Maximal Left Ventricular Wall Thickness Research Articles

Orthostatic hypotension in hereditary ATTR Val30Met amyloidosis: predictors and associated clinical features

Abstract Introduction The prevalence of orthostatic hypotension (OH) in patients with mutated transthyretin (TTR) amyloidosis (mATTR) is 40–60%. According to previous studies, OH is frequent and an early feature in patients with Val30Met mutation (the most prevalent form of mATTR). Aim To characterize TTR Val30Met patients with OH and to identify clinical characteristics associated with OH development. Methods Retrospective study of consecutive Val30Met TTR patients with suspected cardiac involvement observed at our cardiology clinic during 2019. Two groups were defined: group 1: patients without OH; group 2: patients with OH. Data was obtained by chart review. Statistically significant predictors of OH were found using logistic regression. Results We included a total of 248 patients (group 1 – 173; group 2 – 75). Group 1 patients were 52% male, median age 45 [interquartile range (IQR) 39–55] and median age at onset 34 (IQR 29,75–46,25) years. Left ventricle hypertrophy [LVH, defined as maximal LV wall thickness (LVT) ≥12 mm] occurred in 26,5%, with median maximal LVT 10 mm (IQR 9–12); 49,7% had conduction disturbances, 30,6% gastrointestinal (GI), 17,3% genitourinary (GU) manifestations and 5% were in Coutinho staging ≥2/3. Group 2 had 56% male, median age of 49 years at evaluation (IQR 42–65) and 35 years at onset (IQR 30–59). LVH was present in 42,9%, with median maximal LVT 11 mm (IQR 10–14); 74,7% had conduction disturbances, 56% GI and 42,7% GU manifestations and 21% were in Coutinho staging ≥2/3. In univariate analysis, higher age (p=0,005), presence of LVH (p=0,009), conduction disturbances (p<0,001), GU manifestations (p<0,001) and higher Coutinho staging (p<0,001) were all associated with the presence of OH, while age at onset was not (p=0,648). In multivariate analysis, only Coutinho staging [odds ratio (OR) 2.609; 95% confidence interval (95% CI) 1.344–5.065] and GU manifestations (OR 3,151; 95% CI 1,595–6,225) were found to be significant predictors of OH. Conclusion Our study suggests that OH is more associated with GU manifestations and Neurologic staging, than with amyloid cardiomyopathy or age, suggesting a predominant neurogenic component. The prevalence of OH in our sample of Val30Met patients was lower than previously described. Funding Acknowledgement Type of funding sources: None.

Sudden cardiac death risk stratification in hypertrophic cardiomyopathy: discrepancies persist among guidelines

Abstract Background Differing criteria have been provided on sudden cardiac death (SCD) risk stratification in hypertrophic cardiomyopathy (HCM) by current guidelines. Recently, AHA/ACC proposed an algorithm with novel clinical markers. It remains to be established the impact of this new approach. Purpose Evaluate the impact of the 2020 AHA/ACC guideline on the 2014 ESC and 2011 ACCF/AHA criteria regarding SCD risk assessment and primary prevention implantable cardioverter-defibrillator (ICD) in HCM. Methods The database of a HCM center non-referred cohort was accessed for SCD risk profile between March 2007 and March 2020. The agreement for primary prevention ICD recommendations among guidelines was assessed with the Cohen's and Fleiss' Kappa coefficient, P<0.05. SCD or appropriate ICD shock were defined as the primary end-point. Results A total of 100 patients, age 60±13 years, 55 (55%) females, were followed by 5±3 years. The maximal left ventricular (LV) wall thickness was 18±4 mm, 38 (38%) patients showed a family history of SCD, 22 (22%) syncope, 6 (6%) ejection fraction ≤50%, 2 (2%) LV apical aneurysm, 1 (1%) massive LV hypertrophy, 26 (26%) non-sustained ventricular tachycardia, and 23 (23%) extensive late gadolinium enhancement. An ICD was placed in 17 (17%) patients. According to the 2020 AHA/ACC guideline, 57 (57%) patients met class IIa recommendation, 27 (27%) class IIb, and 16 (16%) class III. The 2014 ESC model classified 14 (14%) in class IIa, 18 (18%) in class IIb, and 68 (68%) in class III. The 2011 ACCF/AHA considered 66 (66%) in class IIa, 6 (6%) in class IIb, and 28 (28%) in class III. The Cohen's Kappa was 0.200 (95% CI 0.292–0.107), P=0.0005, between the 2020 AHA/ACC and the 2014 ESC, and 0.520 (95% CI 0.651–0.388), P=0.0005, between the North American approaches. The Fleiss' Kappa was 0.219 (95% CI 0.303–0.135) P=0.0005 among the three guidelines, whereas it reached 0.221 (95% CI 0.334–0.108) for class IIa, 0.244 (95% CI 0.357–0.131) for class IIb and 0.202 (95% CI 0.315–0.089) for class III, P=0.0005. Figure 1 shows the patient's reclassification with the new guideline. The primary end-points occurred in 7 (7%) patients in a median follow-up of 6 (17–0.4) years. All of them were classified as IIa with the 2011 ACCF/AHA guideline, but only 4 (4%) met this class under the 2020 AHA/ACC, and none in the 2014 ESC model. Conclusion A low agreement was found among guidelines, especially between the 2020 AHA/ACC and the 2014 ESC criteria. The North American systems differed moderately, but the new approach has reduced the cases in class IIa and III recommendation for primary prevention ICD. In contrast, the recent 2020 guideline has increased the number of patients in class IIa in relation to the European model, but both strategies have not protected the totality of patients with SCD or appropriate shock. Funding Acknowledgement Type of funding sources: Public hospital(s). Main funding source(s): Hospital de Clínicas de Porto Alegre Figure 1

