=0.84) and the second also included pulmonary venous flow variables (r=0.87). The highest correlation was obtained (r=0.89) by a third equation in the 73 patients without significant mitral regurgitation. Correlation coefficients between estimated and measured pulmonary artery wedge pressure were 0.91 (SEE=2.7 mm Hg) and 0.97 (SEE=1.8 mm Hg) when the first and the second equation, respectively, were applied to the testing group. CONCLUSIONS: These results indicate that, in patients with chronic heart failure due to dilated cardiomyopathy, pulmonary artery wedge pressure can be reliably estimated even when mitral regurgitation is present by combining Doppler echocardiographic variables of mitral and pulmonary venous flow.

Assessing baroreflex sensitivity in post-myocardial infarction patients: comparison of spectral and phenylephrine techniques.

OBJECTIVES: This study sought to compare, in post-myocardial infarction patients, baroreflex sensitivity (BRS) measured by the phenylephrine method (Phe-BRS) with that estimated by the Robbe (Robbe-BRS) and Pagani (alpha-low frequency [LF] and alpha-high frequency [HF]) spectral techniques. BACKGROUND: BRS assessed by Phe-BRS has been shown to be of prognostic value in patients with a previous myocardial infarction, but the need for drug injection limits the use of this technique. Several noninvasive methods based on spectral analysis of systolic arterial pressure and heart period have been proposed, but their agreement with Phe-BRS has never been investigated in post-myocardial infarction patients. METHODS: The linear association and the agreement between each spectral measurement and Phe-BRS were assessed by correlation analysis and by computing the relative bias and the limits of agreement in 51 post-myocardial infarction patients. RESULTS: The correlation with Phe-BRS was r = 0.63 for Robbe-BRS, r = 0.62 for alpha-LF and r = 0.59 for alpha-HF. The relative bias was significant for alpha-LF (2.6 ms/mm Hg, p < 0.001) and alpha-HF (2.5 ms/mm Hg, p = 0.01) and not significant (-0.6 ms/mm Hg, p = 0.3) for Robbe-BRS. The normalized limits of agreement ranged from -98% to 95% for Robbe-BRS, from -67% to 126% for alpha-LF and from -108% to 143% for alpha-HF. When patients were classified according to left ventricular ejection fraction (LVEF, cutoff value 40%), the relative bias was higher in patients with a depressed LVEF, although statistical significance was high only for Robbe-BRS and was borderline for alpha-LF. The limits of agreement were similar in both groups of patients (p > 0.3). CONCLUSIONS: Despite a substantial linear association, the agreement between spectral measurements and Phe-BRS in post-myocardial infarction patients is weak because the difference can be as large as the BRS value being estimated. Phe-BRS is the measurement most associated with hemodynamic impairment. Because several factors within each method contribute to the overall difference, neither method can be defined as being better than the other in estimating baroreflex gain, nor can one be used as an alternative to the other. Ad hoc studies are needed to assess which method provides the most useful physiologic or pathophysiologic information or the most accurate prediction of prognosis.

Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: a prospective study in 344 patients with baseline sinus rhythm.

