Excess mortality and sex differences in outcome in hypertrophic cardiomyopathy: a European multicentre study

Background. Contemporary survival studies in hypertrophic cardiomyopathy (HCM) have shown that the prognosis for most individuals with the disease is much better than described previously, but it remains unclear whether HCM conveys an excess mortality when compared to the general population. Methods. We conducted a retrospective, multicentre longitudinal cohort study of adult HCM patients from 7 European centers. To compare survival to the general population standardized mortality ratios (SMR) were calculated using data from Eurostat stratified by study period, country, sex and age, using a composite endpoint (all-cause mortality, sudden cardiac death (SCD) equivalent, and heart transplantation). Results. The study population consisted of 4893 patients (mean age 49.2 ± 16.4 years; 64% male). After a median follow up of 6.1 years (IQR 3.0-9.8), 796 (16.3%) patients reached the composite endpoint. HCM had an excess mortality compared to the general population (SMR 2.23 (95% Confidence Interval (CI):1.66-2.94)). Females were older at presentation, more symptomatic at baseline (NYHA III/IV: 17.1% vs 7.5%) and more likely to have left ventricular outflow tract obstruction and atrial fibrillation. Female patients had a greater excess mortality than males (SMR 2.87 (95% CI: 2.57-3.19) vs 1.92 (95% CI: 1.76-2.11); p<0.001). Excess mortality in females was present throughout the age spectrum while mortality in male patients after the age of 65 years was similar to the normal population. Female sex was independently associated with a worse prognosis in the multivariable model for the primary composite endpoint (HR 1.19, 95% CI:1.06-1.30;p=0.007) and HF death or transplantation (HR 1.44, 95% CI:1.25-1.59;p<0.001), but not SCD or equivalent. Conclusions. HCM is associated with a significant excess mortality throughout the life course. Women have a worse prognosis that is at least partly due to an excess HF mortality

Cardiac amyloidosis: the great pretender

Cardiac amyloidosis (CA) is often misdiagnosed because of both physician-related and disease-related reasons including: fragmented knowledge among different specialties and subspecialties, shortage of centres and specialists dedicated to disease management, erroneous belief it is an incurable disease, rarity of the condition, intrinsic phenotypic heterogeneity, genotypic heterogeneity in transthyretin-related forms and the necessity of target organ tissue histological diagnosis in the vast majority of cases. Pitfalls, incorrect beliefs and deceits challenge not only the path to the diagnosis of CA but also the precise identification of aetiological subtype. The awareness of this condition is the most important prerequisite for the management of the risk of underdiagnoses and misdiagnosis. Almost all clinical, imaging and laboratory tests can be misinterpreted, but fortunately each of these diagnostic steps can also offer diagnostic “red flags” (i.e. highly suggestive findings that can foster the correct diagnostic suspicion and facilitate early, timely diagnosis). This is especially important because outcomes in CA are largely driven by the severity of cardiac dysfunction and emerging therapies are aimed at preventing further amyloid deposition

Nuclear imaging for cardiac amyloidosis

Histological analysis of endomyocardial tissue is still the gold standard for the diagnosis of cardiac amyloidosis, but has its limitations. Accordingly, there is a need for non-invasive modalities to diagnose cardiac amyloidosis. Echocardiography and ultrasound and magnetic resonance imaging can show characteristics which may not be very specific for cardiac amyloid. Nuclear medicine has gained a precise role in this context: several imaging modalities have become available for the diagnosis and prognostic stratification of cardiac amyloidosis during the last two decades. The different classes of radiopharmaceuticals have the potential to bind different constituents of the amyloidotic infiltrates, with some relevant differences among the various aetiologic types of amyloidosis and the different organs and tissues involved. This review focuses on the background of the commonly used modalities, their present clinical applications, and future clinical perspectives in imaging patients with (suspected) cardiac amyloidosis. The main focus is on conventional nuclear medicine (bone scintigraphy, cardiac sympathetic innervation) and positron emission tomography

Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers

[Abstract] Background. Predictive genetic screening of relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM. Objectives. The aim of this study was to determine the incidence of new HCM diagnosis in SP mutation carriers. Methods. This was a retrospective analysis of adult and pediatric SP mutation carriers identified during family screening who did not fulfill diagnostic criteria for HCM at first evaluation. Results. The authors evaluated 285 individuals from 156 families (median age 14.2 years [interquartile range: 6.8 to 31.6 years], 141 [49.5%] male individuals); 145 (50.9%) underwent cardiac magnetic resonance (CMR). Frequency of causal genes was as follows: MYBPC3 n = 123 (43.2%), MYH7 n = 69 (24.2%), TNNI3 n = 39 (13.7%), TNNT2 n = 34 (11.9%), TPM1 n = 9 (3.2%), MYL2 n = 6 (2.1%), ACTC1 n = 1 (0.4%), multiple mutations n = 4 (1.4%). Median follow-up was 8.0 years (interquartile range: 4.0 to 13.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) fulfilled diagnostic criteria on CMR but not echocardiography. Estimated HCM penetrance at 15 years of follow-up was 46% (95% confidence interval [CI]: 38% to 54%). In a multivariable model adjusted for age and stratified for CMR, independent predictors of HCM development were male sex (hazard ratio [HR]: 2.91; 95% CI: 1.82 to 4.65) and abnormal electrocardiogram (ECG) (HR: 4.02; 95% CI: 2.51 to 6.44); TNNI3 variants had the lowest risk (HR: 0.19; 95% CI: 0.07 to 0.55, compared to MYBPC3). Conclusions. Following a first negative screening, approximately 50% of SP mutation carriers develop HCM over 15 years of follow-up. Male sex and an abnormal ECG are associated with a higher risk of developing HCM. Regular CMR should be considered in long-term screening

The complex interplay among atherosclerosis, inflammation, and degeneration in ascending thoracic aortic aneurysms

OBJECTIVE: To assess the histopathological findings of a large series of ascending thoracic aortic aneurysm (TAA) surgical specimens applying the updated classification on noninflammatory degenerative and inflammatory aortic diseases proposed by the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology clinicopathological correlations. METHODS: A total of 255 patients surgically treated for ascending TAA were enrolled. Surgical ascending aorta specimens were examined. RESULTS: The histopathological substrate of ascending TAAs was mainly degenerative (67.5%), but with a remarkable prevalence of atherosclerotic lesions (18.8%) and aortitis (13.7%). Degenerative patients more frequently had bicuspid aortic valve (37.2%; P = .002). Patients in the atherosclerotic group were older (median age, 69 years; P < .001), more often with a history of hypertension (87.5%; P = .059), hypercholesterolemia (75%; P = .019), diabetes (16.6%; P = .054), current smoking (22.9%; P = .066), and a history of coronary artery disease (18.7%; P = .063). Patients with aortitis represented the older group (median age, 75 years, P < .001), were mostly females (68.6%; P < .001), and had a larger ascending aorta diameter (median, 56 mm; P < .001). Both patients with atherosclerosis and aortitis presented a higher incidence of concomitant abdominal aortic aneurysm (20.8% and 22.8%, respectively; P < .001). CONCLUSIONS: Although degenerative histopathology is the most frequent substrate in ascending TAA, atherosclerosis and inflammation significantly contribute to the development of chronic aortic thoracic disease

Carpal tunnel syndrome in cardiac amyloidosis: implications for early diagnosis and prognostic role across the spectrum of aetiologies

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Differences in cardiac phenotype and natural history of laminopathies with and without neuromuscular onset

Objective: To investigate differences in cardiac manifestations of patients affected by laminopathy, according to the presence or absence of neuromuscular involvement at presentation.Methods: We prospectively analyzed 40 consecutive patients with a diagnosis of laminopathy followed at a single centre between 1998 and 2017. Additionally, reports of clinical evaluations and tests prior to referral at our centre were retrospectively evaluated.Results: Clinical onset was cardiac in 26 cases and neuromuscular in 14. Patients with neuromuscular presentation experienced first symptoms earlier in life (11 vs 39 years; p &lt; 0.0001) and developed atrial fibrillation/flutter (AF) and required pacemaker implantation at a younger age (28 vs 41 years [p = 0.013] and 30 vs 44 years [p = 0.086] respectively), despite a similar overall prevalence of AF (57% vs 65%; p = 0.735) and atrio-ventricular (A-V) block (50% vs 65%; p = 0.500). Those with a neuromuscular presentation developed a cardiomyopathy less frequently (43% vs 73%; p = 0.089) and had a lower rate of sustained ventricular tachyarrhythmias (7% vs 23%; p = 0.387). In patients with neuromuscular onset rhythm disturbances occurred usually before evidence of cardiomyopathy. Despite these differences, the need for heart transplantation and median age at intervention were similar in the two groups (29% vs 23% [p = 0.717] and 43 vs 46 years [p = 0.593] respectively).Conclusions: In patients with laminopathy, the type of disease onset was a marker for a different natural history. Specifically, patients with neuromuscular presentation had an earlier cardiac involvement, characterized by a linear and progressive evolution from rhythm disorders (AF and/or A-V block) to cardiomyopathy