Mario Viganò

Long-Term Outcome and Risk Stratification in Dilated Cardiolaminopathies

OBJECTIVES The aim of this study was to analyze the long-term follow-up of dilated cardiolaminopathies. BACKGROUND Lamin A/C (LMNA) gene mutations cause a variety of phenotypes. In the cardiology setting, patients diagnosed with idiopathic dilated cardiomyopathy (DCM) plus atrioventricular block (AVB) constitute the majority of reported cases. METHODS Longitudinal retrospective observational studies were conducted with 27 consecutive families in which LMNA gene defects were identified in the probands, all sharing the DCM phenotype. RESULTS Of the 164 family members, 94 had LMNA gene mutations. Sixty of 94 (64%) were phenotypically affected whereas 34 were only genotypically affected, including 5 with pre-clinical signs. Of the 60 patients, 40 had DCM with AVB, 12 had DCM with ventricular tachycardia/fibrillation, 6 had DCM with AVB and Emery-Dreifuss muscular dystrophy type 2 (EDMD2), and 2 had AVB plus EDMD2. During a median of 57 months (interquartile range 36 to 107 months), we observed 49 events in 43 DCM patients (6 had a later event, excluded from the analysis). The events were related to heart failure (15 heart transplants, 1 death from end-stage heart failure) and ventricular arrhythmias (15 sudden cardiac deaths and 12 appropriate implantable cardioverter-defibrillator interventions). By multivariable analysis, New York Heart Association functional class III to IV and highly dynamic competitive sports for >or=10 years were independent predictors of total events. By a bivariable Cox model, splice site mutations and competitive sport predicted sudden cardiac death. CONCLUSIONS Dilated cardiomyopathies caused by LMNA gene defects are highly penetrant, adult onset, malignant diseases characterized by a high rate of heart failure and life-threatening arrhythmias, predicted by New York Heart Association functional class, competitive sport activity, and type of mutation.

Prognostic relevance of the echocardiographic assessment of right ventricular function in patients with idiopathic pulmonary arterial hypertension

BACKGROUND In patients with idiopathic pulmonary hypertension (IPAH) progression of the disease and survival are related to the capability of the right ventricle to adapt to the chronically elevated pulmonary artery pressure. Although several echocardiographic variables have been associated with outcome in previous studies, a comparative evaluation of all right ventricular (RV) function indices obtainable at echocardiography has never been performed. METHODS 59 patients consecutively admitted in a tertiary referral centre because of IPAH (22 males, mean age 46.3+/-16.1 years, 68% in WHO class III/IV at referral) underwent right heart catheterization and echocardiography. During a median follow-up period of 52 months, 21 patients died and 2 underwent lung transplantation in emergency conditions. RESULTS The following parameters were associated with survival: tricuspid annular plane systolic excursion (TAPSE), RV fractional area change, degree of tricuspid regurgitation, inferior vena cava collapsibility, superior vena cava flow velocity pattern, left ventricular diastolic eccentricity index. Patients with TAPSE<or=15 mm and left ventricular eccentricity index >or=1.7 had the highest event rate (51.7 per 100 person year); patients with TAPSE>15 mm and mild or no tricuspid regurgitation had the lowest event rate (2.6 per 100 person year). CONCLUSIONS A comprehensive echocardiographic assessment of RV systolic and diastolic function based on TAPSE, left ventricular diastolic eccentricity index and degree of tricuspid regurgitation allows an accurate prognostic stratification of patients with IPAH.

Mitochondrial DNA Mutations and Mitochondrial Abnormalities in Dilated Cardiomyopathy

