Sex differences in disease progression and arrhythmic risk in patients with arrhythmogenic cardiomyopathy.

AIMS: We aimed to assess sex-specific phenotypes and disease progression, and their relation to exercise, in arrhythmogenic cardiomyopathy (AC) patients. METHODS AND RESULTS: In this longitudinal cohort study, we included consecutive patients with AC from a referral centre. We performed echocardiography at baseline and repeatedly during follow-up. Patients' exercise dose at inclusion was expressed as metabolic equivalents of task (MET)-h/week. Ventricular arrhythmia (VA) was defined as aborted cardiac arrest, sustained ventricular tachycardia, or appropriate therapy by implantable cardioverter-defibrillator. We included 190 AC patients (45% female, 51% probands, age 41 ± 17 years). Ventricular arrhythmia had occurred at inclusion or occurred during follow-up in 85 patients (33% of females vs. 55% of males, P = 0.002). Exercise doses were higher in males compared with females [25 (interquartile range, IQR 14-51) vs. 12 (IQR 7-22) MET-h/week, P < 0.001]. Male sex was a marker of proband status [odds ratio (OR) 2.6, 95% confidence interval (CI) 1.4-5.0, P = 0.003] and a marker of VA (OR 2.6, 95% CI 1.4-5.0, P = 0.003), but not when adjusted for exercise dose and age (adjusted OR 1.8, 95% CI 0.9-3.6, P = 0.12 and 1.5, 95% CI 0.7-3.1, P = 0.30, by 5 MET-h/week increments). In all, 167 (88%) patients had ≥2 echocardiographic examinations during 6.9 (IQR 4.7-9.8) years of follow-up. We observed no sex differences in deterioration of right or left ventricular dimensions and functions. CONCLUSION: Male AC patients were more often probands and had higher prevalence of VA than female patients, but not when adjusting for exercise dose. Importantly, disease progression was similar between male and female patients.

Severe biventricular cardiomyopathy in both current and former long-term users of anabolic-androgenic steroids.

AIMS: This study aims to explore the cardiovascular effects of long-term anabolic-androgenic steroid (AAS) use in both current and former weightlifting AAS users and estimate the occurrence of severe reduced myocardial function and the impact of duration and amount of AAS. METHODS AND RESULTS: In this cross-sectional study, 101 weightlifting AAS users with at least 1 year cumulative AAS use (mean 11 ± 7 accumulated years of AAS use) were compared with 71 non-using weightlifting controls (WLC) using clinical data and echocardiography. Sixty-nine were current, 30 former (>1 year since quitted), and 2 AAS users were not available for this classification. Anabolic-androgenic users had higher left ventricular mass index (LVMI) (106 ± 26 vs. 80 ± 15 g/m2, P < 0.001), worse left ventricular ejection fraction (LVEF) (49 ±7 vs. 59 ± 5%, P < 0.001) and right ventricular global longitudinal strain (-17.3 ± 3.5 vs. -22.8 ± 2.0%, P < 0.001), and higher systolic blood pressure (141 ± 17 vs. 133 ± 11 mmHg, P < 0.001) compared with WLC. In current users, accumulated duration of AAS use was 12 ± 7 years and in former 9 ± 6 years (quitted 6 ± 6 years earlier). Compared with WLC, LVMI and LVEF were pathological in current and former users (P < 0.05) with equal distribution of severely reduced myocardial function (LVEF ≤40%) (11 vs. 10%, not significant (NS)). In current users, estimated lifetime AAS dose correlated with reduced LVEF and LVGLS, P < 0.05, but not with LVMI, P = 0.12. Regression analyses of the total population showed that the strongest determinant of reduced LVEF was not coexisting strength training or hypertension but history of AAS use (ß -0.53, P < 0.001). CONCLUSION: Long-term AAS users showed severely biventricular cardiomyopathy. The reduced systolic function was also found upon discontinued use.

In this, to date, largest cardiovascular study comparing 101 weightlifting long-term anabolic­androgenic steroid (AAS) users (11 ± 7 accumulated years of AAS use), with 71 weightlifting controls, we conclude that non-medical use of AAS is associated with adverse cardiovascular effects including enlarged heart muscle, seriously reduced heart function, and increased blood pressure. Both current and former users with accumulated years of AAS use of respectively 12 ± 7 years and 9 ± 6 years (former quitted 6 ± 6 years earlier) had biventricular cardiomyopathy with severely affected left and right myocardium. Of note, 11% of AAS users (10% of current and 11% of former) had severely reduced left ventricular systolic function with ejection fraction < 40%, consistent with heart failure.Regression analyses of the total population showed that the strongest determinant of reduced left ventricle ejection fraction was not coexisting strength training or hypertension but history of AAS use (ß −0.53, P < 0.001).

