Asymmetric Left Ventricular Hypertrophy Research Articles

An In Silico Cardiomyocyte Reveals the Impact of Changes in CaMKII Signalling on Cardiomyocyte Contraction Kinetics in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterised by asymmetric left ventricular hypertrophy, ventricular arrhythmias, and cardiomyocyte dysfunction that may cause sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The aim of this in silico study was to assess the mechanisms that underlie the altered electrophysiological activity, contractility, regulation of energy metabolism, and crossbridge cycling in HCM at the single-cell level. To investigate this, we developed a human ventricular cardiomyocyte model that incorporates electrophysiology, metabolism, and force generation. The model was validated by its ability to reproduce the experimentally observed kinetic properties of human HCM induced by (a) remodelling of several ion channels and Ca2+-handling proteins arising from altered Ca2+/calmodulin kinase II signalling pathways and (b) increased Ca2+ sensitivity of the myofilament proteins. Our simulation showed a decreased phosphocreatine-to-ATP ratio (-9%) suggesting a negative mismatch between energy expenditure and supply. Using a spatial myofilament half-sarcomere model, we also compared the fraction of detached, weakly bound, and strongly bound crossbridges in the control and HCM conditions. Our simulations showed that HCM has more crossbridges in force-producing states than in the control condition. In conclusion, our model reveals that impaired crossbridge kinetics is accompanied by a negative mismatch between the ATP supply and demand ratio. This suggests that improving this ratio may reduce the incidence of sudden death in HCM.

Heart failure in patients with hypertrophic obstructive cardiomyopathy

Hypertrophic cardiomyopathy is a hereditary cardiac disease, diverse in clinical manifestations, cardiac structure and natural progression. Patients with disease are associate with a broad range of clinical presentations, from patients who are asymptomatic, accidentally discovered during routine examination, to patients with chest pain, dyspnea, syncope, and even sudden death. We are presenting the clinical case of a young male patient with hypertrophic cardiomyopathy with rather large left ventricular wall thickness about 37mm who was hospitalized with severe dyspnea accompanied by tachycardia episodes and hypotension. The patient underwent electrical cardioversion, Doppler echocardiography, stress Doppler echocardiography with treadmill, cardiac MRI, basic blood tests, coronary CT angiography and ventriculography. The results showed the patient had a very high NT-proBNP level of 16,271 pg/mL; echocardiography showed asymmetric left ventricular hypertrophy, a maximum resting LVOT gradient of 28 mmHg, increasing to 64mmHg at peak stress, preserved left ventricular systolic function and grade III left ventricular diastolic dysfunction; greatly increased left ventricular mass of 199.6 g/m2, and delayed contrast enhancement involving the subendocardium of both ventricles and transecting the left ventricular free wall on cardiac MRI. We also discuss various treatment option for this young man.

Cardiac Morphology, Function, and Left Ventricular Geometric Pattern in Patients with Hypertensive Crisis: A Cardiovascular Magnetic Resonance-Based Study.

(1) Background: Altered cardiac morphology and function are associated with increased risks of adverse cardiac events in hypertension. Our study aimed to assess left ventricular (LV) morphology, geometry, and function using cardiovascular magnetic resonance (CMR) imaging in patients with hypertensive crisis. (2) Methods: Patients with hypertensive crisis underwent CMR imaging at 1.5 Tesla to assess cardiac volume, mass, function, and contrasted study. Left ventricular (LV) function and geometry were defined according to the guideline recommendations. Late gadolinium enhancement (LGE) was qualitatively assessed and classified into ischemic and nonischemic patterns. Predictors of LGE was determined using regression analysis. (3) Results: Eighty-two patients with hypertensive crisis (aged 48.5 ± 13.4 years, and 57% males) underwent CMR imaging. Of these patients, seventy-eight percent were hypertensive emergency and twenty-two percent were urgency. Diastolic blood pressure was higher under hypertensive emergency (p = 0.032). Seventy-nine percent (92% of emergency vs. 59% of urgency, respectively; p = 0.003) had left ventricular hypertrophy (LVH). The most prevalent LV geometry was concentric hypertrophy (52%). Asymmetric LVH occurred in 13 (22%) of the participants after excluding ischemic LGE. Impaired systolic function occurred in 46% of patients, and predominantly involved hypertensive emergency. Nonischemic LGE occurred in 75% of contrasted studies (67.2% in emergency versus 44.4% in urgency, respectively; p < 0.001). Creatinine and LV mass were independently associated with nonischemic LGE. (5) Conclusion: LVH, altered geometry, asymmetric LVH, impaired LV systolic function, and LGE are common under hypertensive crisis. LVH and LGE more commonly occurred under hypertensive emergency. Longitudinal studies are required to determine the prognostic implications of asymmetric LVH and LGE in hypertensive crisis.