OBJECTIVES: This study investigated the incidence, predisposing factors and significance of the onset of atrial fibrillation (AF) in patients with chronic congestive heart failure (CHF). BACKGROUND: The association between CHF and AF is well documented, but the factors that predispose to the onset of the arrhythmia and its impact remain controversial. Methods. We prospectively followed up 344 patients with CHF and sinus rhythm (SR). Over a period of 19 +/- 12 months (mean +/- SD), 28 patients developed atrial fibrillation (AF), which became chronic in 18. RESULTS: At baseline, no differences were found in any clinical and hemodynamic variables between patients who developed chronic AF and those who did not. Reversible AF occurring during follow-up and lower mitral flow velocity at atrial contraction as detected at the last evaluation in SR were independent predictors of the subsequent development of chronic AF. When AF occurred, New York Heart Association functional class worsened (from 2.4 +/- 0.5 to 2.9 +/- 0.6, p = 0.0001), peak exercise oxygen consumption declined (from 16 +/- 5 to 11 +/- 5 ml/kg per min, p = 0.002), cardiac index decreased (from 2.2 +/- 0.4 to 1.8 +/- 0.4, p = 0.0008), and mitral and tricuspid regurgitation increased (from grade 1.8 +/- 1.1 to grade 2.4 +/- 1.4, p = 0.0001 and from grade 1.0 +/- 1.2 to grade 1.8 +/- 1.2, p = 0.001, respectively). Systemic thromboembolism occurred in 3 of the 18 patients with AF. Nine of 18 patients died after AF, and the occurrence of AF was a predictor of major cardiac events. CONCLUSIONS: In patients with CHF, reversible AF and reduction of left atrial contribution to left ventricular filling predict the subsequent development of chronic AF. The onset of AF is associated with clinical and hemodynamic deterioration and may predispose to systemic thromboembolism and poorer prognosis.

Predictors of nonfatal reinfarction in survivors of myocardial infarction after thrombolysis. Results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) Data Base.

OBJECTIVES: This study was designed to reassess the prediction of recurrent nonfatal myocardial infarction in patients recovering from acute myocardial infarction after thrombolysis. BACKGROUND: Recurrent nonfatal myocardial infarction is a strong and independent predictor of subsequent mortality. Current knowledge of risk factors for nonfatal reinfarction is still largely based on data gathered before the advent of thrombolysis. Thus, this prospective study was planned to identify harbinger of nonfatal reinfarction in the postinfarction patients of the multicenter Grouppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI-2) trial. METHODS: Predictors of nonfatal reinfarction at 6 months were analyzed by multivariate technique (Cox model) in 8,907 GISSI-2 survivors of myocardial infarction with clinical follow-up, relying on a set of prespecified variables reflecting residual ischemia, left ventricular failure or dysfunction, complex ventricular arrhythmias, comorbidity as well as demographic and historical factors. RESULTS: The postdischarge to 6-month incidence rate of nonfatal reinfarction was 2.5%. Independent predictors of nonfatal reinfarction were cardiac ineligibility for exercise test (relative risk 2.97, 95% confidence interval [CI] 1.98 to 4.45), previous myocardial infarction (relative risk 1.70, 95% CI 1.22 to 2.36) and angina at follow-up (relative risk 1.50, 95% CI 1.10 to 2.04). On further multivariate analysis, performed in 6,580 patients with both echocardiographic and electrocardiographic monitoring data available, a history of angina emerged as an additional risk predictor (relative risk 1.58, 95% CI 1.10 to 2.25). CONCLUSIONS: The 6-month incidence of nonfatal reinfarction is rather low in survivors of myocardial infarction after thrombolysis. Cardiac ineligibility for exercise testing and a history of coronary artery disease are risk predictors. Recurrent nonfatal infarction is not predictable by qualitative variables reflecting residual ischemia, except by postdischarge angina. Prediction of nonfatal reinfarction appears less accurate than prediction of mortality, as almost 50% of reinfarctions occur in patients without any of the identified risk factors.

Long-term physical training and left ventricular remodeling after anterior myocardial infarction: results of the Exercise in Anterior Myocardial Infarction (EAMI) trial. EAMI Study Group.

