Maximal Left Ventricular Wall Thickness Research Articles

Relationship Between Maximal Left Ventricular Wall Thickness and Sudden Cardiac Death in Childhood Onset Hypertrophic Cardiomyopathy.

Background:Maximal left ventricular wall thickness (MLVWT) is a risk factor for sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). In adults, the severity of left ventricular hypertrophy has a nonlinear relationship with SCD, but it is not known whether the same complex relationship is seen in childhood. The aim of this study was to describe the relationship between left ventricular hypertrophy and SCD risk in a large international pediatric HCM cohort.Methods:The study cohort comprised 1075 children (mean age, 10.2 years [±4.4]) diagnosed with HCM (1–16 years) from the International Paediatric Hypertrophic Cardiomyopathy Consortium. Anonymized, noninvasive clinical data were collected from baseline evaluation and follow-up, and 5-year estimated SCD risk was calculated (HCM Risk-Kids).Results:MLVWT Z score was <10 in 598 (58.1%), ≥10 to <20 in 334 (31.1%), and ≥20 in 143 (13.3%). Higher MLVWT Z scores were associated with heart failure symptoms, unexplained syncope, left ventricular outflow tract obstruction, left atrial dilatation, and nonsustained ventricular tachycardia. One hundred twenty-two patients (71.3%) with MLVWT Z score ≥20 had coexisting risk factors for SCD. Over a median follow-up of 4.9 years (interquartile range, 2.3–9.3), 115 (10.7%) had an SCD event. Freedom from SCD event at 5 years for those with MLVWT Z scores <10, ≥10 to <20, and ≥20 was 95.6%, 87.4%, and 86.0, respectively. The estimated SCD risk at 5 years had a nonlinear, inverted U-shaped relationship with MLVWT Z score, peaking at Z score +23. The presence of coexisting risk factors had a summative effect on risk.Conclusions:In children with HCM, an inverted U-shaped relationship exists between left ventricular hypertrophy and estimated SCD risk. The presence of additional risk factors has a summative effect on risk. While MLVWT is important for risk stratification, it should not be used either as a binary variable or in isolation to guide implantable cardioverter defibrillator implantation decisions in children with HCM.

Clinical Features and Natural History of Preadolescent Nonsyndromic Hypertrophic Cardiomyopathy

BackgroundUp to one-half of childhood sarcomeric hypertrophic cardiomyopathy (HCM) presents before the age of 12 years, but this patient group has not been systematically characterized. ObjectivesThe aim of this study was to describe the clinical presentation and natural history of patients presenting with nonsyndromic HCM before the age of 12 years. MethodsData from the International Paediatric Hypertrophic Cardiomyopathy Consortium on 639 children diagnosed with HCM younger than 12 years were collected and compared with those from 568 children diagnosed between 12 and 16 years. ResultsAt baseline, 339 patients (53.6%) had family histories of HCM, 132 (20.9%) had heart failure symptoms, and 250 (39.2%) were prescribed cardiac medications. The median maximal left ventricular wall thickness z-score was 8.7 (IQR: 5.3-14.4), and 145 patients (27.2%) had left ventricular outflow tract obstruction. Over a median follow-up period of 5.6 years (IQR: 2.3-10.0 years), 42 patients (6.6%) died, 21 (3.3%) underwent cardiac transplantation, and 69 (10.8%) had life-threatening arrhythmic events. Compared with those presenting after 12 years, a higher proportion of younger patients underwent myectomy (10.5% vs 7.2%; P = 0.045), but fewer received primary prevention implantable cardioverter-defibrillators (18.9% vs 30.1%; P = 0.041). The incidence of mortality or life-threatening arrhythmic events did not differ, but events occurred at a younger age. ConclusionsEarly-onset childhood HCM is associated with a comparable symptom burden and cardiac phenotype as in patients presenting later in childhood. Long-term outcomes including mortality did not differ by age of presentation, but patients presenting at younger than 12 years experienced adverse events at younger ages.

Right Ventricular Enlargement and Dysfunction Are Associated With Increased All-Cause Mortality in Hypertrophic Cardiomyopathy

ObjectiveTo assess whether right ventricular enlargement (RVE) and right ventricular dysfunction (RVD) adversely affect prognosis in hypertrophic cardiomyopathy (HCM). Patients and MethodsData were retrieved from Mayo Clinic’s prospectively collected HCM registry between January 1, 2000, and September 30, 2012. Right ventricle (RV) size and function were semiquantitatively categorized via echocardiography as normal (RV-Norm) versus abnormal (RV-Abn) (RVE or RVD). All-cause mortality was the primary endpoint. ResultsOf 1878 HCM patients studied (mean age 53±15 years; 41.6% female), only 71 (3.8%) had RV-Abn (24 RVE, 28 RVD, 19 combined RVE and RVD). Compared with HCM patients with RV-Norm, RV-Abn patients were older (57±14 vs 53±15 years, P=.02), more symptomatic (New York Heart Association functional class III-IV in 62.0% vs 48.6%, P=.03), had more atrial fibrillation (53.5% vs 17.3%, P<.001), and more prior implantable cardioverter-defibrillator implantation (23.9% vs 11.3%, P=.02). Median follow-up was 9.4 years with 311 deaths. Patients who were RV-Abn had higher all-cause mortality compared with RV-Norm (log-rank P<.001); 24.1% (95% CI, 15.5% to 35.3%) vs 6.1% (95% CI, 5.1% to 7.3%) at 5 years. In multivariable Cox modeling, RV-Abn (hazard ratio, 1.89; 95% CI, 1.18 to 3.03; P=.008) was associated independently with all-cause mortality after adjusting for age, female sex, New York Heart Association functional class, atrial fibrillation, hypertension, coronary artery disease, implantable cardioverter-defibrillator implantation, beta blocker use, prior septal reduction therapy, resting LV outflow tract gradient, maximal LV wall thickness, and moderate or greater tricuspid regurgitation. ConclusionAlthough perturbations in RV size and function were observed in fewer than 5% of patients with HCM, they were associated with nearly two-fold higher all-cause mortality at long-term follow-up.