Abstract P2046: The Role Of A Novel Alpha-crystallin B Chain Variant In Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is a highly complex disease with heterogenous clinical presentation. While mutations in sarcomere genes can account for a substantial proportion of familial cases, 40-50% of HCM patients do not carry such sarcomere variants and the causal mutations for their diseases remain elusive. Recently, we identified a novel variant of the alpha-crystallin B chain (CRYAB R123W ) in a pair of homozygotic twins who developed concordant HCM phenotypes that manifested over a nearly identical time course. Yet, how CRYAB R123W promotes HCM phenotype remains unclear. Here, we generated mice carrying the Cryab R123W -knockin allele and demonstrated that hearts from these animals exhibit increased maximal elastance, reduced diastolic function and are more susceptible to ventricular tachycardia with programmed stimulation. Upon transverse aortic constriction, mice carrying the Cryab R123W allele developed pathogenic left ventricular hypertrophy with substantial cardiac fibrosis and progressively decreased ejection fraction. In contrast to another well-characterized CRYAB variant (R120G) which induced Desmin aggregation, no evidence of protein aggregation was observed in hearts expressing CRYAB R123W despite its potent effect on driving cellular hypertrophy. Unexpectedly, CRYAB R123W appears to enhance calcium signaling by promoting nuclear localization of NFAT through direct interaction with calcineurin. Studies on isolated adult cardiomyocytes reveal altered fractional shortening, calcium dyshomeostasis, prolonged action potential duration, and T-wave alternans. Crossing of CRYAB R123W mice with a mybpc3 knock-in model of HCM did not potentiate pathological hypertrophy in compound heterozygotes, indicating that the pathological mechanisms in this model are independent of the sarcomere. Thus, our data establish the Cryab R123W allele as a novel genetic model of HCM that potentially unveils additional sarcomere-independent mechanisms of cardiac pathological hypertrophy and sudden cardiac death.

A novel αB-crystallin R123W variant drives hypertrophic cardiomyopathy by promoting maladaptive calcium-dependent signal transduction.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray and cardiac fibrosis, HCM is a highly complex disease with heterogenous clinical presentation, onset and complication. While mutations in sarcomere genes can account for a substantial proportion of familial cases of HCM, 40%-50% of HCM patients do not carry such sarcomere variants and the causal mutations for their diseases remain elusive. Recently, we identified a novel variant of the alpha-crystallin B chain (CRYABR123W) in a pair of monozygotic twins who developed concordant HCM phenotypes that manifested over a nearly identical time course. Yet, how CRYABR123W promotes the HCM phenotype remains unclear. Here, we generated mice carrying the CryabR123W knock-in allele and demonstrated that hearts from these animals exhibit increased maximal elastance at young age but reduced diastolic function with aging. Upon transverse aortic constriction, mice carrying the CryabR123W allele developed pathogenic left ventricular hypertrophy with substantial cardiac fibrosis and progressively decreased ejection fraction. Crossing of mice with a Mybpc3 frame-shift model of HCM did not potentiate pathological hypertrophy in compound heterozygotes, indicating that the pathological mechanisms in the CryabR123W model are independent of the sarcomere. In contrast to another well-characterized CRYAB variant (R120G) which induced Desmin aggregation, no evidence of protein aggregation was observed in hearts expressing CRYABR123W despite its potent effect on driving cellular hypertrophy. Mechanistically, we uncovered an unexpected protein-protein interaction between CRYAB and calcineurin. Whereas CRYAB suppresses maladaptive calcium signaling in response to pressure-overload, the R123W mutation abolished this effect and instead drove pathologic NFAT activation. Thus, our data establish the CryabR123W allele as a novel genetic model of HCM and unveiled additional sarcomere-independent mechanisms of cardiac pathological hypertrophy.

P353 A CASE OF FABRY DISEASE WITH ISOLATED CARDIAC INVOLVEMENT

Abstract A 64–year–old patient,hypertensive,ex–smoker,no family history of CAD or MCI,with electrocardiographic abnormalities during checkups for sports activity at age 40,came to our observation for reported brief episodes of heart palpitation.On ecg sinus rhythm,PR 200 msec,elevated QRS voltages,negative T waves from V3–V6 and infero–laterally,isolated BEV. Echocardiogram showed asymmetric left ventricular hypertrophy with involvement of septum and mid–apical segments,absence of obstruction,grade II diastolic dysfunction,enlarged left atrium,ectasia of aortic bulb,ascending aorta and arch with mild valvular insufficiency. Cardiac MRI showed asymmetric hypertrophy with prevalent involvement of the SIV and apex,normal systolic function.Right ventricle within limits.LAM elongated,biatrial dilatation.Areas of enhancement with intramural extension to the inferior SIV and extensive subendocardial area to the infero–lateral wall,picture suggestive of Fabry disease. Holter ecg was performed:RS at mean fc 61 bpm,numerous isolated BEVs and pairs,1 run of TVNS of 11 beats,for which dual–chamber ICD implantation was performed in primary prevention.Genetic examination showed absence of alpha galactosidase enzyme activity and mutation in exon 5 of GLA gene(p.N215S). The patient had no other systemic symptoms typical of Fabry‘s disease such as CRI,acroparesthesias,angiokeratomas,cornea verticillata,gastrointestinal disturbances nor central neurological involvement.In addition,he was starting enzyme replacement therapy with alpha galactosidase on a home regimen.Hypertrophic cardiomyopathy is a frequent finding in clinical practice.In MF, the age of cardiac involvement is usually later than in other forms of cardiomyopathy. Cardiac MRI is the most appropriate technique to place a correct differential diagnosis;numerous studies have demonstrated preferential localization of areas of "delayed enhancement" at the infero–lateral and posterolateral basal wall,present even in the absence of frank ventricular hypertrophy. Systemic involvement, may help in the differential diagnosis because of the presence of characteristic symptoms.In the reported clinical case,however,the diagnosis is even more insidious since in late forms or cardiac variants of MF,as with the p.N215S gene variant,cardiomyopathy may be the only significant clinical manifestation.