Exercise training inhibits left ventricular collagen upregulation in mice with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is estimated to affect 1:500, and is characterised by otherwise unexplained left ventricular (LV) hypertrophy, cardiomyocyte disarray, fibrosis, diastolic dysfunction, and ventricular arrhythmias. Historically, patients with HCM have been discouraged from participation in high intensity sports and exercise. However, the 2020 Sports Cardiology Guidelines recommend that patients with HCM should receive advice about exercise training (ET) based on individual risk assessment. To learn more about the effects of ET in HCM, we exposed mice carrying an HCM-causative sarcomere mutation (Myh6R403Q/+ (R403Q) mice) to high intensity interval training. Purpose To investigate the effect of exercise training on hypertrophic cardiomyopathy in mice. Methods R403Q mice were stratified to treadmill exercise (n=11) or sedentary behaviour (n=11). After 3 weeks, we induced HCM by giving CsA in the feed for 3 weeks, while the ET or sedentary behaviour continued for a total of 6 weeks. Each bout of treadmill running consisted of a 10-minute warm up, followed by 5 intervals of 8 minutes at high intensity (90% of VO2 max speed at week 0) and 2 minutes at medium intensity (60% of VO2 max speed at week 0). Every third day of the ET protocol we increased the high and medium intensity running speeds by 0.6 and 0.4 m/min, respectively. We performed echocardiography after 0, 3, and 6 weeks of the 6-week protocol. After completion of the protocol, we recorded lung and whole heart weight, and harvested LVs for molecular analyses. Results Confirming the expected HCM phenotype, R403Q mice that received CsA (R403Q SED+CsA) had a 1.3-fold increase in whole heart weight (p<0.0001), 1.5-fold increase in lung weight (p<0.001), and 2.4-fold increase in maximal left ventricular posterior wall (LVPW) thickness measured by echocardiography (p<0.0001) compared to sedentary wild type littermates given CsA (WT SED+CsA). Heart weight, lung weight, and maximum LVPW thickness were also increased 1.5- (p<0.0001), 1.6- (p<0.0001), and 2.0-(p<0.0001) fold, respectively, compared to R403Q not given CsA (R403Q SED-CsA). R403Q ET+CsA mice increased their running distance before exhaustion 2.0-fold compared to baseline (p=0.010), and ran 1.6-fold longer than R403Q SED+CsA (p=0.020). In R403Q ET+CsA mice, LV mRNA expression of Col1a2 was 51% (p=0.021), and Col3a1 49% (p=0.013) of R403Q SED+CsA expression levels. Compared to R403Q SED+CsA mice, exercise training did not affect heart weight, maximum LV posterior wall thickness or lung weight in R403Q ET+CsA mice. Conclusion Treadmill ET inhibited upregulation of LV collagen expression in mice with HCM, but did not affect hypertrophy. This could indicate that ET during early development of HCM attenuates development of fibrosis. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): South-Eastern Norway Regional Health Authority (Helse Sør-Øst RHF) and KG Jebsen Cardiac Research Center

Anterior mitral valve leaflet length in cats with hypertrophic cardiomyopathy

IntroductionAnterior mitral valve leaflet (AMVL) elongation is a recognised feature of hypertrophic cardiomyopathy (HCM). However, whether AMVL elongation precedes left ventricular hypertrophy in cats is currently unknown. The aim of this study was to explore the risk of developing an HCM phenotype in cats with an elongated AMVL. Animals: Fifty-five apparently healthy cats with a normal baseline echocardiogram and a follow-up echocardiogram at >one year. Materials and methodsThis was a retrospective longitudinal study. Cats at the baseline were grouped based on whether or not they developed an HCM phenotype at follow-up. AMVL length and left atrial and left ventricular dimensions were measured from two-dimensional images. ResultsThe median follow-up period of the study population was 5.4 years (25th and 75th quartile, 2.7–6.7 years). During this time, 17 cats (30.9%) developed an HCM phenotype. At the baseline, cats that subsequently developed an HCM phenotype had greater AMVL length (9.4 mm [25th and 75th quartile, 9.0–10.6 mm] vs. 8.5 mm [25th and 75th quartile, 7.6–9.1 mm], P < 0.0001) and maximal left ventricular wall thickness (4.5 mm [25th and 75th quartile, 4.1–4.7 mm] vs. 4.0 mm [25th and 75th quartile, 3.7–4.6 mm], P = 0.007) than those that did not. Multiple logistic regression analysis confirmed that both baseline variables were independent predictors for development of an HCM phenotype. ConclusionsThe AMVL length was greater in cats that subsequently developed left ventricular hypertrophy. Further studies investigating the clinical application of AMVL in the natural history of feline HCM are warranted.