OBJECTIVES: The aim of this multicenter randomized study was to investigate whether long-term physical training would influence left ventricular remodeling after anterior myocardial infarction. BACKGROUND: Exercise is currently recommended for patients after myocardial infarction; however, the effects of long-term physical training on ventricular size and remodeling still have to be defined. METHODS: Patients with no contraindications to exercise were studied 4 to 8 weeks after anterior Q wave myocardial infarction and 6 months later by echocardiography at rest and bicycle ergometric testing. After the initial study, patients were randomly allocated to a 6-month exercise training program (n = 49) or a control group (n = 46). A computerized system was used to derive echocardiographic variables of ventricular size, function and topography. RESULTS: After 6 months, a significant (p < 0.01) increase in work capacity (from 4,596 +/- 1,246 to 5,508 +/- 1,335 kp-m) was observed only in the training group, whereas global ventricular size, regional dilation and shape distortion did not change in either the control or the training group. However, compared with patients with an ejection fraction > 40%, patients with an ejection fraction < or = 40% had more significant (p < 0.001) ventricular enlargement at entry and demonstrated further (p < 0.01) global and regional dilation after 6 months, in both the control and the training group (end-diastolic volume from 77 +/- 14 to 85 +/- 17 ml/m2 in the control group and from 74 +/- 11 to 77 +/- 15 ml/m2 in the training group; regional dilation from 46 +/- 18% to 57 +/- 21% in the control group and from 42 +/- 18% to 44 +/- 26% in the training group). Ventricular size and topography did not change in patients with an ejection fraction > 40%. CONCLUSIONS: Patients with poor left ventricular function 1 to 2 months after anterior myocardial infarction are prone to further global and regional dilation. Exercise training does not appear to influence this spontaneous deterioration. Thus, postinfarction patients without clinical complications, even those with a large anterior infarction, may benefit from long-term physical training without any additional negative effect on ventricular size and topography.

Prevalence and characteristics of dystrophin defects in adult male patients with dilated cardiomyopathy.

OBJECTIVES: To assess the prevalence of dystrophin defects in dilated cardiomyopathy (DCM) in male patients and to formulate investigation strategies for their identification. BACKGROUND: Dystrophin defects presenting with predominant or exclusive cardiac involvement may be clinically indistinguishable from "idiopathic" DCM. Diagnosis may be missed, unless specifically investigated. METHODS: Clinical and biochemical evaluation, right ventricular endomyocardial biopsy (EMB), light and electron microscopic and immunohistochemical studies of biopsy samples, six multiplex and two single polymerase chain reactions for 38 exons and automated sequencing of exon 9 and muscle promoter-exon 1 were undertaken in 201 consecutive male patients presenting with DCM, with (n = 14) and without (n = 187) increased serum creatine phosphokinase (sCPK). RESULTS: Dystrophin defects were identified in 13 of the 201 patients (6.5%, age 16-50). Family history was positive in four patients. Serum CPK levels were increased in 11 of 13 patients. Light microscopy examination of EMB was uninformative; ultrastructural study showed multiple membrane defects. Dystrophin immunostain was abnormal. Eight patients, all older than 20, had deletions affecting midrod domain, normal or mildly increased CPK and better outcome than the five remaining cases all younger than 20, with more than five-fold increase of sCPK. Two of these latter had proximal and rod-domain deletions. Sisters of two patients were diagnosed as noncarriers with microsatellite analysis. CONCLUSIONS: Although the overall prevalence of dystrophin defects in our consecutive DCM male series is low (6.5%), immunohistochemical and molecular studies are essential to identify protein and gene defects; screening studies are justified to define prevalence, clinical profile and genotype-phenotype correlation.

Peak exercise oxygen consumption in chronic heart failure: toward efficient use in the individual patient.

OBJECTIVES: This study sought to 1) assess the short-, medium-and long-term prognostic power of peak oxygen consumption (VO2) in patients with heart failure; 2) verify the consistency of a nonmeasurable anaerobic threshold (AT) as a criterion of nonapplicability of peak VO2; 3) develop simple rules for the efficient use of peak VO2 in individualized prognostic stratification and clinical decision making. BACKGROUND: Peak VO2, when AT is identified, is among the indicators for heart transplant eligibility. However, in clinical practice the application of defined peak VO2 cutoff values to all patients could be inappropriate and misleading. METHODS: Six hundred fifty-three patients consecutively considered for eligibility for heart transplantation were followed up. Outcomes (cardiac death and urgent transplantation) were determined when all survivors had a minimum of 6 months of follow-up. RESULTS: Contraindication to the exercise test identified very high risk patients. The relatively small sample of women did not allow inferences to be drawn. In men, peak VO2 stratified into three levels (< or = 10, 10 to 18 and >18 ml/kg per min) identified groups at high, medium and low risk, respectively. The prognostic power of peak VO2 < or = 10 ml/kg per min was maintained even when the AT was not detected. In patients in New York Heart Association functional class III or IV, peak VO2 did not have prognostic power. In patients in functional class I or II, peak VO2 stratification was prognostically valuable, but less so at 6 than at 12 or 24 months. Age did not influence peak VO2 prognostic stratification. CONCLUSIONS: A contraindication to exercise testing should be considered a priority for listing patients for heart transplantation. Only in less symptomatic male patients does a peak VO2 < or = 10 ml/kg per min identify short-, medium- and long-term high risk groups. A peak VO2 >18 ml/kg per min implies good prognosis with medical therapy.

