COVID-19 and renin-angiotensin system inhibition: role of angiotensin converting enzyme 2 (ACE2) - Is there any scientific evidence for controversy?

Renin-angiotensin system (RAS) blockers are extensively used worldwide to treat many cardiovascular disorders, where they are effective in reducing both mortality and morbidity. These drugs are known to induce an increased expression of angiotensin-converting enzyme 2 (ACE2). ACE2 acts as receptor for the novel SARS coronavirus-2 (SARS-CoV-2) which raising the important issue of possible detrimental effects that RAS blockers could exert on the natural history and pathogenesis of the coronavirus disease-19 (COVID-19) and associated excessive inflammation, myocarditis and cardiac arrhythmias. We review the current knowledge on the interaction between SARS-CoV-2 infection and RAS blockers and suggest a scientific rationale for continuing RAS blockers therapy in patients with COVID-19 infection.

Genetics of Dilated Cardiomyopathy: Clinical Implications.

PURPOSE OF REVIEW: This review aims to summarize the current knowledge on the genetic background of dilated cardiomyopathy (DCM), with particular attention to the genotype-phenotype correlations and the possible implications for clinical management. RECENT FINDINGS: Next generation sequencing (NGS) has led to the identification of an increasing number of genes and mutations responsible for DCM. This genetic variability is probably related to the extreme heterogeneity of disease manifestation. Important findings have associated mutations of Lamin A/C (LMNA) and Filamin C (FLNC) to poor prognosis and the propensity to cause an arrhythmic phenotype, respectively. However, a deeper understanding of the genotype-phenotype correlation is necessary, because it could have several implications for the clinical management of the patients. Furthermore, the correct interpretation of pathogenicity of mutations and the clinical impact of genetic testing in DCM patients still represent important fields to be implemented. A pathogenic gene mutation can be identified in almost 40% of DCM patients. The recent discoveries and future research in the field of genotype-phenotype correlation may lead to a more personalized management of the mutation carriers towards the application of precision medicine in DCM.

Prognostic Impact of BNP Variations in Patients Admitted for Acute Decompensated Heart Failure with In-Hospital Worsening Renal Function.

BACKGROUND: The significance of worsening renal function (WRF) in patients admitted for acute decompensated heart failure (ADHF) is still controversial. We hypothesised that changes in brain natriuretic peptide (BNP) might identify patients with optimal diuretic responsiveness resulting in transient WRF, not negatively affecting the prognosis. Our aim was to verify if in-hospital trends of BNP might be helpful in the stratification of patients with WRF after treatment for ADHF. METHODS: 122 consecutive patients admitted for ADHF were enrolled. Brain natriuretic peptide and eGFR were evaluated at admission and discharge. A 20% relative decrease in eGFR defined WRF, whereas a BNP reduction ≥40% was considered significant. The primary combined endpoint was death/urgent heart transplantation and re-hospitalisation for ADHF. RESULTS: Worsening renal function occurred in 23% of patients without differences in outcome between patients with and without WRF (43% vs. 45%, p=0.597). A significant reduction in BNP levels over the hospitalisation occurred in 59% of the overall population and in 71% of patients with WRF. At a median follow-up of 13.0 (IQR 6-36) months, WRF patients with ≥40% BNP reduction had a lower rate of death/urgent heart transplantation/re-hospitalisation compared to WRF patients without BNP reduction (30% and 75%, respectively; p=0.007). Favourable BNP trend was the strongest variable in predicting the outcome in WRF patients (HR 0.222, 95% CI 0.066-0.753, p=0.016). CONCLUSIONS: Worsening renal function does not affect the prognosis of ADHF and, when associated with a significant BNP reduction, identifies patients with adequate decongestion at discharge and favourable outcome.

Applicability and performance of heart failure prognostic scores in dilated cardiomyopathy: the real-world experience of an Italian referral center for cardiomyopathies.