Mitochondrial (mt)DNA defects, both deletions and tRNA point mutations, have been associated with cardiomyopathies. The aim of the study was to determine the prevalence of pathological mtDNA mutations and to assess associated defects of mitochondrial enzyme activity in dilated cardiomyopathy (DCM) patients with ultrastructural abnormalities of cardiac mitochondria. In a large cohort of 601 DCM patients we performed conventional light and electron microscopy on endomyocardial biopsy samples. Cases with giant organelles, angulated, tubular, and concentric cristae, and crystalloid or osmiophilic inclusion bodies were selected for mtDNA analysis. Mutation screening techniques, automated DNA sequencing, restriction enzyme digestion, and densitometric assays were performed to identify mtDNA mutations, assess heteroplasmy, and quantify the amount of mutant in myocardial and blood DNA. Of 601 patients (16 to 63 years; mean, 43.5 +/- 12.7 years), 85 had ultrastructural evidence of giant organelles, with abnormal cristae and inclusion bodies; 19 of 85 (22.35%) had heteroplasmic mtDNA mutations (9 tRNA, 5 rRNA, and 4 missense, one in two patients) that were not found in 111 normal controls and in 32 DCM patients without the above ultrastructural mitochondrial abnormalities. In all cases, the amount of mutant was higher in heart than in blood. In hearts of patients that later underwent transplantation, cytochrome c oxidase (Cox) activity was significantly lower in cases with mutations than in those without or controls (P = 0.0008). NADH dehydrogenase activity was only slightly reduced in cases with mutations (P = 0.0388), whereas succinic dehydrogenase activity did not significantly differ between DCM patients with mtDNA mutations and those without or controls. The present study represents the first attempt to detect a morphological, easily identifiable marker to guide mtDNA mutation screening. Pathological mtDNA mutations are associated with ultrastructurally abnormal mitochondria, and reduced Cox activity in a small subgroup of non-otherwise-defined, idiopathic DCMs, in which mtDNA defects may constitute the basis for, or contribute to, the development of congestive heart failure.

Mechanical Circulatory Support for Advanced Heart Failure

Background—Use of wearable left ventricular assist systems (LVAS) in the treatment of advanced heart failure has steadily increased since 1993, when these devices became generally available in Europe. The aim of this study was to identify in an unselected cohort of LVAS recipients those aspects of patient selection that have an impact on postimplant survival. Methods and Results—Data were obtained from the Novacor European Registry. Between 1993 and 1999, 464 patients were implanted with the Novacor LVAS. The majority had idiopathic (60%) or ischemic (27%) cardiomyopathy; the median age at implant was 49 (16 to 75) years. The median support time was 100 days (4.1 years maximum). Forty-nine percent of the recipients were discharged from the hospital on LVAS; they spent 75% of their time out of the hospital. For a subset of 366 recipients, for whom a complete set of data was available, multivariate analysis revealed that the following preimplant conditions were independent risk factors for survival after LV...

Long-term Outcome after Pulmonary Endarterectomy

RATIONALE There are few follow-up studies on long-term cardiopulmonary function after pulmonary endarterectomy (PEA), the operation of choice for chronic thromboembolic pulmonary hypertension (CTEPH). OBJECTIVES To prospectively evaluate long-term outcome of patients with CTEPH treated with PEA. METHODS Between 1994 and 2006, 157 patients (mean age 55 yr) were treated with PEA at Pavia University Hospital. The patients were evaluated before PEA and at 3 months (n = 132), 1 year (n = 110), 2 years (n = 86), 3 years (n = 69), and 4 years (n = 49) afterward by NYHA class, right heart hemodynamic, spirometry, carbon monoxide transfer factor (Tl(CO)), arterial blood gas, and treadmill incremental exercise test. MEASUREMENTS AND MAIN RESULTS Cumulative survival was 84%. Within 3 months, 18 patients died in-hospital and 2 had lung transplantation; during long-term follow-up, 6 died, 1 had lung transplantation, and 3 had a second PEA (2.5 events per 100 person-years). NYHA class III-IV was the most important predictor of late death, lung transplant, or PEA redo (hazard ratio, 3.94). Extraordinary improvement in NYHA class, hemodynamic, and Pa(O(2)) were achieved in the first 3 months (P < 0.001) and persisted during follow-up; exercise tolerance progressively increased over time (P < 0.001). At 4 years, although 74% of the patients were in NYHA class I and none was in class IV, 24% had pulmonary vascular resistance greater than 500 dyne.s/cm(5) or Pa(O(2)) less than 60 mm Hg; they were significantly older and were more frequently in NYHA class III-IV 3 months after surgery than the others. CONCLUSIONS After PEA, long-term survival and cardiopulmonary function recovery is excellent in most patients.