Increased amount of interstitial fibrosis predicts ventricular arrhythmias, and is associated with reduced myocardial septal function in patients with obstructive hypertrophic cardiomyopathy.

AIMS: Reduced echocardiographic strain is associated with ventricular arrhythmias in hypertrophic cardiomyopathy (HCM) patients. The aim of this cross-sectional study was to investigate which type of histological fibrosis contributes to ventricular arrhythmias and reduced septal longitudinal strain, in obstructive HCM-patients with or without additional coronary artery disease (CAD) and/or hypertension (HT). METHODS AND RESULTS: Sixty-three HCM-patients (mean age 57 ± 13 years) were included. Strain by speckle tracking echocardiography was performed prior to either percutaneous transluminal septal ablation (n = 37) or septal myectomy (n = 26). In 24 patients myectomy specimens were available (histology population) and allowed determination of %area of interstitial and replacement fibrosis. Twenty-nine (46%) patients had concomitant CAD and/or HT, and 15 (24%) experienced ventricular arrhythmias defined as documented ventricular tachycardia or arrhythmogenic suspected syncope. The patients with ventricular arrhythmias had lower septal longitudinal strain compared with those without arrhythmias (-9.0 ± 4.0 vs. -13.6 ± 5.6%, P = 0.006). In the histology population reduced septal longitudinal strain correlated to interstitial (R(2) = 0.36 P = 0.003), but not to replacement fibrosis (R(2) = 0.03 P = 0.43). By logistic regression analyses, interstitial fibrosis predicted ventricular arrhythmias (OR 1.16, 95% CI 1.02-1.32, P = 0.03), while replacement fibrosis did not (OR 1.22, 95% CI 0.93-1.59, P = 0.15). CONCLUSION: Total amount of fibrosis was a marker of ventricular arrhythmias in obstructive HCM-patients. Interstitial fibrosis seemed to be more important compared with replacement fibrosis in arrhythmogenesis, and was related to reduced septal myocardial function. These findings suggest that interstitial fibrosis may play an important role as the arrhythmogenic substrate, and that strain echocardiography can help detection of patients at risk.

Inflammation and Syndecan-4 Shedding from Cardiac Cells in Ischemic and Non-Ischemic Heart Disease.

Circulating biomarkers reflecting cardiac inflammation are needed to improve the diagnostics and guide the treatment of heart failure patients. The cardiac production and shedding of the transmembrane proteoglycan syndecan-4 is upregulated by innate immunity signaling pathways. Here, we investigated the potential of syndecan-4 as a blood biomarker of cardiac inflammation. Serum syndecan-4 was measured in patients with (i) non-ischemic, non-valvular dilated cardiomyopathy (DCM), with (n = 71) or without (n = 318) chronic inflammation; (ii) acute myocarditis (n = 15), acute pericarditis (n = 3) or acute perimyocarditis (23) and (iii) acute myocardial infarction (MI) at day 0, 3 and 30 (n = 119). Syndecan-4 was investigated in cultured cardiac myocytes and fibroblasts (n = 6-12) treated with the pro-inflammatory cytokines interleukin (IL)-1ß and its inhibitor IL-1 receptor antagonist (IL-1Ra), or tumor necrosis factor (TNF)α and its specific inhibitor infliximab, an antibody used in treatment of autoimmune diseases. The levels of serum syndecan-4 were comparable in all subgroups of patients with chronic or acute cardiomyopathy, independent of inflammation. Post-MI, syndecan-4 levels were increased at day 3 and 30 vs. day 0. IL-1Ra attenuated IL-1ß-induced syndecan-4 production and shedding in vitro, while infliximab had no effect. In conclusion, syndecan-4 shedding from cardiac myocytes and fibroblasts was attenuated by immunomodulatory therapy. Although its circulating levels were increased post-MI, syndecan-4 did not reflect cardiac inflammatory status in patients with heart disease.

Pregnancy and Progression of Cardiomyopathy in Women With LMNA Genotype-Positive.