Ventricular Repolarization Dispersion is a Potential Risk for the Development of Life-Threatening Arrhythmia in Children with Hypertrophic Cardiomyopathy.

The risk stratification and early interventions are necessary in patients with hypertrophic cardiomyopathy (HCM), as life-threatening arrhythmia (LTA) is a leading cause of death. This study aimed to explore whether an interval between the peak of the T wave to the end terminal of the T wave (Tp-e), which represents ventricular repolarization dispersion, could predict the risk for LTA in children with HCM. We analyzed electrocardiography at the first and last visits in children (aged < 15years) with HCM, and compared Tp-e interval and theratio of Tp-e interval to QT interval (Tp-e/QT) between children with and without LTA. We studied 25 children with HCM. During the follow-up of 85 (38-146) months, there were 7 children with LTA. The 5-year sudden cardiac death (SCD) risk was 1.4 (1.1-2.5) %, which suggested that our cohort consisted of patients at a lower risk for SCD. Age was significantly older in children with LTA compared to those without it (12.5 vs.1.0years, P = 0.037), although sex, the presence of family history and symptoms at diagnosis, the maximum left ventricular wall thickness Z-score did not differ between the groups. At the last electrocardiography before LTA, corrected Tp-e interval and Tp-e/QT ratio were significantly greater in patients with LTA compared to those in patients without LTA (corrected Tp-e: 103 vs. 78ms, P = 0.020; Tp-e/QT: 0.28 vs. 0.22, P = 0.046). Corrected Tp-e and Tp-e/QT ratio cutoff values of 91ms and 0.28 yielded as the predictors for LTA with sensitivity of 85% and 72%, specificity of 71% and 89%, respectively. Prolonged absolute and corrected Tp-e intervals and an increase in the Tp-e/QT ratio can be useful predictors for LTA in children with HCM. We offer temporal assessments of ventricular repolarization dispersion to stratify the risk for the development of LTA/SCD among children with HCM.

Effects of left ventricular mass on computed tomography derived fractional flow reserve in significant obstructive coronary artery disease

BackgroundIn significant obstructive coronary artery disease (SOCAD), a mismatch in assessment of severity of coronary artery stenosis may occur between invasive coronary angiography (ICA) and computed tomography (CT) derived fractional flow reserve (FFRCT). The present study aimed to identify the factors giving an FFRCT > 0.80 and leading to an underestimation of coronary artery severity in SOCAD vessels. MethodsA total of 141 consecutive patients who underwent both CT angiography including FFRCT and ICA, the latter showing >75% coronary artery stenosis were evaluated. Vessels were divided into two groups according to FFRCT at the distal aspect of the vessel: FFRCT > 0.80 (n = 12) and FFRCT ≤ 0.80 (n = 153). Vessel morphology, plaque characteristics, left-ventricular (LV) wall thickness at each site of the myocardium, and LV mass were also assessed. ResultsLV myocardium-related parameters including LV wall thickness (base, middle, apex, average, and maximal), LV mass, and LV mass index were higher in FFRCT > 0.80, whereas vessel-related parameters including, vessel morphology and plaque characteristics were not significantly different between >0.80 and < 0.80. Vessel morphology and plaque characteristics had no effect on FFRCT, whereas maximum LV wall thickness, LV mass, and LV mass index influenced FFRCT. LV mass index was the strongest predictor of distal FFRCT > 0.80 with an area under the curve of 0.81, and an optimal cut-off value of 66.5 g/m2 (sensitivity 77.8%, specificity 89.6%). ConclusionsThe presence of a high LV mass is a major cause for underestimation of coronary artery severity on FFRCT in SOCAD vessels. LV myocardium-related parameters should be considered when interpreting numerical values of FFRCT.

Divergent Impact of Enzyme Replacement Therapy on Human Cardiomyocytes and Enterocytes Affected by Fabry Disease: Correlation with Mannose-6-phosphate Receptor Expression.

Background: The impact of enzyme replacement therapy (ERT) on cardiomyocytes and intestinal cells, affected by Fabry disease (FD), is still unclear. Methods: Six patients with FD, including five family members with GLA mutation c.666delC and one with GLA mutation c.658C > T, manifesting cardiomyopathy and intestinal symptoms (abdominal pain, diarrhea and malabsorption) were included in the study. Clinical outcome, cardiac magnetic resonance (CMR), endomyocardial and gastro-intestinal biopsies were evaluated before and after 2 years of treatment with agalsidase-α (0.2 mg/kg every other week). Immunohistochemistry and Western blot assessments of mannose-6-phosphate receptors (IGF-II-R) on intestinal and myocardial frozen tissue were obtained at diagnosis and after 2 years of ERT. Results: After ERT left ventricular maximal wall thickness, ranging from pre (<10.5 mm) to mild (<15 mm) and moderate hypertrophy (16 mm), was not associated with significant changes at CMR. Degree of dyspnea, mean cardiomyocyte diameter and % vacuolated areas of cardiomyocytes, representing intracellular GL3, remained unmodified. In contrast, intestinal symptoms improved with disappearance of diarrhea, recovery of anemia and weight gain, correlating with near complete clearance of the enterocytes from GL3 inclusions. IGF-II-R expression was remarkably higher even at histochemistry in intestinal tissue compared with myocardium (p < 0.001) either at baseline and after ERT, thus justifying intestinal recovery. Conclusions: Human cells affected by FD may respond differently to ERT: while cardiomyocytes retain their GL3 content after 2 years of treatment, gastro-intestinal cells show GL3 removal with recovery of function. This divergent response may be related to differences in cellular turnover, as well as tissue IGF-II-R expression.

