Gianfranco Frigo

Mutations in Desmoglein-2 Gene Are Associated With Arrhythmogenic Right Ventricular Cardiomyopathy

Background— Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive myocardial atrophy with fibrofatty replacement. The recent identification of causative mutations in plakoglobin, desmoplakin (DSP), and plakophilin-2 (PKP2) genes led to the hypothesis that ARVC is due to desmosomal defects. Therefore, desmoglein-2 (DSG2), the only desmoglein isoform expressed in cardiac myocytes, was screened in subjects with ARVC. Methods and Results— In a series of 80 unrelated ARVC probands, 26 carried a mutation in DSP (16%), PKP2 (14%), and transforming growth factor-&bgr;3 (2.5%) genes; the remaining 54 were screened for DSG2 mutations by denaturing high-performance liquid chromatography and direct sequencing. Nine heterozygous DSG2 mutations (5 missense, 2 insertion-deletions, 1 nonsense, and 1 splice site mutation) were detected in 8 probands (10%). All probands fulfilled task force criteria for ARVC. An endomyocardial biopsy was obtained in 5, showing extensive loss of myocytes with fibrofatty tissue replacement. In 3 patients, electron microscopy investigation was performed, showing intercalated disc paleness, decreased desmosome number, and intercellular gap widening. Conclusions— This is the first investigation demonstrating DSG2 gene mutations in a significant number of ARVC-unrelated probands. Cardiac phenotype is characterized clinically by typical ARVC features with frequent left ventricular involvement and morphologically by fibrofatty myocardial replacement and desmosomal remodeling. The presence of mutations in desmosomal encoding genes in 40% of cases confirms that many forms of ARVC are due to alterations in the desmosome complex.

Three-Dimensional Electroanatomic Voltage Mapping Increases Accuracy of Diagnosing Arrhythmogenic Right Ventricular Cardiomyopathy/Dysplasia

Background—Three-dimensional electroanatomic voltage mapping offers the potential to identify low-voltage areas that correspond to regions of right ventricular (RV) myocardial loss and fibrofatty replacement in patients with arrhythmogenic RV cardiomyopathy/dysplasia (ARVC/D). Methods and Results—Thirty-one consecutive patients (22 men and 9 women; mean age, 30.8±7 years) who fulfilled the criteria of the Task Force of the European Society of Cardiology and International Society and Federation of Cardiology (ESC/ISFC) for ARVC/D diagnosis after noninvasive clinical evaluation underwent further invasive study including RV electroanatomic voltage mapping and endomyocardial biopsy (EMB) to validate the diagnosis. Multiple RV endocardial, bipolar electrograms (175±23) were sampled during sinus rhythm. Twenty patients (group A; 65%) had an abnormal RV electroanatomic voltage mapping showing ≥1 area (mean 2.25±0.7) with low-voltage values (bipolar electrogram amplitude <0.5 mV), surrounded by a border zone (0.5 to 1.5 mV) that transitioned into normal myocardium (>1.5 mV). Low-voltage electrograms appeared fractionated with significantly prolonged duration and delayed activation. In 11 patients (group B; 35%), electroanatomic voltage mapping was normal, with preserved electrogram voltage (4.4±0.7 mV) and duration (37.2±0.9 ms) throughout the RV. Low-voltage areas in patients from group A corresponded to echocardiographic/angiographic RV wall motion abnormalities and were significantly associated with myocyte loss and fibrofatty replacement at EMB (P<0.0001) and familial ARVC/D (P<0.0001). Patients from group B had sporadic disease and histopathological evidence of inflammatory cardiomyopathy (P<0.0001). During the time interval from onset of symptoms to the invasive study, 11 patients (55%) with electroanatomic low-voltage regions received an implantable cardioverter/defibrillator because of life-threatening ventricular arrhythmias, whereas all but 1 patient with a normal voltage map remained stable on antiarrhythmic drug therapy (P=0.02). Conclusions—Three-dimensional electroanatomic voltage mapping enhanced accuracy for diagnosing ARVC/D (1) by demonstrating low-voltage areas that were associated with fibrofatty myocardial replacement and (2) by identifying a subset of patients who fulfilled ESC/ISFC Task Force diagnostic criteria but showed a preserved electrogram voltage, an inflammatory cardiomyopathy mimicking ARVC/D, and a better arrhythmic outcome.

Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1): confirmation of locus assignment and mutation screening of four candidate genes

Arrhythmogenic right ventricular cardiomyopathy type 1 (ARVD1) is an autosomal dominant disorder characterised by progressive degeneration of right ventricular myocardium, arrhythmias and risk of sudden death. By linkage analysis, we previously mapped the involved gene to chromosome 14q24.3. In the present study we report on linkage analysis of one additional and unrelated family, which enabled to confirm previous locus assignment. Another family is reported, in which genetic and clinical data suggest linkage to the same locus. Direct sequencing of DNA from individuals belonging to established ARVD1 families failed to detect causative mutations in exonic sequences of four genes (POMT2, TGFβ3, KIAAA1036 and KIAA0759) expressed in the heart and which defects could possibly induce plasma membrane instability or apoptosis, key features of ARVD pathogenesis.

Differences and similarities between arrhythmogenic right ventricular cardiomyopathy and athlete’s heart adaptations

Background Regular intensive physical activity is associated with non-pathological changes in cardiac morphology. Differential diagnosis with arrhythmogenic right ventricular cardiomyopathy (ARVC) constitutes a frequent problem, especially in athletes showing ventricular arrhythmias with left bundle branch block morphology. Aim of the study To assess the different clinical and non-invasive instrumental features of the subjects affected by ARVC and by athletes. Methods Three groups of subjects (40 ARVC patients, 40 athletes and 40 controls, mean age 27 (9) years) were examined with family and personal history, physical examination, 12-lead ECG, 24-h ECG, signal-averaged ECG and 2-D and Doppler echocardiography. Results 12-Lead ECG was abnormal in 62% of ARVC patients versus 7.5% of athletes and 2.5% of controls (p<0.0001). Ventricular arrhythmias and late potentials were present in 70% and 55% of ARVC subjects, respectively (vs 5% of athletes and 7.5% of controls, p<0.0001). Left ventricular parietal wall thickness and left ventricular end-diastolic diameters were significantly higher in athletes. Both athletes and ARVC patients presented a right ventricular (RV) enlargement compared with controls. Moreover, RV outflow tract, measured on parasternal long axis and at the level of aortic root, was significantly larger in ARVC patients (33.6 (4.7) mm vs 29.1 (3.4) mm and 35.6 (6.8) mm vs 30.1 (2.9) mm; p<0.0001), and RV fractional shortening and ejection fraction were significantly lower in ARVC patients compared with athletes (40 (7.9)% vs 44 (10)%; p=0.05 and 52.9 (8)% vs 59.9 (4.5)%; p<0.0001). A thickened moderator band was found to be present in similar percentage in ARVC patients and athletes. Conclusions An accurate clinical and instrumental non-invasive evaluation including echocardiography as imaging technique allows to distinguish RV alterations typical of ARVC from those detected in athletes as a consequence of intensive physical activity.

Reproducibility of heart rate measured in the clinic and with 24-hour intermittent recorders

This study was undertaken to assess the reproducibility of office versus ambulatory heart rates in 839 hypertensive subjects participating in the Hypertension and Ambulatory Recording Venetia Study (HARVEST). A 24-hour heart rate was recorded twice; this procedure was repeated three months later. Reproducibility was better for ambulatory than for office measurement, and was greater for 24-hour than for daytime heart rate, and lowest for night-time heart rate. Reproducibility of office heart rate was impaired above 85 bpm, and was poorer in subjects with more severe office hypertension. A small but significant decrease in average daytime (-1 bpm, P < 0.0001) and virtually no change in night-time heart rate (-0.3 bpm, NS) were observed at repeat recording. Heart rate reproducibility indices were related to the extent of the heart rate and blood pressure white-coat effect, but did not vary according to age, gender, body mass index, day-night blood pressure difference, or alcohol or tobacco use. Results indicate that heart rate recorded over the 24 hours has a better reproducibility than office heart rate, and could thus be a better prognostic indicator than traditional measurement of resting heart rate in the hospital setting.

