Andrea Perkan

Long-Term Evolution and Prognostic Stratification of Biopsy-Proven Active Myocarditis

Background— Active myocarditis is characterized by large heterogeneity of clinical presentation and evolution. This study describes the characteristics and the long-term evolution of a large sample of patients with biopsy-proven active myocarditis, looking for accessible and valid early predictors of long-term prognosis. Methods and Results— From 1981 to 2009, 82 patients with biopsy-proven active myocarditis were consecutively enrolled and followed-up for 147±107 months. All patients underwent clinical and echocardiographic evaluation at baseline and at 6 months. At this time, improvement/normality of left ventricular ejection fraction (LVEF), defined as a LVEF increase > 20 percentage points or presence of LVEF≥50%, was assessed. At baseline, left ventricular dysfunction (LVEF<50%) and left atrium enlargement were independently associated with long-term heart transplantation–free survival, regardless of the clinical pattern of disease onset. At 6 months, improvement/normality of LVEF was observed in 53% of patients. Persistence of New York Heart Association III to IV classes, left atrium enlargement, and improvement/normality of LVEF at 6 months emerged as independent predictors of long-term outcome. Notably, the short-term reevaluation showed a significant incremental prognostic value in comparison with the baseline evaluation (baseline model versus 6 months model: area under the curve 0.79 versus 0.90, P=0.03). Conclusions— Baseline left ventricular function is a marker for prognosis regardless of the clinical pattern of disease onset, and its reassessment at 6 months appears useful for assessing longer-term outcome.

Natural history of dilated cardiomyopathy: from asymptomatic left ventricular dysfunction to heart failure--a subgroup analysis from the Trieste Cardiomyopathy Registry.

Background Few data are available in the literature regarding the characteristics and prognosis of asymptomatic patients with idiopathic dilated cardiomyopathy (DCM). Aim To determine the frequency with which patients affected by DCM are diagnosed in the asymptomatic state as well as to evaluate the natural history of such patients and the factors influencing their outcome. Moreover, we sought to compare the outcome of asymptomatic patients with that of patients with signs of overt heart failure at the time of first evaluation. Methods and results We analyzed the data of 747 patients with DCM enlisted in the Heart Muscle Disease Registry of Trieste from 1978 to 2007. We divided our population into four groups; group 1 comprised 118 asymptomatic [New York Heart Association (NYHA) I] patients without a history of congestive symptoms (16%), group 2 comprised 102 asymptomatic (NYHA I) patients (14%) with a positive anamnesis for heart failure stabilized in medical therapy, group 3 comprised 327 patients (44%) with signs of mild heart failure (NYHA II) and group 4 comprised 200 patients (26%) in NYHA III–IV. During the follow-up of 112 ± 63 months, 46 (21%) of 220 asymptomatic patients with DCM died or underwent heart transplantation. By Cox proportional model, left ventricular ejection fraction of 30% or less was a unique independent predictor either for death/heart transplantation (hazard ratio 3.15, 95% confidence interval 1.5–6.7, P = 0.003) or for sudden death/major ventricular arrhythmias (hazard ratio 3.9, 95% confidence interval 1.7–9.3, P = 0.002). Patients from group 1 had a trend for a better outcome with respect to those from group 2 (P = 0.06). In comparison with the asymptomatic patients, those with signs of overt heart failure at baseline had a worse prognosis. Conclusion The proportion of asymptomatic patients with DCM at the moment of first evaluation at our center is significant (30%). Among them, those without a previous history of heart failure had a less advanced disease and a trend for a better long-term outcome on optimal medical treatment. Therefore, early diagnosis may offer better long-term quality of life and even better survival. Further studies on larger populations are indicated.

Dobutamine echocardiography in idiopathic dilated cardiomyopathy: clinical and prognostic implications

The dobutamine echocardiographic test (DET) is frequently used in coronary artery disease to detect viable myocardium, but few data are available about its role in idiopathic dilated cardiomyopathy (IDCM). The aims of this study were to evaluate the clinical role of DET and the prognostic implications of the ‘contractile reserve’ in patients with IDCM treated with optimal medical therapy, including β‐blockade (BB). A total of 51 patients with IDCM underwent DET at diagnosis. A positive response to DET (DET+) was judged to be a significant increase (≥10 points) in left ventricular ejection fraction (LVEF) with a peak value ≥40%, and a reversed restrictive left ventricular filling pattern (RFP) if present at baseline study. Improvement at follow‐up was defined according to combined clinical and echo‐Doppler criteria. In all, 22 patients (43%) were classified as DET+. DET+ patients were less symptomatic (P<0.001), with lower heart rate (P<0.01), less enlarged left and right ventricles (P<0.0001 and P<0.05), higher LVEF (P‐0.0001), less frequent RFP (P‐0.01), and lower pulmonary pressure (P<0.01). At follow‐up (34±16 months), 21 patients had improved, while four had died and seven had received a transplant. Among clinical data, NYHA classes I–II (OR‐0.25, P‐0.07) and BB dosage (OR‐0.97, P<0.005) were significantly associated with higher transplant‐free survival at multivariate analysis. The addition of DET+ (OR‐0.34, P<0.05) showed a moderate but significant improvement of sensitivity, but the predictive power of the model remained low (sensitivity, 0.67; specificity, 0.55). Absence of left bundle branch block (OR‐0.27, P<0.01) and BB dosage (OR‐1.03, P<0.005), but not DET+, were predictive of improvement. In patients with IDCM, DET response is associated with a more favourable outcome, since it suggests an earlier stage of the disease. However, in the light of our data, the incremental prognostic power of DET response compared to clinical evaluation at enrolment, despite being significant, seems to be of limited clinical value. Further studies should be carried out in order to clarify the prognostic value of DET in IDCM patients.