Demonstrable cardiac reinnervation after human heart transplantation by carotid baroreflex modulation of RR interval.

BACKGROUND After heart transplantation, respiration-synchronous fluctuations (0.18 to 0.35 Hz, high frequency [HF]) in RR interval may result from atrial stretch caused by changes in venous return, but slower fluctuations (0.03 to 0.15 Hz, low frequency [LF]) not due to respiration suggest reinnervation. In normal subjects, sinusoidal neck suction selectively stimulates carotid baroreceptors and causes reflex oscillations of RR interval. METHODS AND RESULTS To evaluate the presence of reinnervation, we measured the power of RR-LF and RR-HF in 26 heart transplant recipients and 16 control subjects before and during sinusoidal neck suction at 0.1 Hz and 0.20 Hz (similar to but distinct from that of controlled respiration, 0.25 Hz) and before and during administration of atropine or beta-blocker (esmolol hydrochloride) by spectral analysis. All transplant recipients showed small respiratory HF fluctuations. Nonrespiratory LF fluctuations were present in 13 of 26 transplant recipients and increased with months since transplantation (r = .53, P < .01). HF neck suction induced a 0.20-Hz component in all 16 control subjects and none of the 26 transplant subjects. LF neck suction increased RR-LF (from 0.73 +/- 0.20 to 1.30 +/- 0.26 ln ms2, P < .001), similar to but less than in control subjects (from 6.12 +/- 0.21 to 8.27 +/- 0.21 ln ms2, P < .001). Atropine reduced all fluctuations in control subjects and blocked the HF increase caused by 0.20-Hz neck suction but not the LF increase during 0.10-Hz stimulation. Neck suction-induced changes in LF fluctuations persisted after administration of atropine in transplant recipients but were attenuated by esmolol hydrochloride, suggesting sympathetic rather than vagal reinnervation. CONCLUSIONS The presence of baroreceptor-induced RR oscillations is evidence of functional, although incomplete, autonomic reinnervation.

Coronary atherosclerotic plaques with and without thrombus in ischemic heart syndromes: A morphologic, immunohistochemical, and biochemical study

We investigated incidence, severity, and distribution of coronary atherosclerosis, acute thrombosis, and plaque fissuring in ischemic heart disease (both unstable-acute syndromes and chronic ischemia) and in nonischemic controls. We also studied the structural, immunohistochemical, and biochemical profile of plaques, with and without thrombus, including morphometry, immunophenotyping of inflammatory infiltrates, cytokine presence, and ultrastructural features. Critical coronary stenosis was almost the rule in both acute and chronic ischemic series (greater than 90%) whereas it reached 50% in control subjects. Thrombosis was principally characteristic of unstable-acute ischemic syndromes (unstable angina, 32%; acute myocardial infarction, 52%; cardiac sudden death, 26%) but was also found in chronic ischemia (stable angina, 12%; ischemic cardiomyopathy, 14%) and in control subjects (4%). Plaque fissuring without thrombus occurred in low percentages in lipid-rich, severe eccentric plaques in most series. Major differences were found between pultaceous-rich versus fibrous plaques rather than between plaques with or without thrombus. Pultaceous-rich plaques were frequent in sites of critical stenosis, thrombosis, and ulceration. Inflammatory infiltrates, i.e., T cells, macrophages, and a few beta cells, mostly occurred in lipid-rich, plaques unrelated to thrombus. In adventitia, infiltrates were a common finding unrelated to any syndrome. Necrotizing cytokines such as alpha-TNF were immunohistochemically detected in macrophages, smooth muscle, and intimal cells and detected by immunoblotting in 67% of pultaceous-rich plaques, either with or without thrombus. Immune response mediators such as IL-2 were also expressed in analogous plaques but in a minor percentage (50%-40%). Media were extensively damaged in severely diseased vessels with and without thrombus. Ultrastructural study showed that the fibrous cap was either highly cellular or densely fibrillar. Intimal injury with collagen exposure was often associated with platelet adhesion, whereas foamy cell exposure was not. In conclusion, investigated parameters were essentially similar in plaques, both with and without thrombus, whereas major differences were found between pultaceous-rich and fibrous plaques. Since platelets adhere to exposed collagen and not to foam cells, the type of exposed substrates could play a major role in thrombosis.

