Giovanni Quarta

Evaluation of Techniques for the Quantification of Myocardial Scar of Differing Etiology Using Cardiac Magnetic Resonance

OBJECTIVES The aim of this study was to compare the reproducibility of 7 late gadolinium enhancement (LGE) quantification techniques across 3 conditions in which LGE is known to be important: acute myocardial infarction (AMI), chronic myocardial infarction (CMI), and hypertrophic cardiomyopathy (HCM). BACKGROUND LGE by cardiac magnetic resonance is the gold-standard technique for assessing myocardial scar. No consensus exists on the best method for its quantification, and research in this area is scant. Techniques include manual quantification, thresholding by 2, 3, 4, 5, or 6 SDs above remote myocardium, and the full width at half maximum (FWHM) technique. To date, LGE has been linked to outcome in 3 conditions: AMI, CMI, and HCM. METHODS Sixty patients with 3 LGE etiologies (AMI, n = 20; CMI, n = 20; HCM, n = 20) were scanned for LGE. LGE volume was quantified using the 7 techniques. Mean LGE volume, interobserver and intraobserver reproducibility, and impact on sample size were assessed. RESULTS LGE volume varied significantly with the quantification method used. There was no statistically significant difference between LGE volume by the FWHM, manual, and 6-SD or 5-SD techniques. The 2-SD technique generated LGE volumes up to 2 times higher than the FWHM, 6-SD, and manual techniques. The reproducibility of all techniques was worse in HCM than AMI or CMI. The FWHM technique was the most reproducible in all 3 conditions compared with any other method (p < 0.001). Use of the FWHM technique for LGE quantification in paired analysis would lead to at least a 60% reduction in required sample size compared with any other method. CONCLUSIONS Regardless of the disease under study, the FWHM technique for LGE quantification gives LGE volume mean results similar to manual quantification and is statistically the most reproducible, reducing required sample sizes by up to one-half.

Syncope and risk of sudden death in hypertrophic cardiomyopathy

Background— The prognostic significance of syncope has not been investigated systematically in hypertrophic cardiomyopathy, and treatment strategies have been based largely on intuition and experience. Methods and Results— We assessed the relationship between syncope and sudden death in 1511 consecutive patients with hypertrophic cardiomyopathy. Unexplained (n=153) or neurally mediated (n=52) syncope occurred in 205 patients (14%). Over a 5.6±5.2-year follow-up, 74 patients died suddenly. Relative risk of sudden death was 1.78 (95% confidence interval 0.88 to 3.51, P=0.08) in patients with unexplained syncope and 0.91 (95% confidence interval 0.00 to 3.83, P=1.0) in those with neurally mediated syncope compared with patients without syncope. In multivariable analysis, the temporal proximity of unexplained syncope to initial patient evaluation was independently associated with risk of sudden death (P=0.006). Patients with unexplained syncope within 6 months before the initial evaluation showed a 5-fold increase in risk compared with patients without syncope (adjusted hazard ratio 4.89, 95% confidence interval 2.19 to 10.94), a relationship that was maintained throughout all age groups (<18, 18 to 39, and ≥40 years). Older patients (≥40 years of age) with remote episodes of syncope (>5 years before initial evaluation) did not show an increased risk of sudden death (adjusted hazard ratio 0.38, 95% confidence interval 0.05 to 2.74). Conclusions— In the present large cohort of patients with hypertrophic cardiomyopathy, unexplained syncope was a risk factor for sudden death. Patients with syncopal events that occurred in close temporal proximity to the initial evaluation showed a substantially higher risk of sudden death than patients without syncope. Older patients with remote syncopal events did not show an increased risk.

Assessment and Significance of Left Ventricular Mass by Cardiovascular Magnetic Resonance in Hypertrophic Cardiomyopathy