BACKGROUND: The performance of heart failure (HF) risk models is validated in the general population with HF but in specific aetiological settings, and specifically in dilated cardiomyopathy (DCM), has scarcely been explored. We tested eight of the main prognostic scores used in HF in a large real-world population of patients with DCM. METHODS: We included 784 consecutive DCM patients enrolled, both inpatients and outpatients, enrolled between January 2000 and December 2017. The risk of 1 and/or 3-year all-cause mortality/heart transplantation/durable left ventricular assist device (LVAD) implantation (D/HTx/LVAD) was estimated in our cohort according to the following risk scores SHFM, 3-CHF, CHARM, MAGGIC, GISSI-HF, MECKI, Barcelona Bio-HF, Krakow score and their accuracy calculated through the receiver operator characteristic (ROC) curve analysis. RESULTS: During a median follow-up of 5.8 years (Interquartile Range 3.2-7.6 years), 191 patients (20%) died or underwent HTx/LVAD (158 deaths, 30 heart transplantations, and 3 LVAD implantations). The high missing rate allowed to calculated only four prognostic models (MAGGIC, CHARM, 3-CHF and SHFM). All the scores overestimated the rate of D/HTx/LVAD. The prognostic accuracy was suboptimal for MAGGIC (AUC 0.754) and CHARM (AUC 0.720) scores and only modest for 3-CHF (AUC 0.677) and SHFM (AUC 0.667). CONCLUSIONS: Main prognostic scores for the risk stratification of HF are only partially applicable to real-world patients with DCM. MAGGIC and CHARM scores showed the best accuracy, despite the overestimation of risk. Our findings corroborate the need of specific risk scores for the prognostic stratification of DCM. CLINICAL PERSPECTIVE: What is new? The present study is the largest analysis in literature which investigate how the main existing heart failure prognostic risk scores performed in a real-world of dilated cardiomyopathy population, both in- and outpatients. What are the clinical implications? DCM is a stand-alone model of heart failure, where the performance of multiple heart failure prognostic scores for the risk stratification is quite limited. The need for contemporary, dedicated prognostic scores in this disease is increasingly evident.

Strain analysis reveals subtle systolic dysfunction in confirmed and suspected myocarditis with normal LVEF. A cardiac magnetic resonance study.

AIMS: Lake Louise Criteria (LLC) are time-dependent and some acute myocarditis (AM) with preserved left ventricular ejection fraction (LVEF) could be missed, due to the limited accessibility of Cardiac Magnetic Resonance (CMR). We aimed to assess the potential value of cardiac strain measured by feature tracking (FT) imaging in this population. METHODS AND RESULTS: Eighty-three patients with clinically suspected AM and normal LVEF were divided into 39 "confirmed AM" (positive LLC) and 44 "suspected AM" (negative LLC). An age and gender-matched sample of 42 normal subjects underwent CMR. In all groups, FT-derived biventricular strains and STE- global longitudinal strain (GLS) were assessed, being regularly measurable. Strain values < 5th percentile of the control group were considered abnormal. "Suspected" and "confirmed" AM were similar, except for medium time of CMR evaluation (5.2 vs 1 months from presentation, respectively; p = 0.004). Compared to healthy controls, both "suspected" and "confirmed" AM showed significantly impaired strain values. LV-global circumferential strain (GCS), right ventricular GCS and LV-GLS were abnormal in 15.4% and 15.9%, 20.5% and 15.9%, 7.7% and 9.1% in "confirmed" and "suspected" AM, respectively. STE analysis confirmed the results on LV-GLS, however a weak correlation emerged between STE and CMR-FT LV-GLS (p = 0.08). CONCLUSIONS: Compared to STE, CMR-FT analysis provided a more comprehensive and complementary biventricular strain evaluation that resulted similar in "confirmed" and "suspected" AM with normal LVEF. Conversely, mostly biventricular GCS was significantly reduced in up to 20% of patients, compared to healthy controls.

Reverse remodeling in Dilated Cardiomyopathy: Insights and future perspectives.

Dilated Cardiomyopathy (DCM) has been classically considered a progressive disease of the heart muscle that inexorably progresses towards refractory heart failure, ventricular arrhythmias and heart transplant. However, the prognosis of DCM has significantly improved in the past few years, mostly as the result of successful therapy-induced reverse remodeling. Reverse remodeling is a complex process that involves not only the left ventricle, but also many other cardiac structures and it is now recognized both as a measure of therapeutic effectiveness and as an important prognostic tool. Nevertheless, several aspects of reverse remodeling remain unclear, including the best timing for its quantification, its predictors and its interaction with individual genetic backgrounds. In this review, we summarize our current understanding of reverse remodeling in patients with DCM and provide practical recommendations for the clinical management of this challenging patient population.