Independent and additive prognostic value of right ventricular systolic function and pulmonary artery pressure in patients with chronic heart failure.

OBJECTIVES: We sought a better understanding of the coupling between right ventricular ejection fraction (RVEF) and pulmonary artery pressure (PAP), as it might improve the accuracy of the prognostic stratification of patients with heart failure. BACKGROUND: Despite the long-standing view that systolic function of the right ventricle (RV) is almost exclusively dependent on the afterload that this cardiac chamber must confront, recent studies claim that RV function is an independent prognostic factor in patients with chronic heart failure. METHODS: Right heart catheterization was performed in 377 consecutive patients with heart failure. RESULTS: During a median follow-up period of 17 +/- 9 months, 105 patients died and 35 underwent urgent heart transplantation. Pulmonary artery pressure and thermodilution-derived RVEF were inversely related (r = 0.66, p < 0.001). However, on Cox multivariate survival analysis, no interaction between such variables was found, and both turned out to be independent prognostic predictors (p < 0.001). It was found that RVEF was preserved in some patients with pulmonary hypertension, and that the prognosis of these patients was similar to that of the patients with normal PAP. In contrast, when PAP was normal, reduced RV function did not carry an additional risk. CONCLUSIONS: These observations emphasize the necessity of combining the right heart hemodynamic variables with a functional evaluation of the RV when trying to define the individual risk of patients with heart failure.

Electrocardiographic evolutionary changes and left ventricular remodeling after acute myocardial infarction: results of the GISSI-3 Echo substudy.

OBJECTIVES: The aim of this study was to describe the electrocardiographic (ECG) evolutionary changes after an acute myocardial infarction (AMI) and to evaluate their correlation with left ventricular function and remodeling. BACKGROUND: The QRS complex changes after AMI have been correlated with infarct size and left ventricular function. By contrast, the significance of T wave changes is controversial. METHODS: We studied 536 patients enrolled in the GISSI-3-Echo substudy who underwent ECG and echocardiographic studies at 24 to 48 h (S1), at hospital discharge (S2), at six weeks (S3) and six months (S4) after AMI. RESULTS: The number of Qwaves (nQ) and QRS quantitative score (QRSs) did not change over time. From S2 to S4, the number of negative T waves (nT NEG) decreased (p < 0.0001), wall motion abnormalities (%WMA) improved (p < 0.001), ventricular volumes increased (p < 0.0001) while ejection fraction remained stable. According to the T wave changes after hospital discharge, patients were divided into four groups: stable positive T waves (group 1, n = 35), patients who showed a decrease > or =1 in nT NEG (group 2, n = 361), patients with no change in nT NEG (group 3, n = 64) and those with an increase > or =1 in nT NEG (group 4, n = 76). The QRSs and nQ remained stable in all groups. Groups 3 and 4 showed less recovery in %WMA, more pronounced ventricular enlargement and progressive decline in ejection fraction than groups 1 and 2 (interaction time x groups p < 0.0001). CONCLUSIONS: The analysis of serial ECG can predict postinfarct left ventricular remodeling. Normalization of negative T waves during the follow-up appears more strictly related to recovery of regional dysfunction than QRS changes. Lack of resolution and late appearance of new negative T predict unfavorable remodeling with progressive deterioration of ventricular function.