OBJECTIVES Our aim was to assess the distribution and clinical significance of left ventricular (LV) mass in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND Hypertrophic cardiomyopathy is defined echocardiographically by unexplained left ventricular wall thickening. Left ventricular mass, quantifiable by modern cardiovascular magnetic resonance techniques, has not been systematically assessed in this disease. METHODS In 264 HCM patients (age 43 +/- 18 years; 75% men), LV mass by cardiovascular magnetic resonance was measured, indexed by body surface area, and compared with that in 606 healthy control subjects. RESULTS The LV mass index in HCM patients significantly exceeded that of control subjects (104 +/- 40 g/m(2) vs. 61 +/- 10 g/m(2) in men and 89 +/- 33 g/m(2) vs. 47 +/- 7 g/m(2) in women; both p < 0.0001). However, values were within the normal range (< or = mean +2 SDs for control subjects) in 56 patients (21%), and only mildly increased (mean +2 to 3 SDs) in 18 (16%). The LV mass index showed a modest relationship to maximal LV thickness (r(2) = 0.38; p < 0.001), and was greater in men (104 +/- 40 g/m(2) vs. 89 +/- 33 g/m(2) in women; p < 0.001) and in patients with resting outflow obstruction (121 +/- 43 g/m(2) vs. 96 +/- 37 g/m(2) in nonobstructives; p < 0.001). During a 2.6 +/- 0.7-year follow-up, markedly increased LV mass index proved more sensitive in predicting outcome (100%, with 39% specificity), whereas maximal wall thickness >30 mm was more specific (90%, with 41% sensitivity). CONCLUSIONS In distinction to prior perceptions, LV mass index was normal in about 20% of patients with definite HCM phenotype. Therefore, increased LV mass is not a requirement for establishing the clinical diagnosis of HCM. The LV mass correlated weakly with maximal wall thickness, and proved more sensitive in predicting outcome.

Cardiovascular magnetic resonance measurement of myocardial extracellular volume in health and disease

Objective To measure and assess the significance of myocardial extracellular volume (ECV), determined non-invasively by equilibrium contrast cardiovascular magnetic resonance, as a clinical biomarker in health and a number of cardiac diseases of varying pathophysiology. Design Prospective study. Setting Tertiary referral cardiology centre in London, UK. Patients 192 patients were mainly recruited from specialist clinics. We studied patients with Anderson–Fabry disease (AFD, n=17), dilated cardiomyopathy (DCM, n=31), hypertrophic cardiomyopathy (HCM, n=31), severe aortic stenosis (AS, n=66), cardiac AL amyloidosis (n=27) and myocardial infarction (MI, n=20). The results were compared with those for 81 normal subjects. Results In normal subjects, ECV (mean (95% CI), measured in the septum) was slightly higher in women than men (0.273 (0.264 to 0.282 vs 0.233 (0.225 to 0.244), p<0.001), with no change with age. In disease, the ECV of AFD was the same as in normal subjects but higher in all other diseases (p<0.001). Mean ECV was the same in DCM, HCM and AS (0.280, 0.291, 0.276 respectively), but higher in cardiac AL amyloidosis and higher again in MI (0.466 and 0.585 respectively, each p<0.001). Where ECV was elevated, correlations were found with indexed left ventricular mass, end systolic volume, ejection fraction and left atrial area in apparent disease-specific patterns. Conclusions Myocardial ECV, assessed non-invasively in the septum with equilibrium contrast cardiovascular magnetic resonance, shows gender differences in normal individuals and disease-specific variability. Therefore, ECV shows early potential to be a useful biomarker in health and disease.

Familial Evaluation in Arrhythmogenic Right Ventricular Cardiomyopathy Impact of Genetics and Revised Task Force Criteria