Alpha-adducin Gly460Trp polymorphism, left ventricular mass and plasma renin activity

Objective Left ventricular hypertrophy (LVH) is associated with an increased risk for cardiovascular morbidity and mortality. Epidemiological studies suggest that LVH may be influenced by genetic factors. However, the evidence associating individual genes with left ventricular (LV) mass is inconsistent and contradictory. Methods We investigated the association between angiotensin-converting enzyme insertion/deletion, angiotensinogen M235T and α-adducin Gly460Trp polymorphisms with LV mass and plasma renin activity (PRA) in 162 men with mild, never-treated hypertension who were recruited for the Hypertension and Ambulatory Recording Venetia Study. The effect of each polymorphism on LV mass and PRA was tested in one-way analysis of covariance using LV mass index or PRA as the dependent variable after adjusting for covariates. Results The α-adducin polymorphism was the only individual polymorphism independently associated with LV mass index (F = 7.78, P = 0.006). Patients homozygous for the Trp allele of that polymorphism had a LV mass index (123.4 ± 10.5 g/m2) significantly higher compared with heterozygotes (90.8 ± 2.5 g/m2, P < 0.01) or Gly homozygotes (94.7 ± 1.7 g/m2, P < 0.05). These subjects also have significantly lower PRA (F = 4.2, P = 0.017). Albeit uncommon, 40% of Trp homozygotes of the α-adducin polymorphism had LVH (odds ratio, 15.1; 95% confidence interval, 3.0–82.1). Conclusions The homozygotic state of the Trp allele of α-adducin Gly460Trp polymorphism is independently associated with increased LV mass and low PRA. These data suggest that genetic considerations may contribute importantly to risk stratification, and perhaps therapeutic interventions targeted at LVH and the renin–angiotensin system in hypertensive patients.

G protein β3 subunit gene 825T allele is associated with increased left ventricular mass in young subjects with mild hypertension

BACKGROUND A nucleotide substitution (C-->T) at position 825 of the gene GNB3 encoding the beta3 subunit of heterotrimeric G proteins is associated with alternative splicing and enhanced signal transduction. There is accumulating evidence from different populations that the 825T allele is associated with increased prevalence of hypertension, obesity, and left ventricular hypertrophy. However, it is unclear to what extent the 825T allele has a direct influence on left ventricular structure, independently of the effects of pressure and body mass index. Therefore we explored whether the GNB3 825T allele is associated with increased left ventricular mass index in a selected and homogeneous group of young, never treated, mild hypertensives. PROCEDURES Young subjects (n = 207, aged 18 to 45 years) were genotyped at the GNB3 825 locus. In each patient, 24-h ambulatory blood pressure (BP) measurement and two-dimensional guided M-mode echocardiography combined with Doppler sonography were performed. RESULTS The genotype distribution among patients was in Hardy-Weinberg equilibrium. Patients carrying the 825T allele had an increased left ventricular mass index (95.1 +/- 1.5 v 89.7 +/- 1.5 g/m2; P = .01) in comparison to those with CC genotype. The association between left ventricular mass index and 825T allele was independent of gender, age, BP, heart rate, alcohol intake, and physical activity. CONCLUSIONS In young patients with mild hypertension without heart disease the 825T allele is associated with an increased left ventricular mass index. These hypothesis-generating data suggest that GNB3 825T allele may be considered as one genetic marker predisposing to an increase in left ventricular mass in hypertensives, and justifies larger studies.

Late-onset arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary myocardial pathology usually diagnosed at a young age. Although ARVC is characterized by well-known clinical and instrumental features, the diagnosis in older patients can sometimes be difficult, due to the frequent left ventricular involvement and possible concomitant coronary artery disease. In the present study, we describe two female patients in whom morphological and kinetic abnormalities of the right ventricle, in keeping with the diagnosis of ARVC, appeared when they were aged in their fifties. These two cases indicate that clinical screening should be continued throughout adult life in people who are at risk of ARVC.