Metoprolol in dilated cardiomyopathy: Is it possible toidentify factors predictive of improvement?

Background: Some controlled clinical trials showed a beneficial effect of beta-blockers on symptoms, exercise tolerance, and left ventricular function in dilated cardiomyopathy. The purpose of this study was to investigate if there are clinical variables at baseline that could predict a favorable response to long-term metoprolol therapy.

Right Ventricular Cardiomyocyte Apoptosis in Patients With Acute Myocardial Infarction of the Left Ventricular Wall

Cardiac remodeling after acute myocardial infarction (AMI) is characterized by molecular and cellular mechanisms involving both the left (LV) and right ventricular (RV) walls. Cardiomyoycte apoptosis in the peri-infarct and remote LV myocardium has a central role in cardiac remodeling. Whether apoptosis also occurs in the right ventricle of patients with ischemic heart disease has not been investigated. The aim of the present study was to investigate the presence of cardiomyocyte apoptosis in the right ventricle in patients with AMI. We assessed the number of apoptotic cardiomyocytes using multiple samplings in the LV and RV walls of 12 patients selected at autopsy who died 4 to 42 days after AMI. Five patients without cardiac disease were also selected at autopsy as controls. Apoptotic rates were calculated from the number of cardiomyocytes showing double positive staining for in situ end-labeling of DNA fragmentation (TUNEL) and for activated caspase-3. Potentially false-positive results (DNA synthesis and RNA splicing) were excluded from cell counts. The apoptotic rate in the right ventricle in patients with AMI was significantly higher than in control hearts (median 0.8%, interquartile range 0.3 to 1.0 vs median 0.01%, interquartile range 0.01 to 0.03, p <0.001). RV apoptosis significantly correlated with such parameters of global adverse remodeling as cardiac diameter to LV free wall thickness (R = +0.57, p = 0.050). RV apoptosis was significantly higher in five cases (42%) with infarct involving the ventricular septum and an adjacent small area of the RV walls (median 1.0%, interquartile range 0.8 to 2.2 vs median 0.5%, interquartile range 0.2 to 1.0, p = 0.048, p <0.001 vs controls). The association between apoptotic rate in the right ventricle and cardiac remodeling was apparent even after exclusion of cases with RV AMI involvement (R = +0.82, p = 0.023 for diameter to LV wall thickness ratio and R = -0.91, p = 0.002 for RV free wall thickness). In conclusion, patients with cardiac remodeling after AMI had a significant increase in RV apoptosis even when ischemic involvement of the RV wall was not apparent.

Contrast-induced nephropathy in patients undergoing primary percutaneous coronary intervention without acute left ventricular ejection fraction impairment.

The prognostic relevance of direct contrast toxicity in patients treated with primary percutaneous coronary intervention remains unclear, owing to the confounding hemodynamic effect of acute left ventricular ejection fraction (LVEF) impairment on kidney function estimation. In the present study, 644 consecutive patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention were prospectively enrolled. Contrast-induced nephropathy (CIN) was defined as an increase in serum creatinine >25% or a decrease in the estimated glomerular filtration rate (eGFR) <25% from baseline in the first 72 hours. The primary end point of the study was major adverse cardiovascular events at 1 year (composite of death, myocardial infarction, target lesion revascularization, and bleeding). Among the global population, the interaction between the LVEF and eGFR at admission to define CIN was statistically significant (p <0.001). When only the 385 patients without acute LVEF impairment (i.e., those with LVEF ≥40%) were considered, 27 (7%) developed postprocedural CIN that was associated with increased major adverse cardiovascular events rate at 1 year of clinical follow-up (38% vs 9%; p <0.001). On adjusted Cox multivariate analysis, CIN was an independent predictor of worse outcomes, both when defined according to creatinine (hazard ratio 3.81, 95% confidence interval 1.71 to 8.48, p = 0.001) or eGFR (hazard ratio 3.77, 95% confidence interval 1.53 to 9.28, p = 0.004) variations. In conclusion, in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention, LVEF has a significant interaction with eGFR. When only patients without acute LVEF impairment were considered, CIN confirmed its negative prognostic effect on the 1-year clinical outcomes.

