G. Sabbadini

Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol

OBJECTIVES The purpose of this study was to analyze whether long-term treatment with the nonselective beta-adrenergic blocking agent carvedilol may have beneficial effects in patients with dilated cardiomyopathy (DCM), who are poor responders in terms of left ventricular (LV) function and exercise tolerance to chronic treatment with the selective beta-blocker metoprolol. BACKGROUND Although metoprolol has been proven to be beneficial in the majority of patients with heart failure, a subset of the remaining patients shows long-term survival without satisfactory clinical improvement. METHODS Thirty consecutive DCM patients with persistent LV dysfunction (ejection fraction #40%) and reduced exercise tolerance (peak oxygen consumption ,25 ml/kg/min) despite chronic (.1 year) tailored treatment with metoprolol and angiotensin-converting enzyme inhibitors were enrolled in a 12-month, open-label, parallel trial and were randomized either to continue on metoprolol (n 5 16, mean dosage 142 6 44 mg/day) or to cross over to maximum tolerated dosage of carvedilol (n 5 14, mean dosage 74 6 23 mg/day). RESULTS At 12 months, patients on carvedilol, compared with those continuing on metoprolol, showed a decrease in LV dimensions (end-diastolic volume 28 6 7 vs. 17 6 6 ml/m 2 ,p 5 0.053; end-systolic volume 27 6 5 vs. 16 6 4 ml/m 2 ,p 5 0.047), an improvement in LV ejection fraction (17 6 3% vs. 21 6 2%, p 5 0.045), a reduction in ventricular ectopic beats (212 6 9 vs. 162 6 50 n/h, p 5 0.05) and couplets (20.5 6 0.4 vs. 11.5 6 0.6 n/h, p 5 0.048), no significant benefit on symptoms and quality of life and a negative effect on peak oxygen consumption (20.6 6 0.6 vs. 11.3 6 0.5 ml/kg/min, p 5 0.03). CONCLUSIONS In DCM patients who were poor responders to chronic metoprolol, carvedilol treatment was associated with favorable effects on LV systolic function and remodeling as well as on ventricular arrhythmias, whereas it had a negative effect on peak oxygen consumption. (J Am Coll Cardiol 1999;33:1926 ‐34)

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.

Are Nonsustained Ventricular Tachycardias Predictive of Major Arrhythmias in Patients with Dilated Cardiomyopathy on Optimal Medical Treatment

Background: To evaluate the role of nonsustained ventricular tachycardias (NSVT) for the prediction of major ventricular arrhythmias (MVA) in patients with idiopathic dilated cardiomyopathy (DCM) after optimization of medical treatment.

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.

Bilateral arcuate foramen associated with partial defect of the posterior arch of the atlas in a medieval skeleton: case report and review of the literature. Looking backward to go forward

PurposeWe observed a complex atlas (C1) dysmorphism in a human medieval skeleton dug up from the sixth to the seventh century necropolis located in the north-eastern Italy. We analyzed such a dysmorphism in the light of pertinent literature and discussed the functional and clinical implications related to this type of C1 structural malformation.MethodsMacroscopical and CT-SCAN examinations of the atlas were carried out.ResultsBone findings consisted of partial aplasia of the posterior arch of the C1 accompanied by a bilateral arcuate foramen. In addition, the spinous processes of C7 and T1 were found to be bifid.ConclusionsAlthough such abnormalities are supposed to be clinically inconspicuous, yet they may become challenging or even dangerous in the context of trauma. They may even complicate specific diagnostic or surgical procedures. In addition, they may cause a great number of symptoms, ranging from headache and neck pain to loss of postural muscle tone and consciousness, due to the close and complex relationship of bone structures with nerves, blood vessels, muscles, and ligaments. As a result, radiologists, clinicians, surgeons, and chiropractors should consider in their clinical reasoning the possibility that atlas dysmorphisms may occur.