Background We aimed to assess the association between number of pregnancies and long-term progression of cardiac dysfunction, arrhythmias, and event-free survival in women with pathogenic or likely pathogenic variants of gene encoding for Lamin A/C proteins ( LMNA+). Methods and Results We retrospectively included consecutive women with LMNA+ and recorded pregnancy data. We collected echocardiographic data, occurrence of atrial fibrillation, atrioventricular block, sustained ventricular arrhythmias, and implantation of cardiac electronic devices (implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator). We analyzed retrospectively complications during pregnancy and the peripartum period. We included 89 women with LMNA+ (28% probands, age 41±16 years), of which 60 had experienced pregnancy. Follow-up time was 5 [interquartile range, 3-9] years. We analyzed 452 repeated echocardiographic examinations. Number of pregnancies was not associated with increased long-term risk of atrial fibrillation, atrioventricular block, sustained ventricular arrhythmias, or implantable cardioverter defibrillator/cardiac resynchronization therapy defibrillator implantation. Women with previous pregnancy and nulliparous women had a similar annual deterioration of left ventricular ejection fraction (-0.5/year versus -0.3/year, P=0.37) and similar increase of left ventricular end-diastolic diameter (0.1/year versus 0.2/year, P=0.09). Number of pregnancies did not decrease survival free from death, left ventricular assist device, or need for cardiac transplantation. Arrhythmias occurred during 9% of pregnancies. No increase in maternal and fetal complications was observed. Conclusions In our cohort of women with LMNA+, pregnancy did not seem associated with long-term adverse disease progression or event-free survival. Likewise, women with LMNA+ generally well-tolerated pregnancy, with a small proportion of patients experiencing arrhythmias.

Low Molecular Mass Myocardial Hyaluronan in Human Hypertrophic Cardiomyopathy.

During the development of hypertrophic cardiomyopathy, the heart returns to fetal energy metabolism where cells utilize more glucose instead of fatty acids as a source of energy. Metabolism of glucose can increase synthesis of the extracellular glycosaminoglycan hyaluronan, which has been shown to be involved in the development of cardiac hypertrophy and fibrosis. The aim of this study was to investigate hyaluronan metabolism in cardiac tissue from patients with hypertrophic cardiomyopathy in relation to cardiac growth. NMR and qRT-PCR analysis of human cardiac tissue from hypertrophic cardiomyopathy patients and healthy control hearts showed dysregulated glucose and hyaluronan metabolism in the patients. Gas phase electrophoresis revealed a higher amount of low molecular mass hyaluronan and larger cardiomyocytes in cardiac tissue from patients with hypertrophic cardiomyopathy. Histochemistry showed high concentrations of hyaluronan around individual cardiomyocytes in hearts from hypertrophic cardiomyopathy patients. Experimentally, we could also observe accumulation of low molecular mass hyaluronan in cardiac hypertrophy in a rat model. In conclusion, the development of hypertrophic cardiomyopathy with increased glucose metabolism affected both hyaluronan molecular mass and amount. The process of regulating cardiomyocyte size seems to involve fragmentation of hyaluronan.

Strain echocardiography is related to fibrosis and ventricular arrhythmias in hypertrophic cardiomyopathy.

AIMS: Hypertrophic cardiomyopathy (HCM) patients are at risk of ventricular arrhythmias (VAs). We aimed to explore whether systolic function by strain echocardiography is related to VAs and to the extent of fibrosis by cardiac magnetic resonance imaging (CMR). METHODS AND RESULTS: We included 150 HCM patients and 50 healthy individuals. VAs were defined as non-sustained and sustained ventricular tachycardia and aborted cardiac arrest. Left ventricular function was assessed by ejection fraction (EF) and by global longitudinal strain (GLS) assessed by speckle tracking echocardiography. Mechanical dispersion was calculated as standard deviation (SD) of time from Q/R on ECG to peak longitudinal strain in 16 left ventricular segments. Late gadolinium enhancement (LGE) was assessed by CMR. HCM patients had similar EF (61 ± 5% vs. 61 ± 8%, P = 0.77), but worse GLS (-15.7 ± 3.6% vs. -21.1 ± 1.9%, P < 0.001) and more pronounced mechanical dispersion (64 ± 22 vs. 36 ± 13 ms, P < 0.001) compared with healthy individuals. VAs were documented in 37 (25%) HCM patients. Patients with VAs had worse GLS (-14.1 ± 3.6% vs. -16.3 ± 3.4%, P < 0.01), more pronounced mechanical dispersion (79 ± 27 vs. 59 ± 16 ms, P < 0.001), and higher %LGE (6.1 ± 7.8% vs. 0.5 ± 1.4%, P < 0.001) than patients without VAs. Mechanical dispersion correlated with %LGE (R = 0.52, P < 0.001) and was independently associated with VAs (OR 1.6, 95% CI 1.1-2.3, P = 0.02) and improved risk stratification for VAs. CONCLUSION: GLS, mechanical dispersion, and LGE were markers of VAs in HCM patients. Mechanical dispersion was a strong independent predictor of VAs and related to the extent of fibrosis. Strain echocardiography may improve risk stratification of VAs in HCM.