B-PO03-165 MEAN SCAR ENTROPY PREDICTS VENTRICULAR ARRHYTHMIAS EVENTS IN HYPERTROPHIC CARDIOMYOPATHY USING LATE GADOLINIUM ENHANCEMENT CARDIAC MAGNETIC RESONANCE

Ventricular arrhythmias (VAs) is associated with sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). Previous studies have found late gadolinium enhanced (LGE) on cardiac magnetic resonance (CMR)was independently associated with VAs in HCM. Risk stratification of VAs remains complex and LGE is present in the majority of HCM patients. This study was to determine whether the LGE by CMR derived entropy within the scar and the left ventricular (LV) myocardium predicts VAs in HCM. Consecutive HCM patients with scar by LGE-CMR were included. Routine left ventricular function parameters including LV ejection fraction (LVEF) and %LGE defined as percentage of LGE to LV mass (%LGE) using software CVI 42. The scar heterogeneity, quantified by entropy within the scar and LV myocardium was derived. The presence of VAs was defined as previous aborted cardiac arrest, documented sustained ventricular tachycardia (VT) and non-stained VT (nsVT) by Holter or implantable cardiac devices (ICD) monitoring. A total of 68 HCM patients (54.6 ±14.3 years, 69.1% male, LVEF 67.2 ±12.9 %) with LGE CMR were enrolled with a median follow-up of 25 (IQR 13-13) months. Thirty-one patients in VAs group and 37 patients in No-VAs group were included. From multivariable analysis, higher entropy of the scar (Hazard ratio [HR] 2.682;95% confidence interval [CI]:1.022 to 7.037; P=0.039) was independently associated with VAs, after adjusting for LVEF, %LGE, the LV maximal wall thickness (MWT) and the left atrium (LA) diameter. High entropy within the scar was an independent predictor of VAs and may indicate an arrhythmogenic scar. It seemed to be valuable for assessing the clinical status of VAs in HCM patients.

B-PO03-169 MYOCARDIAL SCAR BURDEN QUANTIFIED BY CARDIAC MAGNETIC RESONANCE IMAGING IS PREDICTIVE OF VENTRICULAR TACHYCARDIA IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY

Patients with hypertrophic cardiomyopathy (HCM) are at a higher risk of developing ventricular tachycardia (VT) and sudden cardiac death (SCD). Previous studies have demonstrated a correlation between late gadolinium enhancement (LGE) measured by cardiac magnetic resonance imaging (MRI) quantified as % of myocardial mass and VT; however, the predictive value of a more practical and routinely performed semi-quantitative assessment of LGE remains unknown. To determine whether a semi-quantitative assessment of myocardial fibrosis by cardiac MRI (number of myocardial segments with LGE) is predictive of VT in patients with HCM. We identified 65 patients (mean age 47±17, 34% female) with a clinical diagnosis of HCM who had a cardiac MRI prior to an implantable cardioverter defibrillator (ICD) implantation for primary prevention of SCD. VT was defined as appropriate anti-tachycardia pacing or shocks for sustained ventricular arrhythmias. The MRI was analyzed by an experienced radiologist blinded to the clinical data. LGE was assessed by both quantitative (% of total myocardial mass) and semi-quantitative (number of myocardial segments involved) methods. During the follow-up period (median 33 months), seven patients experienced VT. Patients with > 6 myocardial segments with LGE were at higher risk to develop VT (OR: 5.7, p=0.03) which remained significant after adjusting for age, maximum left ventricular wall thickness, left atrial size, maximum left ventricular outflow gradient, history of nonsustained VT, unexplained syncope, and family history of SCD (p=0.03). Similarly, patients with a higher fibrosis burden (LGE >10% myocardial mass) were more likely to develop VT (OR: 8.6, p=0.01) even after adjusting for the abovementioned traditional risk factors (p=0.04). The extent of LGE, assessed by both quantitative and semi-quantitative measures, is strongly associated with ventricular arrhythmias requiring ICD therapy in patients with HCM even after accounting for traditional risk factors. Fibrosis burden as detected by cardiac MRI may serve as an imaging biomarker to improve risk stratification and patient selection for primary prevention ICD implantation in patients with HCM.

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

AimsThe aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies.Methods and results In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94–30.02, P = 8.05e−11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31–24.87, P < 2.2e−16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP−), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP− and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP− and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation.Conclusions Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

Severe right ventricular hypertrophy in hypertrophic cardiomyopathy: Serious symptoms, complex surgical procedures, and poor prognosis in Fuwai Hospital.