Relation between the plasma levels of LDL-cholesterol and the expression of the early marker of inflammation long pentraxin PTX3 and the stress response gene p66ShcA in pacemaker-implanted patients.

Our goal was to set up a pilot study to explore the possible relation between the expression of p66((ShcA)) and PTX3, two emerging regulators of stress response and inflammation processes, respectively, and the circulating levels of LDL-cholesterol (LDL), a factor implicated in the development of inflammation and oxidative-stress associated diseases such as atherosclerosis. p66((ShcA)) and PTX3 mRNA contents were determined locally, in subcutaneous adipose specimens of non-diabetic pacemaker-implanted patients, and systemically in the circulating white blood cells (WBC) obtained from the same patients. The mean of the circulating LDL levels (125 mg/dl) was chosen as a threshold to identify two groups here considered to have high (>125 mg/dl) and low (<125 mg/dl) LDL plasma levels. Our data show that PTX3 and p66((ShcA)) mRNA levels are significantly more elevated in WBCs and in adipose tissue samples of patients with high levels of LDL compared to those with low levels. Additionally, a multiple regression analysis indicates that among LDL, TG, HDL, total cholesterol, CRP, creatinine and glucose levels, the only variable significantly affecting p66((ShcA)) and PTX3 mRNA expressions either in adipose tissue or in WBCs is represented by the circulating amount of LDL. In conclusion, our results suggest a potential link between the level of LDL and the expression of two genes involved in inflammation/oxidative stress pathways, i.e., p66((ShcA)) and PTX3, thus contributing to further understand the mechanism through which LDL may mediate the pathogenesis of inflammation and oxidative-stress associated diseases such as atherosclerosis.

Lamin A/C gene mutation associated with dilated cardiomyopathy with variable skeletal muscle involvement.

BACKGROUND: Dilated cardiomyopathy is a form of heart muscle disease characterized by impaired systolic function and ventricular dilation. Familial transmission of the disease is frequently observed, and genetic heterogeneity is indicated by clinical and morphological variability in the disease phenotype. In the family MDDC1 reported here, the disease phenotype is severe and characterized by an autosomal dominant pattern of transmission. In addition, the majority of affected family members show signs of mild skeletal muscle involvement. METHODS AND RESULTS: On the basis of the clinical observation of both cardiac and skeletal muscle abnormalities in the MDDC1 family, the lamin A/C gene was examined in this kindred. Coding regions were polymerase chain reaction-amplified from genomic DNA and sequenced. A single nucleotide deletion was identified within exon 6, and all affected individuals were found to be heterozygous for this deletion. CONCLUSIONS: Heterozygosity for a single nucleotide deletion in exon 6 of lamin A/C segregates with both the cardiac and skeletal abnormalities observed in the MDDC1 family.

Restrictive left ventricular filling pattern in dilated cardiomyopathy assessed by Doppler echocardiography: clinical, echocardiographic and hemodynamic correlations and prognostic implications. Heart Muscle Disease Study Group.

OBJECTIVES: This study was undertaken to evaluate the frequency of restrictive left ventricular filling pattern in dilated cardiomyopathy, as well as its clinical and hemodynamic correlations and prognostic implications. BACKGROUND: In dilated cardiomyopathy, as in other heart diseases, different left ventricular filling patterns were observed on Doppler echocardiography. Some patients showed a "restrictive filling pattern," similar to that associated with restrictive cardiomyopathy, characterized by predominant E waves and a shortened E deceleration time. METHODS: Pulsed Doppler transmitral curves were analyzed in 79 consecutive patients with dilated cardiomyopathy assigned to two study groups according to E deceleration time: group 1 (n = 36) had a restrictive left ventricular filling pattern (E deceleration time < 115 ms); group 2 (n = 43) had an E deceleration time > or = 115 ms. RESULTS: Patients in group 1 were significantly younger, in a higher New York Heart Association functional class, more frequently had a third heart sound and had a higher left ventricular filling pressure at catheterization. In addition, they showed more severe left and right ventricular dysfunction and dilation, a larger left atrium and more severe mitral regurgitation. A restrictive filling pattern was associated at Doppler study with a higher E wave velocity, lower A wave velocity and higher E/A ratio. During a follow-up interval of 22 +/- 14 months, all 14 patients who subsequently died or required heart transplantation showed a restrictive left ventricular filling pattern. At multivariate analysis, E deceleration time was the most powerful independent prognostic indicator of poor outcome or transplantation. CONCLUSIONS: Restrictive left ventricular filling pattern is frequent in dilated cardiomyopathy, is associated with more severe disease and is a powerful indicator of increased mortality risk and need for heart transplantation.