Noninvasive assessment of myocardial fibrosis in patients with obstructive hypertrophic cardiomyopathy.

OBJECTIVE: Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) imaging is the reference standard for non-invasive assessment of fibrosis. In hypertrophic cardiomyopathy (HCM) patients the histological substrate for LGE is still unknown. The aim of this study was to assess the ability of LGE and strain echocardiography to detect type and extent of myocardial fibrosis in obstructive HCM patients undergoing septal myectomy. METHODS: Thirty-two HCM patients (age 60±10) were included in this cross-sectional study and preoperatively examined by speckle-tracking strain echocardiography and LGE-CMR (n=21). Histological fibrosis was classified as interstitial, replacement and total. RESULTS: Histological fibrosis was present in 31 patients. The percentage of total, interstitial and replacement fibrosis was 15(7, 31)%, 11(5, 24)% and 3(1, 6)%, respectively. Reduced longitudinal septal strain correlated with total (r=0.50, p=0.01) and interstitial (r=0.40, p=0.03), but not with replacement fibrosis (r=0.28, p=0.14). Septal LGE was detected in 13/21 (62%), but percentage LGE did not correlate with total fibrosis (r=0.25, p=0.28). Extent of fibrosis did not differ between patients with and without septal LGE (20(9, 58)% versus 14(5, 19)% p=0.41). Patients with ventricular arrhythmias (n=8) had lower septal longitudinal strain and increased extent total and interstitial fibrosis in myectomy specimens, but no differences were demonstrated in LGE. Reduced longitudinal septal strain and increased extent of interstitial fibrosis predicted ventricular arrhythmias independently of age and gender. CONCLUSIONS: In myectomised HCM patients, reduced longitudinal septal strain correlated better with interstitial and total fibrosis in myectomy specimens, and was a more powerful tool to predict arrhythmias than LGE.

Familial globotriaosylceramide-associated cardiomyopathy mimicking Fabry disease.

OBJECTIVE: To characterise a globotriaosylceramide (Gb3) storage cardiomyopathy mimicking Fabry. METHODS: We investigated five patients from two unrelated families with early adult onset unexplained left ventricular hypertrophy. Endomyocardial biopsy was performed in all patients and diagnostic kidney biopsies in two of them. We measured α-galactosidase A activity in all patients. Three patients were checked for LAMP1 or LAMP2 deficiency and screened for congenital disorders of glycosylation. Gb3 concentration was quantified in plasma, urinary sediment and cardiac muscle. We sequenced the Fabry and Danon genes and looked for other genetic causes by single-nucleotide polymorphism array haplotyping and whole exome sequencing. RESULTS: Three patients had a striking fat distribution around the buttocks and upper thighs. All patients developed bradyarrhythmias and needed pacemakers. Cardiac transplantation was performed in three patients due to end-stage heart failure, one patient died before transplantation. The cardiomyocytes contained lysosomal vacuoles with lamellar myelin-like deposits. Interstitial cells had vacuoles containing granular material. Deposits were found in the kidneys without renal dysfunction. The histological pattern was atypical for Fabry disease. Biochemical studies revealed normal activity of α-galactosidase A and other relevant enzymes. There was a selective accumulation of Gb3 in cardiomyocytes, at levels found in patients with Fabry disease, but no mutations in the Fabry gene, and Fabry disease was excluded. Other known lysosomal storage diseases were also excluded. Single-nucleotide polymorphism array haplotyping and whole exome sequencing could not identify the genetic cause. CONCLUSIONS: We describe a novel familial Gb3-associated cardiomyopathy. Autosomal recessive inheritance is likely, but the genetic and metabolic cause remains to be identified.