Background— With recognition of disease-causing genes in arrhythmogenic right ventricular cardiomyopathy, mutation analysis is being applied. Methods and Results— The role of genotyping in familial assessment for arrhythmogenic right ventricular cardiomyopathy was investigated, including the prevalence of mutations in known causal genes, the penetrance and expressivity in genotyped families, and the utility of the 2010 Task Force criteria in clinical diagnosis. Clinical and molecular genetic evaluation was performed in 210 first-degree and 45 second-degree relatives from 100 families. In 51 families, the proband was deceased. The living probands had a high prevalence of ECG abnormalities (89%) and ventricular arrhythmia (78%) and evidence of more severe disease than relatives. Definite or probable causal mutations were found in 58% of families and 73% of living probands, of whom 28% had an additional desmosomal variant (ie, mutation or polymorphism). Ninety-three relatives had a causal mutation; 33% fulfilled the 2010 criteria, whereas only 19% satisfied the 1994 version ( P =0.03). An additional desmosomal gene variant was found in 10% and was associated with a 5-fold increased risk of developing penetrant disease (odds ratio, 4.7; 95% confidence interval, 1.1 to 20.4; P =0.04). Conclusions— Arrhythmogenic right ventricular cardiomyopathy is a genetically complex disease characterized by marked intrafamilial phenotype diversity. Penetrance is definition dependent and is greater with the 2010 criteria compared with the 1994 criteria. Relatives harboring >1 genetic variant had significantly increased risk of developing clinical disease, potentially an important determinant of the phenotypic heterogeneity seen within families with arrhythmogenic right ventricular cardiomyopathy. # Clinical Perspective {#article-title-19}Background— With recognition of disease-causing genes in arrhythmogenic right ventricular cardiomyopathy, mutation analysis is being applied. Methods and Results— The role of genotyping in familial assessment for arrhythmogenic right ventricular cardiomyopathy was investigated, including the prevalence of mutations in known causal genes, the penetrance and expressivity in genotyped families, and the utility of the 2010 Task Force criteria in clinical diagnosis. Clinical and molecular genetic evaluation was performed in 210 first-degree and 45 second-degree relatives from 100 families. In 51 families, the proband was deceased. The living probands had a high prevalence of ECG abnormalities (89%) and ventricular arrhythmia (78%) and evidence of more severe disease than relatives. Definite or probable causal mutations were found in 58% of families and 73% of living probands, of whom 28% had an additional desmosomal variant (ie, mutation or polymorphism). Ninety-three relatives had a causal mutation; 33% fulfilled the 2010 criteria, whereas only 19% satisfied the 1994 version (P=0.03). An additional desmosomal gene variant was found in 10% and was associated with a 5-fold increased risk of developing penetrant disease (odds ratio, 4.7; 95% confidence interval, 1.1 to 20.4; P=0.04). Conclusions— Arrhythmogenic right ventricular cardiomyopathy is a genetically complex disease characterized by marked intrafamilial phenotype diversity. Penetrance is definition dependent and is greater with the 2010 criteria compared with the 1994 criteria. Relatives harboring >1 genetic variant had significantly increased risk of developing clinical disease, potentially an important determinant of the phenotypic heterogeneity seen within families with arrhythmogenic right ventricular cardiomyopathy.

Mutations in the Lamin A/C gene mimic arrhythmogenic right ventricular cardiomyopathy.

AIMS Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease predominantly caused by mutations in desmosomal protein genes. Lamin A/C gene (LMNA) mutations are associated with dilated cardiomyopathy, conduction abnormalities and high incidence of sudden cardiac death. In this study, we screened a large cohort of ARVC patients for LMNA mutations. METHODS AND RESULTS One hundred and eight patients from unrelated families with borderline (n = 27) or definite (n = 81) diagnosis of ARVC were genetically tested for five desmosomal genes and LMNA. Sixty-one (56.5%) were positive for desmosomal gene mutations. Standard polymerase chain reaction (PCR) amplification of the 12 protein-coding LMNA exons was performed and mutational screening performed by direct sequencing. Four patients (4%) without desmosomal gene mutations carried LMNA variants. Three had severe right ventricular involvement, and during follow-up three died (two suddenly and one from congestive heart failure); all three had conduction abnormalities on resting 12-lead electrocardiogram (ECG). Myocardial tissue from two patients showed myocyte loss and fibro-fatty replacement. In one of these, immunohistochemical staining with antibody to plakoglobin showed reduced/absent staining of the intercalated discs in the myocardium. CONCLUSION Lamin A/C gene mutations can be found in severe forms of ARVC. Lamin A/C gene should be added to desmosomal genes when genetically testing patients with suspected ARVC, particularly when they also have ECG evidence for conduction disease.

Diffuse myocardial fibrosis in severe aortic stenosis: an equilibrium contrast cardiovascular magnetic resonance study

AIMS Haemodynamics alone do not fully explain symptoms and prognosis in clinically severe aortic stenosis (AS). Myocardial disease, specifically diffuse myocardial fibrosis (DMF), may contribute. We used equilibrium contrast cardiovascular magnetic resonance (EQ-CMR) and sought to non-invasively measure DMF in severe AS and determine its clinical significance before and after valve replacement. METHODS AND RESULTS Patients with severe AS underwent echocardiography, brain natriuretic peptide (BNP), 6 min walk test (6MWT), and EQ-CMR pre- (n = 63) at baseline and at 6 months post- (n = 42) aortic valve replacement (AVR). EQ-CMR was also performed in 30 normal controls. Baseline: patients with AS had more DMF than controls (18 vs. 13%, P = 0.007) with a wide range (5-38%) that overlapped controls. The extent of diffuse fibrosis correlated inversely with the 6MWT performance (r(2) = 0.22, P = 0.001). Those with severe diastolic dysfunction had more DMF (P = 0.01). On multivariable analysis, the predictors of performance at 6MWT were diffuse fibrosis and BNP (P = 0.003 and 0.02, respectively). Post-op: following valve replacement, morphological and functional parameters improved [6 MWT, LA area, BNP, left ventricular (LV) hypertrophy, and volumes]. LV hypertrophy regression was shown to be cell volume reduction (P < 0.001) and not fibrosis regression (P = 0.54). Of the five deaths over six-month follow-up, four occurred in patients in the highest tertile of DMF. CONCLUSION DMF as measured by EQ-CMR is elevated in severe AS vs. normal controls but with a considerable overlap. It correlates with functional capacity at baseline. LV hypertrophy regression 6 months after AVR is cellular rather than fibrosis resolution.