Isolated systolic hypertension is associated with increased left ventricular mass index and aortic stiffness in adolescents: a cardiac magnetic resonance study.

Despite the high prevalence of isolated systolic hypertension (ISH) among hypertensive adolescents, its clinical significance is not determined. In addition, it is hypothesized that ISH with normal central blood pressure (BP) in young patients is a benign phenomenon and was hence labeled spurious hypertension (sHTN). Using cardiac magnetic resonance we evaluated a group of 73 patients with suspected primary hypertension, aged 13-17 years (median: 16.9, interquartile range 15.8-17.4; 13 girls), in whom, based on 24-h ambulatory BP monitoring either ISH (n = 30) or white-coat hypertension (WCH) (n = 43) was diagnosed. Based on noninvasive central BP measurement 13 participants in the ISH group were classified as having sHTN and 17 were diagnosed with true hypertension. Compared with WCH adolescents, ISH patients presented with higher indexed left ventricular mass index (LVMI) (P < 0.001), maximal left ventricular (LV) wall thickness (P < 0.001), LV concentricity (P = 0.001) and more often had LV hypertrophy (47 vs. 14%, P = 0.002). They had higher average pulse wave velocity (PWV) in the proximal aorta (P = 0.016) and the whole thoracic aorta (P = 0.008). In addition, we observed higher indexed LV stroke volume (P = 0.025) in patients with ISH. The sHTN subgroup had significantly higher LVMI and aortic PWV, and more often had LV hypertrophy compared with the WCH group. The sHTN and true hypertension subgroups did not differ in terms of aortic PWV, LVMI or LV geometry. Compared with adolescents with WCH patients with ISH, including the sHTN subtype, have more pronounced markers of cardiac end-organ damage, higher aortic stiffness and stroke volume.

Segmental analysis of microvascular dysfunction and tissue characterization in hypertrophic cardiomyopathy by magnetic resonance imaging

Abstract Funding Acknowledgements Type of funding sources: None. Background While left ventricular hypertrophy (LVH) and myocardial fibrosis are frequently evaluated in hypertrophic cardiomyopathy (HCM), microvascular dysfunction is often overlooked. The aim of this study was to assess the association between wall thickness, microvascular dysfunction and tissue characteristics in HCM patients (P), comparing individual myocardial segments. Methods Prospective evaluation of adult P with HCM (P with "end-stage" HCM, prior septal reduction therapy or epicardial coronary artery disease were excluded). All underwent a cardiac magnetic resonance (CMR) protocol (1.5-T), from which the following parameters were analysed: maximal LV wall thickness (MLVWT), T1 and T2 mapping, extracellular volume (ECV), late gadolinium enhancement (LGE) and stress perfusion. Results were stratified according to the 16 American Heart Association segments. Multivariate regression analyses for perfusion defects and tissue characteristics were performed. Results 75 P (total of 1200 myocardial segments analysed), 63% male, mean age 55 ± 15 years, MLVWT of 20 ± 4.5mm (61% asymmetric septal LVH, 29% apical LVH and 8% concentric LVH). 28% presented LV outflow tract obstruction. MLVWT was greater in the basal and mid septum (table 1). Among the 424 segments (35.3%) with a perfusion defect, 286 (23.8%) had a defect only in the endocardial layer and 138 (11.5%) in both endocardial and epicardial layers with defects more often detected in hypertrophied segments. This association was verified in segments with MLVWT 12-14mm and MLVWT ≥15mm (OR 7.83, 95% CI 5.75-10.67, p &amp;lt; 0.001) (table 2). Among the 660 segments with normal MLVWT (≤11mm), 123 (19%) presented perfusion defects. A perfusion defect was more frequent in segments of obstructive HCM P (OR 1.48, 95% CI 1.13-1.92, p = 0.004). Microvascular dysfunction was associated with changes in tissue characteristics. For the same thickness, segments with perfusion defects had a higher T1 mapping (β-estimate 20.91, 95% CI 16.87-24.96, p &amp;lt; 0.001) and T2 mapping mean values than those without. Furthermore, regardless of MLVWT, segments with perfusion defects had LGE more often (OR 4.16, 95% CI 3.19-5.41, p &amp;lt; 0.001) and a higher ECV. On the other hand, among the 424 segments with a perfusion defect, 115 (27%) did not present LGE. MLVWT was associated with tissue characteristics. Comparing to non-hypertrophied segments, T1 mapping mean value was higher in segments with MLVWT 12-14mm and with ≥15mm (β-estimate 37.71, 95% CI 31.2-44.21, p &amp;lt; 0.001). Segments with MLVWT ≥15mm showed a significantly superior ECV mean value comparing to non-hypertrophied segments. LGE was more frequent in the more hypertrophied segments: MLVWT 12-14mm and ≥15mm (OR 9.02, 95% CI 6.42-12.67, p &amp;lt; 0.001) (Table 2). Conclusion Microvascular dysfunction is more prevalent in obstructive HCM, particularly in the more hypertrophied segments. The presence of microvascular dysfunction is associated with diffuse tissue abnormalities and replacement fibrosis. Abstract Table 1: Characteristics of AHA segments Abstract Table 2: Multivariable analyses