Nonpredictive value of fibrosis in dilated cardiomyopathy treated with metoprolol

Therapy with β-adrenergic blocking agents has been advocated as a potential useful approach in heart failure. Recent studies suggest that histologic parameters may be helpful in assessing the effectiveness of β-blocker treatment in dilated cardiomyopathy (DCM). In order to predict the response to β-blockers in DCM, fibrous tissue was evaluated at endomyocardial biopsy (EMB) in 45 patients (pts) with a mean left ventricular ejection fraction of 0.28 ± 0.07, who were successively long-term treated with metoprolol (M) (mean dosage 138 ±26 mg/die). EMB was performed from left (n = 32) or right (n = 13) ventricle by means of a Kings bioptome or the Cordis adaptation of this instrument. Quantification of fibrous tissue was performed at 9 × magnification and with a computerized morphometric system. Qualitative evaluation at light microscopy distinguished four types of fibrosis: pericellular, perivascular, focal, and endocardial. Volume fraction of fibrous tissue ranged from 1.3 to 35.5% (mean 12.1 ± 9.3%) and was not significantly correlated with any clinical variable considered. After 24 ± 12 months of treatment, 25 pts were considered improved (group A), whereas the remaining 20 pts were considered not improved (group B), according to criteria based on ejection fraction, left ventricular end-diastolic diameter, filling pattern at Doppler-Echocardiography, cardiothoracic ratio, NYHA functional class, and exercise duration at ergometric test. Volume fraction of fibrous tissue did not differ significantly between the two groups (group A = 12.1 ± 9.1%; group B = 11.3 ± 9.6%;p = NS). Dominant pericellular type of fibrosis was equally distributed between the two groups (group A = 9 25 pts, 36%; group B = 10 20 pts, 50%), whereas a perivascular and/or focal replacement fibrosis was more frequent in group A (group A = 10 20 pts, 50%; group B = 2 20 pts, 10%; p = .05, OR 5.55 at univariate analysis). At multivariate analysis mean aortic blood pressure was the only variable discriminating the two groups; the type of fibrosis, although not statistically significant, maintained a high value of odds-ratio (5.23). In conclusion, extent of total fibrosis assessed by EMB may range widely in patients with DCM, is not correlated with the most important clinical variables, and is not predictive of long-term response to β-blocker treatment. Otherwise, prevalent perivascular and/or focal replacement fibrosis could be associated with a higher probability of improvement after long-term β-blocker treatment.

Synergistic effect of thrombus aspiration and abciximab in primary percutaneous coronary intervention

Previous studies failed to assess the individual prognostic role of thrombus aspiration (TA) or abciximab in primary percutaneous coronary intervention (pPCI), due their prevalent combined use.

The challenge of cardiomyopathies in 2007.

The last 20 years have seen impressive progress in the study of cardiomyopathies. The improved understanding of these diseases has made clear that cardiomyopathies are extremely complex entities that defy current classification standards. The 1980 and 1995 WHO/ISFC Task Forces, and very recently an American Heart Association (AHA) Scientific Statement expert panel, have systematically approached new advances as well as emerging problems. In spite of this effort and an increasingly growing understanding of myocardial disorders, several issues remain unresolved. Without a doubt, the identification of genetic defects responsible for many forms of cardiomyopathies has changed our perspective of myocardial diseases. In fact, in the last few years, we have seen that (1) clinically defined cardiomyopathies, previously considered single entities, are actually the result of mutations in different genes, (2) different mutations in the same gene may be the cause of different clinical entities and (3) in the group of cardiomyopathies, a large phenotypic and genetic heterogeneity exists that is expected to increase in the future. Genotype knowledge is a fundamental advance in medicine and in particular in the field of cardiomyopathies and is becoming increasingly more important in clinical practice for disease diagnosis and prevention, prognostic stratification and possible future therapies. Knowledge of the phenotype, including clinical, morphological and physiological features, however, continues to provide the clinical basis for diagnosis and classification of cardiomyopathies, prognostic evaluation and symptomatic treatment, and should not be abandoned.

Natural History of Idiopathic Dilated Cardiomyopathy

Idiopathic dilated cardiomyopathy (IDC) continues to be an etiological and pathogenetic enigma. Many possible causes have been considered and are being studied at present. Genetic factors, virus infections, autoimmunity alcohol, pregnancy, and slight hypertension may play a role. However the etiology continues to be unknown in a large percentage of patients. The possibility of different etiological factors and of various pathogenetic mechanisms may explain the heterogeneity of clinical presentation, functional status, complications, and characteristics of evolution and response to therapy of the disease [22].