Clinical effects of early angiotensin-converting enzyme inhibitor treatment for acute myocardial infarction are similar in the presence and absence of aspirin: systematic overview of individual data from 96,712 randomized patients. Angiotensin-converting Enzyme Inhibitor Myocardial Infarction Collaborative Group.

OBJECTIVES: We sought to determine whether the clinical effects of early angiotensin-converting enzyme (ACE) inhibitor (ACEi) treatment for acute myocardial infarction (MI) are influenced by the concomitant use of aspirin (ASA). BACKGROUND: Aspirin and ACEi both reduce mortality when given early after MI. Aspirin inhibits the synthesis of vasodilating prostaglandins, and, in principle, this inhibition might antagonize some of the effects of ACEi. But it is uncertain whether, in practice, this influences the effects of ACEi on mortality and major morbidity after MI. METHODS: This overview sought individual patient data from all trials involving more than 1,000 patients randomly allocated to receive ACEi or control starting in the acute phase of MI (0-36 h from onset) and continuing for four to six weeks. Data on concomitant ASA use were available for 96,712 of 98,496 patients in four eligible trials (and for none of 1,556 patients in the one other eligible trial). RESULTS: Overall 30-day mortality was 7.1% among patients allocated to ACEi and 7.6% among those allocated to control, corresponding to a 7% (standard deviation [SD], 2%) proportional reduction (95% confidence interval 2% to 11%, p = 0.004). Angiotensin-converting enzyme inhibitor was associated with similar proportional reductions in 30-day mortality among the 86,484 patients who were taking ASA (6% [SD, 3%] reduction) and among the 10,228 patients who were not (10% [SD, 5%] reduction: chi-squared test of heterogeneity between these reductions = 0.4; p = 0.5). Angiotensin-converting enzyme inhibitor produced definite increases in the incidence of persistent hypotension (17.9% ACEi vs. 9.4% control) and of renal dysfunction (1.3% ACEi vs. 0.6% control), but there was no good evidence that these effects were different in the presence or absence of ASA (chi-squared for heterogeneity = 0.4 and 0.0, respectively; both not significant). Nor was there good evidence that the effects of ACEi on other clinical outcomes were changed by concomitant ASA use. CONCLUSIONS: Both ASA and ACEi are beneficial in acute MI. The present results support the early use of ACEi in acute MI, irrespective of whether or not ASA is being given.

Baseline characteristics of patients recruited into the CARE-HF study.

BACKGROUND: Cardiac resynchronization therapy (CRT) is a promising new treatment for patients with heart failure and cardiac dyssynchrony. The CARE-HF study is a morbidity/mortality trial designed to provide conclusive evidence of the effects of CRT in patients with moderate to severe heart failure. METHODS: A description of the baseline characteristics of patients randomised in the CARE-HF trial. RESULTS: 813 Patients with predominantly NYHA class III (94%) heart failure were randomised in 82 centres. Their mean age was 65 (interquartile range [IQR] 59 to 72) years, 34% were aged >70 years and 27% were women. Thirty-eight percent of the patients had ischaemic heart disease. Mean heart rate was adequately controlled at 70 (IQR 60 to 78) bpm consistent with the use of beta-blockers. Supine systolic blood pressure was low at 117 (IQR 105 to 130) mm Hg. Eighty-eight percent of patients had a QRS > or =150 ms. Mean LV ejection fraction was 26% (IQR 22 to 29) and end-diastolic dimension was 7.2 (IQR 6.4 to 7.8) cm. Ninety-four percent of patients were receiving loop diuretics, 95% an ACE inhibitor or angiotensin receptor blocker (ARB), 72% a beta-blocker and 56% were taking spironolactone. CONCLUSIONS: The patients enrolled in CARE-HF had moderately severe heart failure and cardiac dysfunction with evidence of cardiac dyssynchrony. The population appears at high risk of events despite pharmacological therapy and therefore appropriate for a trial of CRT.