Microvascular dysfunction and myocardial fibrosis impact on left ventricular myocardial deformation in hypertrophic cardiomyopathy: per segment analysis by magnetic resonance imaging

Abstract Funding Acknowledgements Type of funding sources: None. Background Left ventricular hypertrophy (LVH) and microvascular dysfunction are hallmarks of hypertrophic cardiomyopathy (HCM). We hypothesized that microvascular dysfunction contributes to LV myocardial deformation impairment. Methods Prospective evaluation of adult patients with HCM (patients with "end-stage" HCM, prior septal reduction therapy or epicardial coronary artery disease were excluded). All underwent a cardiac magnetic resonance (CMR) protocol (1.5-T), from which the following parameters were analysed: maximal LV wall thickness (MLVWT), T1 and T2 mapping, extracellular volume, late gadolinium enhancement (LGE) and stress perfusion. Three-dimensional strain analysis was obtained by using feature-tracking from cine images. Results were stratified according to the 16 American Heart Association segments. Multivariate regression analyses for longitudinal, circumferential and radial strain were performed. Results A total of 1200 myocardial segments were analysed (Table 1) (75 patients, 63% male, age 54.6 ± 14.7 years) including 61% with asymmetric septal LVH, 29% with apical LVH, 8% with concentric LVH, 28% exhibiting LV outflow tract obstruction. The mean MLVWT was 20 ± 4.5mm. Higher values of longitudinal strain (lower deformation) were found in segments with MLVWT ≥15mm (β-estimate: 2.31, 95% CI 0.91-3.70, p &amp;lt; 0.001) and in patients with obstructive HCM (β-estimate: 2.44, 95% CI 1.15-3.72, p &amp;lt; 0.001]) (Table 2). No association was found between perfusion defects, LGE and longitudinal strain. Higher values of circumferential strain (lower deformation) were found in segments with MLVWT 12-14mm (β-estimate: 2.31, 95% CI 1.36-3.25, p &amp;lt; 0.001), MLVWT ≥15mm (β-estimate: 5.29, 95% CI 4.47-6.12, p &amp;lt; 0.001), with perfusion defects (β-estimate: 2.75, 95% CI 2.0-3.5, p &amp;lt; 0.001), with LGE (β-estimate: 2.49, 95% CI 1.77-3.22, p &amp;lt; 0.001) and in patients with obstructive HCM (β-estimate: 1.25, 95% CI 0.44-2.06, p = 0.003). Lower radial strain values were found in segments with MLVWT 12-14mm (β-estimate: -10.64, 95% CI -13.95 to -7.33, p &amp;lt; 0.001), with MLVWT ≥15mm (β-estimate: -20.67, 95% CI -23.36 to -17.97, p &amp;lt; 0.001), with perfusion defects (β-estimate: -10.60, 95% CI -13.08 to -8.13, p &amp;lt; 0.001), and with LGE (β-estimate: -10.49, 95% CI -12.86 to -8.11) (table 2). Diabetes, hypertension and BMI &amp;gt; 25 kg/m2 were also associated with impaired myocardial deformation. Male gender correlated with worse radial and circumferential strain values. No association was found between parametric mapping values and LV myocardial deformation. Conclusion In patients with HCM, three-dimensional speckle tracking parameters for LV systolic function were particularly impaired in segments with LVH, microvascular dysfunction or fibrosis. LVH was associated with abnormal longitudinal, circumferential and radial strain while perfusion defects and LGE correlated with impaired circumferential strain and radial strain. Abstract Table 1: Characteristics of AHA segments Abstract Table 2: Multivariate analysis

Three-dimensional myocardial deformation parameters are associated with functional capacity assessed by cardiopulmonary exercise testing in patients with hypertrophic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Myocardial deformation parameters, derived from three-dimensional (3D) speckle-tracking echocardiography (3DSTE) are useful tools to determine left ventricular (LV) systolic function, and are often abnormal before a decline in ejection fraction (EF). Aims To study the correlation between systolic function evaluated by myocardial deformation parameters obtained by 3DSTE and functional capacity in patients with HCM. Methods HCM patients seen prospectively at outpatient cardiomyopathy clinic at a tertiary centre were included. Systolic function was assessed by strain measures – global longitudinal, circumferential and radial strain - obtain by 3DSTE, LVEF by 2D and 3D echocardiography were also assessed. Functional capacity was evaluated by CPET. Results Of 67 P with HCM (mean age 57 ± 14 years, 41 males), 38 P (56.7%) were in New York Heart Association (NYHA) functional class I, 24 (35.8%) in class II and 5 (7.5%) in class III. 46P (68.7%) had obstructive (HCM), with a maximum LV wall thickness (MWT) of 20 (7) mm. 3DSTE and CPET parameters are reported in Table 1. Absolute values of 3D global radial strain showed correlation with pVO2 (r=-0.336, p = 0.006), as well as longitudinal strain (r=-0.280, p= 0.024). No association was found between LVEF and pVO2. MWT did not correlate with 3DSTE strain measures. Conclusion Impaired myocardial deformation was associated with worse functional capacity assessed by peak oxygen consumption.