The long-term survival and the risks and benefits of implantable cardioverter defibrillators in patients with hypertrophic cardiomyopathy

Objective Implantable cardioverter defibrillators (ICDs) are routinely used to prevent sudden cardiac death (SCD) in selected hypertrophic cardiomyopathy (HCM) patients, but the determinants of device-related complications, therapies and long-term cardiovascular mortality in ICD recipients are not known. Design Retrospective observational cohort study. Setting Single-centre tertiary referral cardiomyopathy clinic. Patients 334 consecutively evaluated HCM patients (median age 40 years, 62% male, 92% primary prevention) at risk of SCD treated with ICD. Thirty-six patients (11%) received concurrent cardiac resynchronisation therapy for heart failure symptoms. Results During the 1286 patient-years of follow-up, cardiovascular mortality (including transplantation) occurred in 22 (7%) patients (1.7%/year) and was associated with New York Heart Association (NYHA) class III/IV (adjusted HR=9.38, 95% CI 3.31 to 26.55, p≤0.001), percentage fractional shortening (HR=0.92, 95% CI 0.87 to 0.96, p=0.001) and implantation for secondary prevention (HR=0.07, 95% CI 0.01 to 0.86, p=0.04). There were no SCD. Twenty-eight (8%) patients received appropriate shocks (2.3%/year), which were predicted by baseline fractional shortening (HR=0.96, 95% CI 0.92 to 0.99, p=0.04). Fifty-five (16%) patients received inappropriate shocks (4.6%/year). Sixty (18%) patients experienced implant-related complications (5.1%/year), including two deaths. Adverse ICD-related events (inappropriate shocks and/or implant complications) were seen in 101 (30%) patients (8.6%/year). Patients with cardiac resynchronisation therapy were more likely to develop implant complications than those with single-chamber ICDs (HR=4.39, 95% CI 1.44 to 13.35, p=0.009) and had a higher 5-year cardiovascular mortality than did the rest of the cohort (21% vs 6%, p<0.001). Conclusions HCM patients with an ICD have a significant cardiovascular mortality and are exposed to frequent inappropriate shocks and implant complications. These data suggest that new strategies are required to improve patient selection for ICDs and to prevent disease progression in those that receive a device.

Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study

Aims Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin. Methods and results Murine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S1–S2 protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation–repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P= 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution. Conclusion Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction–repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification.

Prevalence of Anderson–Fabry disease in patients with hypertrophic cardiomyopathy: the European Anderson–Fabry Disease Survey

Objectives The prevalence of Anderson–Fabry disease (AFD) in patients presenting with unexplained left ventricular hypertrophy (LVH) is controversial. The aim of this study was to determine the prevalence of AFD in a large, consecutive cohort of patients with hypertrophic cardiomyopathy (HCM) using rapid mutation screening. Design, Setting and Patients A European multicentre cross-sectional study involving 13 referral centres. Inclusion criteria for the study were: men aged at least 35 years and women aged at least 40 years with unexplained LVH (maximum left ventricular wall thickness ≥1.5 cm). All patients were screened using a denaturing high-performance liquid chromatography protocol for rapid mutation screening of the α-galactosidase A (α-Gal A) gene and, if a sequence variant was found, direct sequencing was performed. 1386 patients (63.9% men, mean age 57.9±12.0 years) were enrolled in the study. Results Seven (0.5%) patients (age 57.4±9.0 years (45–72); three (43%) men) had pathogenic α-galactosidase A mutations. Polymorphisms were identified in 283 patients (20.4%). Maximal left ventricular wall thickness in patients carrying a disease-causing mutation was 18±2 mm (range 15–22); four patients had concentric LVH and the remainder had asymmetric septal hypertrophy. Conclusions The prevalence of AFD gene mutations in a large, consecutive cohort of European patients with unexplained LVH is 0.5%.