Persistence of restrictive left ventricular filling pattern in dilated cardiomyopathy: an ominous prognostic sign.

OBJECTIVES: We sought to assess the prognostic implications of the evolution of restrictive left ventricular filling pattern (RFP) in dilated cardiomyopathy (DCM). BACKGROUND: Previous work has demonstrated that a RFP in DCM is associated with a poor prognosis. Few data are available on the prognostic implications of the evolution of this pattern. METHODS: The evolution of left ventricular filling was studied by Doppler echocardiography in 110 patients with DCM. According to the left ventricular filling pattern at presentation and after 3 months of treatment, the patients were classified into three groups: Group 1A (n = 24) had persistent restrictive filling; Group 1B (n = 29) had reversible restrictive filling; and Group 2 (n = 57) had nonrestrictive filling. RESULTS: During follow-up (41 +/- 20 months), mortality plus heart transplantations was significantly higher in Group 1A than in Groups 1B and 2 (p < 0.0001). On multivariate analysis, the model incorporating E wave deceleration time at 3 months was more powerful at predicting mortality with respect to this variable at baseline (p = 0.0039). Clinical improvement at 1 and 2 years was significantly more frequent in Groups 1B and 2 than in Group 1A (p < 0.0001 at 2 years). CONCLUSIONS: In patients with DCM, the persistence of restrictive filling at 3 months is associated with a high mortality and transplantation rate. The patients with reversible restrictive filling have a high probability of improvement and excellent survival. Doppler echocardiographic reevaluation of these patients after 3 months of therapy gives additional prognostic information with respect to the initial study.

Improved exercise hemodynamic status in dilated cardiomyopathy after beta-adrenergic blockade treatment.

OBJECTIVES: This study was performed to investigate exercise hemodynamic status in a double-blind, placebo-controlled trial and was a substudy in the Metoprolol in Dilated Cardiomyopathy Trial. BACKGROUND: Previous open studies have shown beneficial effects on exercise hemodynamic status after beta-adrenergic blocking agent therapy in patients with congestive heart failure. METHODS: The study included 41 patients with idiopathic dilated cardiomyopathy with ejection fraction < 0.40 (metoprolol, 20 patients; placebo, 21 patients) whose hemodynamic status was investigated at rest and during supine submaximal exercise, at baseline and after 6 and 12 months of treatment. Myocardial metabolism was evaluated in a subset of 19 patients. RESULTS: Metoprolol-treated patients responded favorably, as expressed by improved exercise cardiac index ([mean +/- SD] placebo 4.8 +/- 1.6 to 4.7 +/- 1.8 liters/min per m2, metoprolol 4.3 +/- 1.1 to 5.4 +/- 1.9 liters/min per m2, p = 0.0001) and stroke work index (placebo 44 +/- 20 to 41 +/- 27 g.m/m2, metoprolol 35 +/- 16 to 58 +/- 28 g.m/m2, p < 0.0001). Exercise systolic arterial pressure increased (placebo 161 +/- 25 to 151 +/- 23 mm Hg, metoprolol 155 +/- 29 to 165 +/- 37 mm Hg, p = 0.0003) as well as exercise oxygen consumption index (placebo 463 +/- 194 to 474 +/- 232 ml/min per m2, metoprolol 406 +/- 272 to 507 +/- 298 ml/min per m2, p = 0.045). There was a significant increase in exercise duration in the metoprolol group (63 +/- 38 s) compared with the placebo group (-24 +/- 42 s) (p = 0.01). Net myocardial lactate extraction increased in the metoprolol group, suggesting less myocardial ischemia (placebo 17 +/- 22 to 9.5 +/- 6.4 mmol/min, metoprolol -32 +/- 100 to 42 +/- 45 mmol/min, p = 0.03). Peripheral levels of norepinephrine tended to decrease at rest and during exercise, whereas myocardial net spillover was unchanged. CONCLUSIONS: Metoprolol improved hemodynamic status in patients with dilated cardiomyopathy at rest and had a more pronounced effect during exercise. These positive effects were achieved along with improved or stable myocardial metabolic data.