Red blood cell distribution width and maximum left ventricular wall thickness predict poor outcomes in patients with hypertrophic cardiomyopathy

AbstractAimTo evaluate the prognostic utility of red blood cell distribution width (RDW) and maximum left ventricular wall thickness (MLVWT) in patients with hypertrophic cardiomyopathy (HCM).Patients and methodsThis study is a retrospective cohort analysis. Patients diagnosed with HCM at the First Affiliated Hospital of Sun Yat‐sen University from March 2014 to March 2019 were included. HCM patients were stratified into two groups based on the occurrence of major adverse cardiac events (MACE). Receiver operating characteristic (ROC) curves were then constructed and Cox regression models were employed to gauge the prognostic relevance of RDW and MLVWT for HCM patients. Kaplan–Meier analysis evaluated the survival and MACE‐free rate in patients with different level of RDW and MLVWT.ResultsA total of 300 patients with HCM were enrolled in this study and followed up for 40.56±18.33 months. Among them, 117 MACE (39.00%), 40 all‐cause deaths (13.33%), and 29 cardiovascular deaths (9.67%). The level of RDW, MLVWT, creatinine (Cr), and B‐type pro‐brain natriuretic peptide (NT‐ProBNP) were statistically different between the MACE group and non‐MACE group (P &lt; .05). Multivariate analysis showed that after adjusting for confounding factors, RDW and MLVWT were independent predictors of all‐cause mortality and MACE in HCM patients. ROC showed that RDW &gt; .13 and MLVWT &gt; 23 mm are the cut‐off value to predict all‐cause mortality and MACE. The area under the ROC curve AUC of the combination predicting the occurrence of all‐cause mortality and MACE are .823 and .820, respectively. Kaplan–Meier analysis showed that the survival rate and MACE‐free survival rate of group 1 (RDW≦.13 and MLVWT≦23 mm) were significantly higher than group 2 (RDW &gt; .13 or MLVWT &gt; 23 mm), and group 3 (RDW &gt; .13 and MLVWT &gt; 23 mm) (P = .000).ConclusionWe determined that increased RDW and MLVWT was independently associated with MACE incidence and risk of mortality in HCM patients. Combined evaluation of RDW and MLVWT yielded a more accurate predictive model of HCM patient outcomes relative to the use of either of these metrics in isolation. Our research can provide a theoretical basis in the occurrence of MACE for the high‐risk HCM and intervene them properly and timely.

Effect of Cis-Compound Variants in MYH7 on Hypertrophic Cardiomyopathy With a Mild Phenotype

Patients with hypertrophic cardiomyopathy (HC) caused by compound variants have severe clinical manifestations, but significant clinical heterogeneity remains. Clinical diversity in these patients may result from different combinations of variants. We analyzed the role of cis-compound variants in a Chinese HC pedigree. Exome sequencing was performed in the proband. Identified variants were detected with bi-directional Sanger sequencing in a pedigree that comprised 3 generations and 28 family members. Follow-up was performed for 16 years. Two missense variants (c.2465T>C, p.Met822Thr; c.4258C>T, p.Arg1420Trp) were identified in the MYH7 gene. These variants were absent in our 761 in-house people without HC and predicted to be pathogenic.Both variants were detected in 11 family members, thus they were believed to inherit cis. In the 11 members, only 5 developed HC, the other 6 were asymptomatic variant carriers with an abnormal electrocardiogram. The HC members had mild hypertrophy with a maximum left ventricular wall thickness of 13 to 21 mm and showed a low incidence of cardiovascular events. In conclusion, the cis-compound variants of Met822Thr and Arg1420Trp in MYH7 are causal but relatively benign, variants associated with familial HC. This finding suggests that different types of compound variants might need to be analyzed for a genotype-phenotype study.

Mean Scar Entropy by Late Gadolinium Enhancement Cardiac Magnetic Resonance Is Associated With Ventricular Arrhythmias Events in Hypertrophic Cardiomyopathy.

Background: Ventricular arrhythmias are associated with sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM). Previous studies have found the late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) was independently associated with ventricular arrhythmia (VA) in HCM. The risk stratification of VA remains complex and LGE is present in the majority of HCM patients. This study was conducted to determine whether the scar heterogeneity from LGE-derived entropy is associated with the VAs in HCM patients.Materials and Methods: Sixty-eight HCM patients with scarring were retrospectively enrolled and divided into VA (31 patients) and non-VA (37 patients) groups. The left ventricular ejection fraction (LVEF) and percentage of the LGE (% LGE) were evaluated. The scar heterogeneity was quantified by the entropy within the scar and left ventricular (LV) myocardium.Results: Multivariate analyses showed that a higher scar [hazard ratio (HR) 2.682; 95% CI: 1.022–7.037; p = 0.039] was independently associated with VA, after the adjustment for the LVEF, %LGE, LV maximal wall thickness (MWT), and left atrium (LA) diameter.Conclusion: Scar entropy and %LGE are both independent risk indicators of VA. A high scar entropy may indicate an arrhythmogenic scar, an identification of which may have value for the clinical status assessment of VAs in HCM patients.

Abstract 13438: Obesity is Uncommon in Patients With Transthyretin Cardiac Amyloidosis

Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome that includes distinct subtypes with different pathophysiologies, genetics, and treatment. Distinguishing HFpEF due to transthyretin cardiac amyloidosis (ATTR-CA) is critical given its specific treatable pathophysiology. Obesity is a common driver of HFpEF, but it has been noted clinically that low body mass index (BMI) is a common finding in ATTR-CA. Methods: A single center, retrospective study of patients undergoing 99mTc-pyrophosphate (PYP) scans from 2010-2019 was analyzed for BMI association with ATTR-CA and the Val122Ile variant. BMI differences were prospectively evaluated in the ongoing multicenter Screening for Cardiac Amyloidosis Using Nuclear Imaging for Minority Populations (SCAN-MP) study. The association of BMI with ATTR-CA/Val122Ile was compared by Wilcoxon rank sum analysis and combined with age, sex, and maximum LV wall thickness in a multivariable logistic regression in both the retrospective and SCAN-MP cohorts. Results: In the retrospective analysis, BMI (in kg/m 2 ) among those with ATTR-CA/Val122Ile (n=198, 40%) was lower (25.8, IQR 23.4-28.9) than in other patients (27.1, IQR 23.9-32.0) (p&lt;0.001). In multivariable logistic regression, BMI &lt; 30 (OR 2.60, 95% CI 1.49-4.54), remained independently associated with ATTR-CA/Val122Ile. In the first 221 patients enrolled in SCAN-MP, 18 (8%) had ATTR-CA (n=11) or were carriers of the Val122Ile variant (n=7) with negative PYP scans. Among those subjects, BMI was significantly lower (25.6 [IQR 24.3-28.3]) than in other patients (32.6 [27.9-38.1]) (p&lt;0.001). BMI did not differ between ATTR-CA patients (27.5 [25.3-28.9]) and Val122Ile allele carriers with negative 99mTc-pyrophosphate scans (25.3 [24.3-28.2]). When combined with age, sex, and maximum LV wall thickness, BMI&lt;30 (OR 11.8 [CI 2.47-56.14]) and maximum LV wall thickness (OR 1.38/mm [95% CI 1.10-1.74]) were associated with ATTR-CA/Val122Ile. Conclusions: Lower BMI is associated with a diagnosis of ATTR-CA/Val122Ile in heart failure with increased LV wall thickness and may be useful in selecting patients benefiting from evaluation for ATTR-CA.

External validation of the HCM Risk-Kids model for predicting sudden cardiac death in childhood hypertrophic cardiomyopathy.

AimsSudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM). The newly developed HCM Risk-Kids model provides clinicians with individualized estimates of risk. The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort.Methods and resultsA retrospective, longitudinal cohort of 421 patients diagnosed with HCM aged 1–16 years independent of the HCM Risk-Kids development and internal validation cohort was studied. Data on HCM Risk-Kids predictor variables (unexplained syncope, non-sustained ventricular tachycardia, maximal left ventricular wall thickness, left atrial diameter, and left ventricular outflow tract gradient) were collected from the time of baseline clinical evaluation. The performance of the HCM Risk-Kids model in predicting risk at 5 years was assessed. Twenty-three patients (5.4%) met the SCD end-point within 5 years, with an overall incidence rate of 2.03 per 100 patient-years [95% confidence interval (CI) 1.48–2.78]. Model validation showed a Harrell’s C-index of 0.745 (95% CI 0.52–0.97) and Uno’s C-index 0.714 (95% 0.58–0.85) with a calibration slope of 1.15 (95% 0.51–1.80). A 5-year predicted risk threshold of ≥6% identified 17 (73.9%) SCD events with a corresponding C-statistic of 0.702 (95% CI 0.60–0.81).ConclusionsThis study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualized risk predictions and shared decision-making in children with HCM.

Predictive factors for requiring heart transplantation in patients with hypertrophic cardiomyopathy: data from a referral center

Abstract Background Heart transplant (HT) remains the last treatment option for patients with non-obstructive hypertrophic cardiomyopathy (HCM) who develop end-stage heart failure (HF). Early identification of patients who may require a HT in the future is crucial in order to advise them, establish the appropriate follow-up and determine the appropriate time to include them in the waiting list. Objectives Our study sought to find predictive factors related with requiring HT during follow-up in patients with HCM. Methods Consecutive patients with HCM referred to a HCM monographic clinic from 2018 to 2020 (HCM controls) and transplanted patients due to HCM in the same tertiary HT hospital since 2003 (cases) were included. Baseline (on the date of HCM diagnosis) and longitudinal data regarding clinical, genetic, ECG and echocardiographic variables were retrospectively evaluated. Follow-up was registered from HCM diagnosis to HT (in cases) or last medical check up (controls). Results A total of 157 patients (24 HCM-HT cases and 133 HCM controls) were included (45±19 yo; 57% male). At the time of MCH diagnosis (Table), cases were significantly younger than controls, were more frequently symptomatic and showed significantly higher BNP levels and more advanced diastolic dysfunction (larger left atrium, higher E/A ratio and lower e'); also, HCM-HT reported more family history and had higher proportion of pathogenic mutations (being MYH7 the most frequently involved). Left ventricular (LV) systolic function was slightly reduced in HCM-HT cases. In contrast, HCM controls were more frequently diagnosed by casual findings or family screening and had more LV outflow tract obstruction at first medical evaluation. LV maximal wall thickness (MWT) did not differ between groups. During a median follow-up since HCM diagnosis of 6.2 years (median follow-up of 8.9 and 7.1 years in cases and controls, respectively), HCM-HT cases presented a higher incidence of sustained ventricular tachycardia or ICD therapy (HR=4.0; CI95%:1.6–10.0 p=0.03) and HF admissions (HR=3.9; CI95%:1.8–8.1 p&amp;lt;0.001). There were no cardiovascular deaths during follow-up. Conclusions The presence of symptoms in a young non-obstructive HCM patient, along with family history and a pathogenic mutation, should advice clinicians a closer follow-up and early transfer to a HT referral center, especially if associated with diastolic dysfunction and high BNP values. Funding Acknowledgement Type of funding sources: None. Table 1

Clinical characteristics and natural history of pre-adolescent non-syndromic hypertrophic cardiomyopathy