Severe right ventricular hypertrophy (SRVH) in hypertrophic cardiomyopathy (HCM) is rare. We studied the clinical characteristics and prognosis of 36 patients with HCM and SRVH in a Chinese cohort. Patients with HCM and SRVH were enrolled between 2013 and 2017. The clinical characteristics, treatment therapies, and clinical outcomes of the 36 patients were retrospectively studied and compared with those of 128 patients without SRVH. Patients in the group with SRVH were younger than those in the group without SRVH (27.58±15.09 years vs 40.34±13.21 years, respectively; p<0.001). Patients with SRVH had more serious clinical symptoms and a higher New York Heart Association functional class than those without SRVH. Most patients in the group with SRVH exhibited diffuse RV hypertrophy, and 13 patients presented with biventricular outflow tract obstruction. Maximal left ventricular (LV) wall thickness (27.29±7.95 mm vs 24.33±5.85 mm, respectively; p=0.027) and LV outflow tract gradient (80.83±24.41 mm Hg vs 42.3±5.7 mm Hg, respectively; p=0.000) were significantly greater in patients with SRVH than in those without SRVH. A total of 30 patients in the group with SRVH underwent surgical correction. During a median follow-up period of 48 months, six patients with SRVH reached primary clinical endpoints (four sudden cardiac deaths, one heart failure-related death, and one heart transplantation), whereas only two deaths occurred in the patients without SRVH. We conclude that patients with HCM and SRVH exhibit serious symptoms and have complex surgical requirements and poor clinical outcomes.

Prevention of sudden cardiac death by the implantable cardioverter-defibrillator in adults with inherited heart disease. long term follow-up

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND Inherited heart diseases include all inheritable channelopathies or cardiomyopathies. Sudden cardiac death (SCD) might be the first and last clinical presentation. ICD implantation is established as a therapeutic tool according to risk criteria. OBJETIVES The aim of this study is to analyze the population characteristics in ICD/ CRT-ICD recipients in patients with inherited heart disease and establish possible risk predictor factors of arrhytmogenic events during follow-up. MÉTHODS: This is a prospective single-center registry. We included all patients from January1, 2012, to December 31, 2020 who subsequently underwent ICD/ ICD-CRT implantation. RESULTS A total of 172 patients were included with a mean age of 60.47 ± 13,1 years and a mean follow-up duration of 49.71 ± 41.8 months. The most frequent underlying cardiac condition was dilated cardiomyopathy (58.1%), followed by hypertrophic cardiomyopathy (15.7%), arrythmogenic cardiomyopathy (2.3%), long QT syndrome (1.7%), Brugada syndrome (1.2%), catecholaminergic (2.9%) , idiopathic (7%) and others (11%). 89 ICDs (51.7%) and 83 ICD-CRTs (48.2%) were implanted for primary prevention of SCD. During follow-up, 13.4% of the patients experienced arrhythmogenic events. Only 4.1% of the patients experienced inappropriate shock, secondary to supraventricular arrhythmias all of them. Genetic testing was done in only 14.1% of our patients. In the 27 cases of hypertrophic cardiomyopathy, 25 (92.6%) underwent ICD implantation for primary prevention. 14 patients (51.9%) had family history of SCD, 8 (29.6%) had unexplained syncope and 16 (59.3%) had ventricular tachycardia in the Holter monitoring. The mean left atrial size was 44.15 ± 7.2mm, mean maximum LV-wall thickness 22.85 ± 5,25mm, and a mean LVOT gradient of 30.56 ± 31.3mmHg, with a mean actual HCM SCD-score of SCD over 5 years of 5.84 ± 3.53%. According to traditional parameters, 100% of the HCM sample meet criteria for ICD implantation in primary prevention compared to 66.7% according to the new score. During follow-up 2 patients (7.4% ) experienced arrhythmogenic events, and 3 patients (11.1%) had inappropriate shocks secondary to supraventricular arrhythmias. Genetic testing was done in 22.2% of the patients and was positive for a known pathogenic mutation in half of the cases. None of the parameters evaluated in the current score, a high risk of SCD according to it, having old high risk criteria or implanted of ICD in secondary prevention were related in our study with more arrhytmogenic events. CONCLUSIONS ICD implatation for primary prevention is the main indication in our population. Either classic factors or the new HCM SCD-score were no related in our study with the presence of arrhytmogenic events during follow-up.

Correlación genotipo-fenotipo en miocardiopatía hipertrófica: un estudio multicéntrico en Portugal y España sobre la variante p.Arg21Leu de TPM1

Introduction and objectivesTPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. MethodsTPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. ResultsThe TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. ConclusionsTPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.

Sudden cardiac death risk in hypertrophic cardiomyopathy: comparison between echocardiography and magnetic resonance imaging

In hypertrophic cardiomyopathy (HCM) patients, left ventricular (LV) maximal wall thickness (MWT) is one of the most important factors determining sudden cardiac death (SCD) risk. In a large unselected sample of HCM patients, we aimed to simulate what changes would occur in the calculated SCD risk according to the European HCM Risk-SCD calculator when MWT measured using echocardiography was changed to MWT measured using MRI. All consecutive patients with HCM who underwent cardiac MRI were included. MWT measured with echocardiography and MRI were compared, and 5-year SCD risk according to the HCM Risk-SCD calculator was computed using four different models. The final population included 673 patients [389 (57.8%) males, median age 50 years, interquartile range (36–60)]. The median MWT was lower measured by echocardiography than by MRI [20 (17–24) mm vs 21 (18–24) mm; p < 0.0001]. There was agreement between echocardiography and MRI in the measurement of maximal LV wall thickness in 96 patients (14.3%). The largest differences between echo and MRI were − 13 mm and + 9 mm. The differences in MWT by echocardiography and MRI translated to a maximal difference of 8.33% in the absolute 5-year risk of SCD, i.e., the echocardiography-based risk was 8.33% lower than the MRI-based estimates. Interestingly, 13.7% of patients would have been reclassified into different SCD risk categories if MRI had been used to measure MWT instead of echocardiography. In conclusion, although there was high general intermodality agreement between echocardiography and MRI in the MWT measurements, the differences in MWT translated to significant differences in the 5-year risk of SCD.