Regulatory CD4+CD25+ T cells in the peripheral blood of lung transplant recipients: correlation with transplant outcome.

Background. The subset of CD4+CD25+ regulatory T cells, recently identified in humans, may play a central role in the regulation of immune tolerance to graft survival. Methods. This study assesses the frequency and functional profile of CD4+CD25+CD69− cells in the peripheral blood of lung transplant recipients (>3 years from transplantation), 10 of whom were in a stable clinical condition and 11 of whom demonstrated chronic rejection (bronchiolitis obliterans syndrome). We also studied a group of seven healthy subjects. Results. The frequency of CD4+ T cells expressing CD25 (CD4+CD25+) and the highest levels (CD25high) were lower in patients with bronchiolitis obliterans syndrome compared with healthy subjects and subjects in a stable clinical condition (P ≤0.01). Purified CD4+CD25+ cells exhibited a regulatory functional profile in vitro: they were hyporesponsive, suppressed the proliferation of CD4+CD25− cells, and produced interleukin-10. Conclusion. These results provide in vivo evidence that peripheral CD4+CD25+ T cells may represent an important regulatory subset in lung transplantation.

Plaque composition in plexogenic and thromboembolic pulmonary hypertension: the critical role of thrombotic material in pultaceous core formation.

Background: Patients with pulmonary hypertension develop intimal plaques in large pulmonary arteries. Objective: To test the hypothesis that the composition of such plaques differs depending on whether the aetiology of the disease is thromboembolic or hypertensive. Design: Chronic thromboembolic and plexogenic pulmonary hypertension (primary and secondary (Eisenmenger syndrome)) were investigated. These are spontaneous human models and were used to examine the independent role of thrombus and hypertension in plaque composition. Setting: A national tertiary referral centre for lung transplantation and pulmonary thromboendoarterectomy. Patients: Thirty nine patients with chronic thromboembolic pulmonary hypertension who had undergone thromboendoarterectomy (n = 32) or lung transplantation (n = 7), 28 with plexogenic diseases (nine primary and 19 Eisenmenger), and three with Eisenmenger syndrome complicated by thromboembolic events. Interventions: The lung and thromboendoarterectomy samples were sectioned, stained with Movat pentachrome, and immunostained with antibodies for fibrin, platelets, inflammatory cells, smooth muscle cells, and erythrocyte membrane glycophorin A. Main outcome measure: Composition of the plaques affecting large pulmonary arteries. Results: Two types of intimal lesion were distinguished in chronic thromboembolic pulmonary hypertension: fibrous plaques with angioneogenesis; and core-rich atherosclerotic plaques with pultaceous cores largely consisting of glycophorin immunoreactive material, with cholesterol clefts (61.5%), CD68 positive macrophages (84.6%), T lymphocytes (87%), and calcification (46.1%). The samples from the patients with Eisenmenger syndrome and thromboembolic complications had similar characteristics, whereas those from patients with uncomplicated primary pulmonary hypertension had core-free fibrous plaques, spotted with macrophages and T lymphocytes. Conclusions: Chronic thromboembolic pulmonary hypertension is associated with atherosclerotic plaques with glycophorin-rich pultaceous cores, and plexogenic pulmonary hypertension with fibrous plaques. Thromboembolic material thus plays a critical role in the formation of pultaceous cores, of which erythrocyte membrane derived glycophorin is a major component.

Desmin accumulation restrictive cardiomyopathy and atrioventricular block associated with desmin gene defects

Primary desminopathies are caused by desmin gene [DES (MIM*125660)] mutations. The clinical spectrum includes pure myopathies, cardiomuscular diseases and cardiomyopathies. Patients with restrictive cardiomyopathy (RCM) plus atrioventricular block (AVB) due to DES defects are frequently unrecognized unless desmin accumulation is specifically investigated in endomyocardial biopsy (EMB) by ultrastructural study.