Impact of Atrial Fibrillation on Outcome of Patients with Idiopathic Dilated Cardiomyopathy: Data from the Heart Muscle Disease Registry of Trieste

Objective: There is a paucity and inconsistency of data regarding the natural history of patients affected by idiopathic dilated cardiomyopathy (IDCM) and atrial fibrillation (AF). We examined the prognostic implications of AF in a subset of patients with IDCM. Methods: We analyzed the data of 539 patients with IDCM enrolled in the Heart Muscle Disease Registry of Trieste. Results: At baseline, 52 (9.6%) of 539 patients had AF. There was no difference in survival of patients with either AF or sinus rhythm at enrollment (P=.28). During long-term follow-up (90±58 months), AF was detected on ECG/ECG-Holter monitoring in 28 (5.7%) of 487 patients in sinus rhythm at baseline. Predictors of new onset of AF at multivariate analysis were a more dilated left atrium (OR 1.35, 95% CI 1.06–1.72; P=.01) and a lower left ventricle ejection fraction (for 10% decrease, OR 2.41, 95% CI 1.24–4.69, P=.016). Patients developing AF had higher mortality/heart transplantation rate compared to patients who maintained sinus rhythm during follow-up (P<.001). At multivariate analysis, new onset AF (HR 3.67, 95% CI 2.07–6.5; P<.001) in the first three years after diagnosis, but not baseline AF, was found to be independently associated with a worse outcome. Conclusions: Atrial fibrillation is relatively frequent in patients with IDCM. The early development of AF during follow-up, but not its presence at baseline, is associated with poor survival.

A keyhole-shaped sternal defect in an ancient human skeleton

We observed a sternal foramen contiguous with a small sternal cleft in a human skeleton coming from North-Eastern Italy and dating back to between the sixteenth and seventeenth century AD. Both of these types of anomalies result from a defective midline fusion of the developing sternum. Sternal foramen is a relatively common bony defect that usually comes to light as an incidental finding. Sternal cleft is a rarer morphological anomaly that can have a wide spectrum of clinical manifestations and outcomes, depending on the extent of the bony defect as well as on the presence and severity of other abnormalities. The coexistence of a sternal foramen and a sternal cleft has very rarely been described in the literature. We report here one such unusual association and discuss its potential practical implications. In most cases, sternal foramina and small sternal clefts are clinically uneventful; yet, lack of awareness about the existence of these subtle anatomical variations can sometimes lead to misinterpretation of radiological and pathological findings or make sternal biopsy and acupuncture unsafe.

Long-term oral carvedilol in chronic heart failure

The long-term β-blockade strategy with carvedilol, metoprolol succinate or bisoprolol is now strongly recommended to reduce the rates of mortality and morbidity in patients with chronic heart failure (CHF). Although the benefits observed with such drugs are viewed as a class effect, theoretically, carvedilol might be superior to the other two agents, considering its unique pharmacological profile, which includes a more comprehensive antiadrenergic activity and potentially relevant ancillary properties. So far, carvedilol has been proven to be effective and safe in a broader range of CHF patients than metoprolol and bisoprolol. Moreover, a recent large clinical trial has shown a significantly greater survival benefit with carvedilol as directly compared with metoprolol tartrate. Therefore, carvedilol may be the preferred β-blocking agent to treat patients with CHF.

Deleterious impact of mild anemia on survival of young adult patients (age 45 ± 14 years) with idiopathic dilated cardiomyopathy: Data from the Trieste Cardiomyopathies Registry

OBJECTIVE The study objective was to evaluate the impact of anemia on a large population of young patients with idiopathic dilated cardiomyopathy (DCM) who were receiving optimal medical treatment. METHODS The data of 491 patients with DCM who were enlisted in the Trieste Heart Muscle Disease Registry were analyzed. Anemia was defined as hemoglobin less than 13 g/dL for male patients and less than 12 g/dL for female patients. RESULTS At baseline, 13% of our patients were anemic. During the follow-up of 134 ± 56 months, 144 patients died or underwent heart transplantation: 36.5% anemic patients and 28% non-anemic patients (P = .05). Anemia present at baseline was an independent predictor of outcome (hazard ratio = 1.85, P = .014). Serial hemoglobin determinations during the entire follow-up were available in 122 of 428 patients without anemia at baseline. The impact of new-onset anemia was analyzed in this cohort of patients. Forty-seven patients (39%) developed anemia during follow-up. The new onset of anemia was an independent predictor of poor outcome (hazard ratio = 2.85, P = .02). CONCLUSION The presence or development of mild anemia in young patients with optimally treated idiopathic DCM is frequent and associated with a worse outcome.