Optical Coherence Tomography Angiography for the Evaluation of Retinal Vasculature in Fabry Disease: Our Experience and Review of Current Knowledge.

Purpose: Optical coherence tomography angiography (OCTA) is a non-invasive and objective tool for the evaluation of the retinal microvascular changes in Fabry disease (FD). We investigated changes in retinal vasculature in FD patients, and the possible correlation with systemic parameters, by using OCTA, and reviewed the current status of literature.Methods: Thirteen FD patients (eight females, five males, mean age 49.85 ± 14.7 years) were compared with 13 age- and sex-matched healthy controls. OCTA 3 × 3 mm macular scans were performed in all subjects. We evaluated the vessel density and vessel perfusion in distinct macular areas (whole, inner, and outer) of both the superficial capillary plexus (SCP VD and SCP VP) and of the deep capillary plexus (DCP VD and DCP VP). We also evaluated the foveal avascular zone (FAZ) metrics (area, perimeter, and circularity), and correlation between systemic and OCTA parameters. A literature review on the current understanding of OCTA in FD is then presented.Results: FD patients showed significantly lower SCP VD values in the whole area (17.37 ± 2.08 mm−1 vs. 18.54 ± 1.21 mm−1; p-value 0.022), as well as in the outer area (17.46 ± 2.10 mm−1 vs. 19.08 ± 1.14 mm−1; p-value 0.002), but not in the inner. Even the DCP VD was significantly lower in all the imaged areas: whole (17.75 ± 3.93 mm−1 vs. 19.71 ± 1.20 mm−1; p-value 0.024), outer (18.25 ± 4.17 mm−1 vs. 20.33 ± 1.20 mm−1; p-value 0.023), and inner (19.54 ± 4.17 mm−1 vs. 21.96 ± 1.55 mm−1; p-value 0.011). There were no significant differences in vessel perfusion parameters (both SCP VP and DCP VP ones) and FAZ. No significant correlations were found between the OCTA parameters and systemic parameters (maximal left ventricular wall thickness and glomerular filtration rate) in FD patients.Conclusions: OCTA can be considered as a promising non-invasive tool, which enables a quantitative evaluation of retinal vascular involvement in FD, despite the varying data reported in literature. Our results support the use of OCTA as an objective tool to evaluate retinal vascular abnormalities in FD. The utility of OCTA in FD needs to be validated by longitudinal studies taking into account the overall progression of the disease.

Patterns of Left Ventricular Hypertrophy and Late Gadolinium Enhancement on Cardiac MRI in Patients with Hypertrophic Cardiomyopathy and their Prognostic Significance - An Experience from a South Asian Country.

Objectives:Cardiac magnetic resonance (CMR) imaging is very pertinent in the diagnosis and risk stratification of patients with hypertrophic cardiomyopathy (HCM). We aimed to assess the patterns of left ventricular (LV) hypertrophy, late gadolinium enhancement (LGE), and their prognostic significance in HCM patients in Pakistani population, as no such data are available from Pakistan.Material and Methods:This was a retrospective, single center study. All patients who had confirmed diagnosis of HCM on CMR at Aga Khan University Hospital during the period of 2011–2019 were identified and included in the study.Results:A total of 74 patients were included with the mean age of 45.6 ± 15 years and the majority 71.6 % (n = 53) being male. Maximal LV wall thickness was 21.1 ± 5 mm, asymmetrical septal hypertrophy being the most common pattern (62.2%, n = 46). LGE was present in 75.7% (n = 56) with most common site being septum plus LV free wall (24.3%, n =18). Mean ejection fraction% was found to be lower in patients with LGE (P < 0.001). Major adverse cardiac events (MACE) were observed in 40.5% (n = 30). Presence of LGE and right ventricular involvement was found to have a statistically significant association with MACE (P value 0.018 and 0.046, respectively). In multivariable analysis, only LGE was significantly associated with MACE (odd ratio: 4.65; 95% CI: 1.21–17.88).Conclusion:Asymmetrical septal hypertrophy was the most common pattern of hypertrophy. LGE was present in three fourth of the study population and it was significantly associated with MACE.