Abstract Background The clinical presentation and natural history of pre-adolescent sarcomeric hypertrophic cardiomyopathy (HCM) has not been systematically characterised. The aim of this study was to describe the clinical characteristics and outcomes of a large, international, multicentre cohort of children diagnosed with non-syndromic HCM below the age of 12. Methods Data from the International Paediatric Hypertrophic Cardiomyopathy Consortium on 639 children meeting diagnostic criteria for HCM below 12 years of age (pre-adolescent) were collected and compared with 568 diagnosed aged 12–16 years. Patients with syndromic and metabolic HCM were excluded. Results Of 639 (male n=417, 65.3%) children with pre-adolescent HCM, 339 (53.1%) had a family history of HCM and 57 (8.9%) a family history of sudden cardiac death (SCD). At the time of baseline assessment; 132 (20.7%) had heart failure symptoms and 39 (6.1%) reported unexplained syncope. Median maximal left ventricular wall thickness on echocardiogram was 13.6mm (IQR 10–19) with a corresponding median z-score of 8.7 (5.3–14.4). 145 (22.7%) had left ventricular outflow tract obstruction (LVOTO) (maximal LVOT gradient≥30mmHg) and 35 (5.5%) had severe LVOTO (gradient≥90mmHg). Over a median follow up 5.6 years (IQR 2.3–10), 10.5% underwent a myectomy and 23.2% implantable cardiac defibrillator (ICD) implantation for primary (81.8%) or secondary (14.2%) prevention. 42 (6.7%) patients died [SCD 4.9%, heart failure death 0.8%, other 1%] and 21 (3.3%) underwent cardiac transplantation. 69 (10.8%) patients had an arrhythmic event (SCD n=31, resuscitated cardiac arrest n=17, appropriate ICD therapy n=14, sustained VT with haemodynamic compromise n=7). Compared to those presenting after 12 years, those under 12 were less likely to have a family history of SCD (8.9% vs 13%, p:0.047) or report unexplained syncope (6.1% vs 12.3%, p&amp;lt;0.00). The degree of hypertrophy did not differ but a higher proportion of pre-adolescent patients had LVOTO (22.7% vs 14.4%, p&amp;lt;0.00). A higher proportion of pre-adolescent underwent a myectomy (10.5% vs 7.2%, p:0.045) but a lower proportion received a primary prevention ICD (18.9% vs 30.1%, p:0.041). The overall proportion of patients reaching the mortality or arrhythmic end-points did not differ, but SCD and resuscitated cardiac arrest events were more frequent in pre-adolescent patients (4.9% vs 3.9% and 2.7 vs 1.6% respectively). Conclusion Pre-adolescent HCM is associated with a high symptom burden and variable cardiac phenotype, comparable to those presenting later in childhood. Despite baseline similarities and equal overall survival, younger patients were less likely to receive a primary prevention ICD despite being more likely to experience a SCD or resuscitated cardiac arrest. This study suggests that younger patients should not be considered a distinct entity for risk stratification and that similar management strategies to older HCM patients should be employed. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): BHF (British Heart Foudnation) MRC (Medical Research Council)

Effects of left ventricular mass index on computed tomography derived fractional flow reserve in significant obstructive coronary artery disease

Abstract Background In significant obstructive coronary artery disease (SOCAD), a mismatched assessment of the severity of coronary artery stenosis may occur between invasive coronary angiography and computed tomography (CT) derived fractional flow reserve (FFRCT). The exact mechanisms of unexpected underestimation of FFRCT remain unknown. Purpose The aims of this study are (1) to clarify the mechanisms of underestimation on FFRCT; and (2) to identify the predictive factors of FFRCT underestimation above the value of 0.80 in SOCAD vessels. Methods A total of 1160 outpatients who underwent CT angiography (CTA) with FFRCT analysis for suspected coronary artery disease (CAD) between January 2017 and June 2020 were evaluated. Among them, 141 consecutive patients who had both CTA coupled to FFRCT analysis and invasive angiogram showing &amp;gt;75% coronary stenosis were included for analysis. Vessels were divided into two groups according to FFRCT at the distal vessel: FFRCT &amp;gt;0.80 (n=12) and FFRCT ≤0.80 (n=153). Vessel-related parameters, including vessel morphology (vessel length and lumen volume) and plaque components (non-calcified plaque volume and calcified plaque volume) and left ventricular (LV) myocardial-related parameters, including LV wall thickness at each site of the myocardium, and LV mass were evaluated semi-automatically. Results Vessel morphology and plaque components did not differ between FFRCT &amp;gt;0.80 and ≤0.80, whereas LV wall thickness (average; 10.7±2.7 vs. 8.4±1.6 mm, and maximal; 13.5±3.0 vs. 10.6±1.8 mm, all p value &amp;lt;0.001), LV mass (136.4±38.4 vs. 98.8±26.8 g, p&amp;lt;0.001), and LV mass index (73.8±22.6 vs. 51.8±12.2 g/m2, p&amp;lt;0.001) were significantly higher in FFRCT &amp;gt;0.80. Next, we investigated the parameters that correlated with FFRCT. Of all, vessel morphology and plaque components were not related to FFRCT, whereas maximal LV wall thickness, r=0.24, p=0.01; LV mass, r=0.19. p=0.04; and LV mass index, r=0.30, p=0.001) correlated with FFRCT. In the vessels showing FFRCT &amp;gt;0.80, only LV mass (r=0.84, p=0.005) and LV mass index (r=0.67, p=0.047) correlated with FFRCT. (Figure 1). LV mass index was the strongest predictor of a distal FFRCT of &amp;gt;0.80 with the area under curve (AUC) 0.81, 95% CI 0.62 – 1.00, P&amp;lt;0.0001 and an optimal cut-off value of 66.5 g/m2 sensitivity 77.8%, specificity 89.6% (Figure 2). Conclusions FFRCT is affected not by vessel-related parameters but LV myocardial-related parameters in SOCAD. The presence of an excessive LV mass is a major predictor of underestimation of FFRCT in SOCAD vessels. LV myocardial-related parameters should be considered when interpreting numerical values of FFRCT to avoid the possibility of overlooked SOCAD. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Clinical characterisation of hypertrophic cardiomyopathy caused by MYH7 gene variants in children