Long-term effects of carvedilol in idiopathic dilated cardiomyopathy with persistent left ventricular dysfunction despite chronic metoprolol. The Heart-Muscle Disease Study Group.

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 < or =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 = 16, mean dosage 142+/-44 mg/day) or to cross over to maximum tolerated dosage of carvedilol (n = 14, mean dosage 74+/-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 -8+/-7 vs. +7+/-6 ml/m2, p = 0.053; end-systolic volume -7+/-5 vs. +6+/-4 ml/m2, p = 0.047), an improvement in LV ejection fraction (+7+/-3% vs. -1+/-2%, p = 0.045), a reduction in ventricular ectopic beats (-12+/-9 vs. +62+/-50 n/h, p = 0.05) and couplets (-0.5+/-0.4 vs. +1.5+/-0.6 n/h, p = 0.048), no significant benefit on symptoms and quality of life and a negative effect on peak oxygen consumption (-0.6+/-0.6 vs. +1.3+/-0.5 ml/kg/min, p = 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.

Familial dilated cardiomyopathy: evidence for genetic and phenotypic heterogeneity. Heart Muscle Disease Study Group.

OBJECTIVES: This study was performed to evaluate the characteristics, mode of inheritance and etiology of familial dilated cardiomyopathy (FDC). BACKGROUND: A genetic form of disease transmission has been identified in a relevant proportion of patients with dilated cardiomyopathy (DCM). Variable clinical characteristics and patterns of inheritance, and an increased frequency of cardiac antibodies have been reported. An analysis of FDC may improve the understanding of the disease and the management of patients. METHODS: Of 350 consecutive patients with idiopathic DCM, 281 relatives from 60 families were examined. Family studies included clinical examination, electrocardiography, echocardiography and blood sampling. Of the 60 DCM index patients examined, 39 were attributable to FDC and 21 were due to sporadic DCM. Clinical features, histology, mode of inheritance and autoimmune serology were examined, molecular genetic studies were undertaken and the difference between familial and sporadic forms was analyzed. RESULTS: Only a younger age (p = 0.0005) and a higher ejection fraction (p = 0.03) could clinically distinguish FDC patients from those with sporadic DCM. However, a number of distinct subtypes of FDC were identified: 1) autosomal dominant, the most frequent form (56%); 2) autosomal recessive (16%), characterized by worse prognosis; 3) X-linked FDC (10%), with different mutations of the dystrophin gene; 4) a novel form of autosomal dominant DCM with subclinical skeletal muscle disease (7.7%); 5) FDC with conduction defects (2.6%), and 6) rare unclassifiable forms (7.7%). The forms with skeletal muscle involvement were characterized by a restrictive filling pattern; the forms with isolated cardiomyopathy had an increased frequency of organ-specific cardiac autoantibodies. Histologic signs of myocarditis were frequent and nonspecific. CONCLUSIONS: Familial dilated cardiomyopathy is frequent, cannot be predicted on a clinical or morphologic basis and requires family screening for identification. The phenotypic heterogeneity, different patterns of transmission, different frequencies of cardiac autoantibodies and the initial molecular genetic data indicate that multiple genes and pathogenetic mechanisms can lead to FDC.

Nonpredictive value of fibrosis in dilated cardiomyopathy treated with metoprolol.

Therapy with ß-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 ß-blocker treatment in dilated cardiomyopathy (DCM). In order to predict the response to ß-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 King's 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 ß-blocker treatment. Otherwise, prevalent perivascular and/or focal replacement fibrosis could be associated with a higher probability of improvement after long-term ß-blocker treatment.

Familial right ventricular dysplasia with biventricular involvement and inflammatory infiltration. Heart Muscle Disease Study Group.

The aetiology of right ventricular dysplasia/cardiomyopathy is presently unknown. A genetic background has been suggested, but myocarditis may play a part in its pathogenesis. Two familial cases of right ventricular dysplasia, one of whom had also a diagnosis of myocarditis, are reported. Both patients presented with ventricular arrhythmias. The father subsequently had a "flu-like" syndrome, heart failure, and biventricular dysfunction; "active" myocarditis was found at endomyocardial biopsy. Then the patient died suddenly. The daughter developed progressive biventricular dysfunction; then she was resuscitated from a cardiac arrest, and subsequently died suddenly. In both patients necropsy showed severe right ventricular atrophy and fibro-adipose substitution, associated with biventricular fibrosis. Inflammatory infiltration was also present in the first patient. This study shows the association of right ventricular dysplasia and myocarditis in the same family. These cases may represent a link between inherited and acquired ("inflammatory") forms of the disease.