Genotype-phenotype correlations in hypertrophic cardiomyopathy: a multicenter study in Portugal and Spain of the TPM1 p.Arg21Leu variant

Introduction and objectivesTPM1 is one of the main hypertrophic cardiomyopathy (HCM) genes. Clinical information on carriers is relatively scarce, limiting the interpretation of genetic findings in individual patients. Our aim was to establish genotype-phenotype correlations of the TPM1 p.Arg21Leu variant in a serie of pedigrees. MethodsTPM1 was evaluated by next-generation sequencing in 10 561 unrelated probands with inherited heart diseases. Familial genetic screening was performed by the Sanger method. We analyzed TPM1 p.Arg21Leu pedigrees for cosegregation, clinical characteristics, and outcomes. We also estimated the geographical distribution of the carrier families in Portugal and Spain. ResultsThe TPM1 p.Arg21Leu variant was identified in 25/4099 (0.61%) HCM-cases, and was absent in 6462 control individuals with other inherited cardiac phenotypes (P<.0001). In total, 83 carriers (31 probands) were identified. The combined LOD score for familial cosegregation was 3.95. The cumulative probability of diagnosis in carriers was 50% at the age of 50 years for males, and was 25% in female carriers. At the age of 70 years, 17% of males and 46% of female carriers were unaffected. Mean maximal left ventricular wall thickness was 21.4 ±7.65mm. Calculated HCM sudden death risk was low in 34 carriers (77.5%), intermediated in 8 (18%), and high in only 2 (4.5%). Survival free of cardiovascular death or heart transplant was 87.5% at 50 years. Six percent of carriers were homozygous and 18% had an additional variant. Family origin was concentrated in Galicia, Extremadura, and northern Portugal, suggesting a founder effect. ConclusionsTPM1 p.Arg21Leu is a pathogenic HCM variant associated with late-onset/incomplete penetrance and a generally favorable prognosis.

Clinical and molecular characterization of seven patients with Danon disease.

Danon disease is an X-linked glycogen storage disease characterized by skeletal myopathy, cardiomyopathy and intellectual impairment. It is caused by a loss-of-function mutation in the lysosome-associated membrane protein-2 (LAMP2) gene. In the present study, exon and boarding intron analysis of 96 cardio disease-associated genes was performed in 770 patients with hypertrophic cardiomyopathy (HCM) using second-generation sequencing. Next, the identified mutations were confirmed in family members of the patients and 300 healthy controls. Detailed clinical, electrocardiographic (ECG) and echocardiographic findings were recorded. A pathogenic mutation in LAMP2 was identified in 7 patients who phenotypically presented with HCM. A total of four patients had a fragmented QRS complex (fQRS) on surface ECG. In addition, two patients presented with ventricular preexcitation with a short PR interval. Compared with the patients with protein kinase AMP-activated non-catalytic subunit γ2 syndrome and Fabry disease, the 7 patients with Danon disease presented at an earlier age, had a smaller left atrial size, a thinner maximal left ventricular wall thickness and a lower probability of pacemaker implantation. Compared with 12 sex- and age-matched patients with sarcomere-protein mutations, the 4 patients with Danon disease had a lower left ventricular outflow tract gradient and worse diastolic function. The present study provided a comprehensive comparison of different pathologies presenting with HCM and reported on features of early-onset Danon disease, including the characteristic preexcitation and fQRS on ECG. This may provide valuable information that may be utilized for the early diagnosis and treatment of patients with Danon disease. The present study was registered as a clinical trial with ClinicalTrials.gov (Sep. 2, 2016; registry no. NCT02888132).

Clinical, functional and prognostic correlates of blunted heart rate reserve during exercise stress echocardiography in hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Background Blunted heart rate reserve (HRR) during exercise is associated with cardiac autonomic dysfunction and poor outcome. Purpose To evaluate the anatomical, functional and prognostic correlates of HRR during exercise stress echocardiography (ESE) in hypertrophic cardiomyopathy (HCM). Methods We prospectively recruited a consecutive sample of 121 HCM patients [age 47 ± 13 years, 67 males; NYHA class 1.7 ± 0.7; left ventricular (LV) ejection fraction 71 ± 9 %; LV maximal wall thickness 24 ± 5 mm; 58 (48%) with LV outflow tract obstruction (LVOTO, gradient ≥ 50 mmHg) at rest] who underwent semi-supine bicycle ESE from January 2006 to September 2019. HRR was calculated as the peak/rest heart rate (HR) ratio. All patients were followed-up for a median of 7.5 years. Results HR was 68 ± 11 bpm at rest and 105 ± 19 bpm at peak stress. Receiver-operating characteristic analysis was used to determine the best cut-off value of HRR (≤ 1.48, blunted) to predict all-cause death. A blunted HRR was present in 52 patients (43 %, Group 1). Patients with blunted HRR had more frequently hypertension (Group 1= 41/52 vs Group 2= 40/69, 79 vs 58 %, p = 0.019), resting systolic anterior motion of the mitral valve [(SAM) , Group 1= 41/52 vs Group 2= 40/69, 79 vs 58 %, p = 0.019] and rest LVOTO (Group 1= 31/52 vs Group 2= 27/69, 60 vs 39 %, p = 0.029). Patients in Group 1 had larger left atrial diameter (48.8 ± 6.5 vs 46.5 ± 7.6, p = 0.076), lower LV end-diastolic [(EDD) , 44.8 ± 4.6 vs 46.7 ± 4.6 mm p = 0.02] and LV end-systolic diameter [(ESD), 25.2 ± 5.3 vs 27.6 ± 5.5 mm p = 0.02] at rest. Patients in Group 1 had higher NYHA class (1.9 ± 0.6 vs 1.6 ± 0.7, p = 0.009), resting HR (71.5 ± 11.4 vs 64.6 ± 10.6 bpm p &amp;lt; 0.001), and shorter total exercise time (6.3 ± 3.1 vs 9.1 ± 2.8 min, p &amp;lt; 0.001) compared to patients in Group 2. During the follow-up, 13 patients died. All-cause death was observed in 10/52 patients of Group 1 and 3/69 patients of Group 2 (19 vs 4 %, p &amp;lt; 0.05). Cox multivariate regression survival analysis revealed that HRR ≤ 1.48 (Hazard ratio 3.7, 95% CI 0.96-14.5, p = 0.048) and left atrial diameter (Hazard ratio 1.15, 95% CI 1.04-1.28, p = 0.003) were independent predictors of all-cause mortality, either on or off beta-blocker therapy. Conclusion HRR is a simple non-imaging biomarker of cardiac autonomic function and is frequently abnormal in HCM. The blunted increase in frequency is associated with NYHA functional class, exercise time, rest HR, rest LVOTO, SAM, LV EDD and ESD. HRR independently predicts survival in HCM. The lower the HRR, the worse the outcome. Abstract Figure.