Abstract Background Variants in the cardiac Beta Myosin Heavy chain 7 gene (MYH7) are a common cause of hypertrophic cardiomyopathy (HCM) in adults, but their role in paediatric-onset HCM has not been systematically characterised. This study aims to describe the presentation, clinical characteristics and outcomes of childhood HCM secondary to disease-causing MYH7 variants. Methods Retrospective, longitudinal, data from 70 individuals meeting diagnostic criteria for HCM under the age of 18 years with disease-causing MYH7 variants from a single specialist centre (1991–2019) were collected. A Major Adverse Cardiac Event was defined as sudden cardiac death (SCD), heart failure-related death, cardiac transplantation, haemodynamically-compromising sustained ventricular arrhythmia or appropriate implantable cardioverter defibrillator (ICD) therapy. Results Median age at diagnosis was 9.2 years (IQR 4.2–13.3 years); 47 patients (67.1%) were less than 12 years and 7 (10.0%) were under the age of 1 at diagnosis. Twenty-two patients (31.4%) were probands. MYH7 variants were missense (n=67) or truncating (n=1). Reason for presentation were: family screening (n=45, 64.3%); cardiac symptoms (n=12, 17.1%); incidental finding (n=11, 15.7%); and out of hospital cardiac arrest (n=2, 2.9%). At baseline, mean maximum left ventricular wall thickness (MLVWT) z-score was 9.6 (±5.8), 11 patients (15.7%) had resting left ventricular outflow tract obstruction (left ventricular outflow tract gradient ≥30mmHg). Baseline phenotype did not significantly differ between probands and non-probands (MLVWT Z score 11.9 (±4.5) vs 8.5 (±6.1), p-value 0.0675). Over a median follow up of 3.6 years (IQR 1.8–7.9 years), 10 patients (14.3%) underwent a left ventricular septal myectomy at a median age 6.4 years (IQR 3.4–12.1 years) and 27 (38.6%) had an implantable cardioverter defibrillator (ICD) for primary (n=24, 34.3%) or secondary (n=3, 4.3%) prevention. Three patients (4.3%) died (SCD, n=1; heart-failure related, n=1; non-cardiac, n=1) and 3 (4.3%) underwent cardiac transplantation. Ten patients (14.3%) experienced a MACE. Patients who experienced a MACE were more likely to be probands [n= 6 (60.0%) vs n=16 (26.7%); p=0.036] but did not differ in terms of baseline phenotype (p=0.134). Conclusion MYH7 variants can cause infantile and childhood-onset disease, which is associated with significant early cardiac morbidity and mortality. Adverse outcomes were more common in those presenting as probands. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Medical Research Council, Great Ormond Street Hospital charity.

External validation of the HCM Risk-Kids model for predicting sudden cardiac death in childhood hypertrophic cardiomyopathy

Abstract Background Sudden cardiac death (SCD) is the most common mode of death in childhood hypertrophic cardiomyopathy (HCM). The newly developed HCM Risk-Kids model provides clinicians with individualised estimates of risk. The aim of this study was to externally validate the model in a large independent, multi-centre patient cohort. Methods A retrospective, longitudinal cohort of patients diagnosed with HCM aged 1–16 years independent of the HCM-Risk-Kids development and internal validation cohort was studied. Data on HCM Risk-Kids predictor variables (unexplained syncope, non-sustained ventricular tachycardia, maximal left ventricular wall-thickness, left atrial diameter and left ventricular outflow tract gradient) were collected from the time of baseline clinical evaluation. The performance of the HCM Risk-Kids model in predicting risk at 5 years was assessed. Results The cohort consisted of 421 patients with a median age at baseline evaluation of 12.3 years (IQR 7.3, 14.4). Over a median total follow up 3.48 years (IQR 1.83, 6.62, range 1 month – 20.7 years). Fourteen patients (3.3%) died and 10 (2.4%) underwent cardiac transplantation. Twenty-three patients (5.4%) met the SCD end-point within 5-years, with an overall incidence rate of 2.03 per 100 patient years (95% CI 1.48–2.78). Model validation showed a Harrell's C-index of 0.745 (95% CI 0.52–0.97) and Uno's C-index 0.714 (95% 0.58–0.85) with a calibration slope of 1.15 (95% 0.51–1.80). Figure 1a describes the agreement between predicted and observed 5-year cumulative proportion of SCD or equivalent events for each tertile of predicted risk in one imputed data set. One hundred and twenty-five (29.7%) patients had a predicted 5-year risk of ≥6%. SCD events occurred in 6 patients (2.0%) with a predicted risk &amp;lt;6% and 17 (13.6%) with a predicted risk ≥6. A 5-year predicted risk threshold of ≥6% identified 17 (73.9%) SCD-events with a corresponding C-statistic of 0.702 (95% CI 0.60–0.81) (Figure 1b). Conclusions This study reports the first external validation of the HCM Risk-Kids model in a large and geographically diverse patient population. A 5-year predicted risk of ≥6% identified over 70% of events, confirming that HCM Risk-Kids provides a method for individualised risk predictions and shared decision making in children with HCM. Incorporation of the model into routine clinical care will enable independent prospective model validation and assessment of the effect of its use in clinical practice. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): British Heart FoundationMedical Research Council Observed vs predicted risk by tertilesObserved vs predicted by threshold