Long-term survival effect of metoprolol in dilated cardiomyopathy. The SPIC (Italian Multicentre Cardiomyopathy Study) Group.

OBJECTIVE: To evaluate the additive effect of metoprolol treatment on long-term incidence of fatal and non-fatal cardiac events in idiopathic dilated cardiomyopathy. DESIGN: 586 patients with idiopathic dilated cardiomyopathy were prospectively enrolled in a multicentre registry and followed up for a mean (SD) of 52 (32) months. Metoprolol, carefully titrated to the maximum tolerated dose, was added to conventional heart failure treatment in 175 patients. RESULTS: Survival and transplant-free survival at seven years were significantly higher in the 175 metoprolol treated patients than in the remaining 411 on standard treatment (81% v 60%, p < 0.001, and 69% v 49%, p < 0.001, respectively). By multivariate analysis, metoprolol independently predicted survival and transplant-free survival (relative risk reduction values for all cause mortality and combined mortality or transplantation 51% (95% confidence interval 21% to 69%), p = 0.002, and 34% (5% to 53%), p = 0.01, respectively). New York Heart Association class, left ventricular end diastolic diameter, and pulmonary wedge pressure were also predictive. Seven year survival (80% v 62%, p = 0.004) and transplant-free survival (68% v 51%, p = 0.005) were significantly higher in 127 metoprolol treated cases than in 127 controls selected from the entire control cohort and appropriately matched. Metoprolol was associated with a 30% reduction in all cause mortality (7% to 48%, p = 0.015) and a 26% reduction in mortality or transplantation (7% to 41%, p = 0.009). CONCLUSIONS: The addition of metoprolol to standard heart failure treatment, including angiotensin converting enzyme inhibitors, was effective in the long-term, reducing both all cause mortality and transplantation in patients with idiopathic dilated cardiomyopathy.

Dystrophin gene abnormalities in two patients with idiopathic dilated cardiomyopathy.

Two new cases of dilated cardiomyopathy (DC) caused by dystrophinopathy are reported. One patient, a 24 year old man, had a family history of X linked DC, while the other, a 52 year old man, had sporadic disease. Each had abnormal dystrophin immunostaining in muscle or cardiac biopsy specimens, but neither had muscle weakness. Serum creatine kinase activity was raised only in the patient with familial disease. Analysis of dystrophin gene mutations showed a deletion of exons 48-49 in the patient with familial DC and of exons 49-51 in the other. Dystrophin transcription in cardiac tissue from the patient with sporadic disease showed abundant expression, predominantly of the muscle isoform. This study, together with previous reports, suggests that some patients with DC have a dystrophinopathy that can be diagnosed using a combination of biochemical and genetic analyses.

Potential risk of beta-blockade withdrawal in congestive heart failure due to abrupt autonomic changes.

Beta-Blockers reduce mortality in patients with congestive heart failure and a proposed mechanism has been changes of autonomic tone. Heart rate variability is a non-invasive tool to estimate cardiac autonomic tone. The aim was to study changes of heart rate variability in patients with congestive heart failure on placebo, on the beta1-selective antagonist metoprolol or 24 h after metoprolol withdrawal. Forty-five patients with congestive heart failure were studied with Holter recordings. Heart rate variability measurements were performed before, after 6-12 months of treatment with 150 mg metoprolol/placebo, or 24 h after discontinued metoprolol. After treatment, patients on beta-blockade had a significantly longer mean RR interval and changes of heart rate variability, suggesting elevated vagal tone. Patients monitored in the rebound phase of beta-blocker withdrawal had a significant vagal reduction to the level of the placebo group. There was also a nonsignificant trend towards increased sympathetic tone (LF/HF over 24 h), compared with the beta-blockade group. Heart rate variability indicates an elevated vagal tone during treatment with metoprolol but beta-blockade withdrawal shifts the autonomic balance towards lower vagal and higher sympathetic tone within 24 h. These results could imply a potential risk when abruptly discontinuing beta-blockade medication in these patients.