Cardiac remodelling and heart failure symptoms in patients with apical hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Background Although earlier publications suggested a more benign clinical course for patients (pts) with apical hypertrophic cardiomyopathy (ApHCM), recent studies report increased morbidity and mortality, comparable to the prognosis of other HCM variants. Moreover, information regarding cardiac remodelling and its relationship with symptoms in pts with ApHCM is scarce. The aim of our study was to assess left ventricular (LV), right ventricular (RV) and left atrial (LA) remodelling in pts with ApHCM in comparison with non-apical variants of HCM (nonApHCM), and the impact of cardiac remodelling on heart failure symptoms. Methods One hundred fifty-one consecutive pts with HCM (52 ± 16 yrs, 47% men) in sinus rhythm and with preserved LV ejection fraction (16 pts with ApHCM and 135 pts with nonApHCM), were prospectively enrolled. Comprehensive echocardiography was performed in all, including the measurement of maximal LV wall thickness (LVWT), RV free wall thickness (RVWT) and maximal LA volume indexed to body surface area (LAVi). Global LV strain (ɛ), RVɛ, LAɛ and end-diastolic LA strain rate (ASr) were measured using speckle-tracking echocardiography (STE). The ratio of E to average e’ was used to estimate LV filling pressure. The degree of mitral regurgitation (1/2/3) has also been assessed. Heart failure symptoms were defined according to the New York Heart Association (NYHA) classification. Results Forty-eight pts in nonApHCM group had intraventricular obstruction. There were no significant differences between pts with and without ApHCM regarding: age (58 ± 20 vs 52 ± 16 yrs), gender distribution, RVWT, LVɛ (-14.9 ± 2.7 vs -13.9 ± 3.5 %), RVɛ (-19.6 ± 3.6 vs -10.0 ± 5.0%), LAɛ (19.2 ± 5.8 vs 16.4 ± 7.1%)(p &amp;gt; 0.05 for all). Pts with ApHCM had lower values for LVWT (17.2 ± 1.9 vs 21.4 ± 5.2 mm, p = 0.002), E/e’ (12.0 ± 5.8 vs 17.6 ± 8.5, p = 0.02) and LAVi (48 ± 16 vs 61 ± 25, p = 0.03) compared to pts with nonApHCM. Pts with ApHCM had slightly better LA contractile function as assessed by ASr (-1.23 ± 0.50 vs -0.97 ± 0.49 sec-1, p = 0.05). Mitral regurgitation was more often severe in nonApHCM pts (56/42/31 vs 10/4/0, p &amp;lt; 0.001). There was no significant difference between the percentage of symptomatic pts (NYHA class ≥2) in ApHCM vs nonApHCM group (p = 0.3). In the ApHCM group, symptomatic pts had significantly lower ASr compared to asymptomatic pts (-0.98 ± 0.35 vs -1.61 ± 0.46 sec-1, p = 0.01). Conclusions Despite of lower LVWT values, less severe MR and no obstruction, pts with apical HCM have similar prevalence of heart failure symptoms, and similar LV, RV and LA dysfunction compared to pts with non-apical HCM. Symptomatic pts with apical HCM have worse LA contractile function compared to asymptomatic pts.

What if HCM Risk-SCD was assessed with CMR maximum LV wall thickness measurements?

Abstract Funding Acknowledgements Type of funding sources: None. Introduction The HCM Risk-SCD estimates the risk of sudden cardiac death at 5 years in patients (pts) with hypertrophic cardiomyopathy (HCM). According to ESC Guidelines, in pts with a 5-year risk of SCD &amp;lt;4%, an implantable cardioverter defibrillator (ICD) is generally not indicated, in pts with a risk of 4 to less than 6%, an ICD may be considered and in pts with a 5-year risk ≥6%, an ICD should be considered. The association between the degree of LVH and sudden cardiac death (SCD) has been based on measurements of maximum LVWT by echocardiography which is part of HCM Risk-SCD score. However, cardiac magnetic resonance (CMR) has shown a superior resolution in characterization of cardiac structures, with additional role in SCD risk stratification. Whether measurements of LVWT by echocardiography and CMR are interchangeable has been brought to question. Purpose We sought to evaluate the incidence of discrepant measurements of maximal LVWT between echocardiography and CMR and determine its implication in HCM Risk-SCD score and ICD indication. Methods Unicentric, retrospective analysis of pts submitted to CMR who had HCM as definitive diagnosis, between 1/2013 and 9/2019. CMR and echocardiographic measures were compared, as well as HCM Risk-SCD score calculated with these values (maximum LVWT was the only variable that differed between measures). Subsequently, pts were divided in three groups according to HCM Risk-SCD score: pts with a 5-year risk of SCD &amp;lt;4% (G1), risk of 4 to less than 6% (G2) and risk ≥6% (G3). Results Out of the 781 CMR studies evaluated, 59 pts were found to have HCM (7.6%) with mean age of 62 ± 11 years and female predominance (50.8%). 12 pts had obstructive phenotype (20.3%). Mean LVWT was 20.0 ± 4.6mm when measured by CMR and 18.8 ± 4.6mm by echo; when comparing the measures by echo with CMR, there was a positive correlation between them (p &amp;lt; 0.001; r 0.719). Mean HCM Risk-SCD was 2.80 ± 1.51% when measured by CMR and 2.69 ± 1.53% by echo; there was a positive correlation between these measures too (p &amp;lt; 0.001; r 0.963). Maximum LV thickness evaluated by CMR showed a positive correlation (p = 0.006, r 0.384) with the HCM risk-score assessed by CMR. Only 1 pt changed risk group with CMR measurement of maximum LVWT (from G1 to G2). Conclusion: In this cohort, there was a positive, linear relationship between maximum LVWT and HCM Risk-SCD score measured by CMR and echocardiogram. Only 1 pt changed risk stratification group (5-year risk of SCD &amp;lt;4% to 4 to less than 6%). Although CMR measurements, when interpreted correctly, are more precise compared with echocardiography, in this cohort there was no impact on the patient"s future clinical orientation regarding ICD implantation.

Analysis on related factors of myocardial fibrosis in patients with hypertrophic cardiomyopathy

Objective: To investigate the related factors of myocardial fibrosis in patients with hypertrophic cardiomyopathy. Methods: Patients with hypertrophic cardiomyopathy, hospitalized in the First People's Hospital of Yunnan Province from January 2016 to May 2020, were included in this cross-sectional study. Patients were divided into delayed enhancement positive group (fibrosis group) and non-delayed enhancement group (non-fibrosis group). According to the maximum left ventricular end diastolic wall thickness (LVMWT), patients in the fibrosis group was further divided into mild hypertrophy group, moderate hypertrophy group and severe hypertrophy group. The baseline clinical data of patients were collected by medical record management system. All enrolled patients underwent cardiac magnetic resonance imaging (CMR). The presence and location of myocardial fibrosis were identified by CMR gadolinium contrast delayed enhancement (LGE). The range of LGE (LGE%) was calculated by visual analysis. The levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI) in peripheral blood were measured. Results: A total of 48 patients ( age (46.4±14.3) years, 42 (87.5%) males) were enrolled. There were 34 LGE positive cases (fibrosis group) and 14 LGE negative cases (non-fibrosis group). Compared with non-fibrosis group, patients in fibrosis group were younger (P=0.038) and prevalence of NYHA grade Ⅲ/Ⅳ was higher (P=0.00). Compared with non-fibrosis group, patients in fibrosis group had thicker LVMWT (P= 0.008), higher left ventricular mass index(LVMI) (P=0.001), higher left ventricular end diastolic volume (LVEDV) (P=0.043), lower left ventricular ejection fraction (LVEF) and cardiac index (CI) (all P <0.05). The levels of NT-proBNP and cTnI were significantly higher in fibrosis group than in non-fibrosis group (2 760.5 (1 503.4, 3 783.6) ng / L vs. 861.3 (552.2, 1 092.8) ng / L, P=0.002; 0.970 (0.448, 1.684)μg / L vs. 0.147 (0.033, 0.251)μg / L, P=0.041).In fibrosis group, there were 15 cases of mild hypertrophy (mild hypertrophy group), 10 cases of moderate hypertrophy (moderate hypertrophy group), and 9 cases of severe hypertrophy (severe hypertrophy group). The LGE% and NT-proBNP and cTnI increased in proportion with increasing myocardial hypertrophy (P<0.05). LGE% was negatively correlated with age (r=-0.618, P=0.011), and positively correlated with NT-proBNP and cTnI levels (r=0.271, P=0.010; r=0.111,P=0.013, respectively), and positively correlated with LVEDV, LVMWT and LVMI (r=0.438, P=0.09; r=0.735, P=0.001; r=0.532, P=0.034, respectively). Conclusions: In patients with hypertrophic cardiomyopathy, the extent of myocardial fibrosis increases with the increase of myocardial hypertrophy. Myocardial fibrosis is negatively correlated with age, and positively correlated with NT-proBNP and cTnI, as well as LVEDV, LVMWT and LVMI in this patient cohort.

Tip of the iceberg: a tertiary care centre retrospective study of left ventricular hypertrophy aetiologies

AimsTo phenotype patients referred to a tertiary centre for the exploration of a left ventricular hypertrophy (LVH) starting from 12 mm of left ventricular wall thickness (LVWT).Methods and resultsConsecutive patients...