CE-454610-3 VT STORM DUE TO HYPERTROPHIC CARDIOMYOPATHY TREATED WITH ALCOHOL SEPTAL ABLATION

Radiofrequency (RF) ablation is a guideline-recommended therapy for ventricular tachycardia (VT). However, certain locations can be inaccessible through endocardial or epicardial approach. There are several documented unconventional techniques in these cases where VT is either treatment-refractory to RF ablation, or ablation is unlikely to be successful due to deep intramural substrate. N/A N/A A 66-year-old gentleman with a history of coronary artery disease (CAD) presents with four days of palpitations and lightheadedness to the emergency department. An ECG was performed which showed monomorphic VT from a basal septal focus. He was hemodynamically stable and thus started on a lidocaine drip and intermittent metoprolol IV pushes with conversion to sinus rhythm. Given the history of CAD, primary differential concerns were ischemia-mediated or scar-mediated VT. Thus, the patient underwent a coronary angiogram which revealed stable non-obstructive CAD. The patient then underwent a cardiac MRI which revealed severe asymmetric left ventricular hypertrophy measuring up to 18 mm in the mid-basal interventricular septum with mid-myocardial late gadolinium enhancement in the same area. This was most consistent with hypertrophic cardiomyopathy (HCM) as the etiology for the patient’s VT. As the patient continued to have significant ventricular ectopy and recurrent bouts of sustained VT on medical management, options for VT ablation were discussed. Overall, given the deep intramural location of the suspected VT substrate, endocardial and epicardial approaches were thought to have a low probability of success. Transarterial coronary ethanol ablation (TCEA) of the septum was thought to have the highest likelihood of success at controlling the patient’s VT in the setting of HCM. The patient underwent successful TTE guided TCEA of the first septal branch. Left ventricular outflow tract (LVOT) gradient improved from 45 to 17 mmHg. The patient was observed for 24 hours without evidence of VT. An ICD was subsequently implanted for secondary prevention. The patient was discharged in stable condition on an oral beta blocker without any additional anti-arrhythmic medications. In patients with VT due to HCM where there is a deep intramural substrate not amenable to traditional RF catheter ablation, TCEA is a reasonable approach. We describe a case of successful TCEA in both decreasing a patient’s LVOT gradient as well as cessation of the patient’s treatment refractory VT.

Cardiac magnetic resonance-feature tracking technique can assess cardiac function and prognosis in patients with myocardial amyloidosis

To quantitatively assess cardiac functions in patients with cardiac amyloidosis (CA) and hypertrophic cardiomyopathy (HCM) using cardiac magnetic resonance-feature tracking (CMR-FT) technique and evaluate the prognostic value of CMR-FT in patients with CA. We retrospectively collected the data from 31 CA patients with systemic amyloidosis confirmed by Congo red staining and serum immunohistochemistry after extracardiac tissue biopsy undergoing CMR at our hospital from March, 2013 to June, 2021.Thirty-one age and gender matched patients with asymmetric left ventricular wall hypertrophy and 31 healthy individuals without organic or functional heart disease served as the controls.Radial, circumferential and longitudinal strains and strain rates of the left ventricle at the global level and in each myocardial segment (basal, middle and apical) were obtained with CMR-FT technique and compared among the 3 groups.The predictive value of myocardial strains and strain rates for all-cause mortality in CA patients was analyzed using a stepwise COX regression model. The left ventricular volume, myocardial mass, ejection fraction and cardiac output differed significantly among the groups (P < 0.05).Except for apical longitudinal strain, the global and segmental strains were all significantly lower in CA group than in HCM group (P < 0.05).The global and segmental strains were all significantly lower in CA group than in the healthy individuals (P < 0.05).The basal strain rates in the 3 directions were significantly lower in CA group than in the healthy individuals (P < 0.05), but the difference in apical strain rates was not statistically significant between the two groups.Multivariate stepwise COX analysis showed that troponin T (HR=1.05, 95%CI: 1.01-1.10, P=0.017) and middle peak diastolic circumferential strain rate (HR=6.87, 95%CI: 1.52-31.06, P=0.012) were strong predictors of death in CA patients. Strain and strain rate parameters derived from CMR-FT based on cine sequences are new noninvasive imaging markers for assessing cardiac impairment in CA and cardiac function changes in HCM, and provide independent predictive information for all-cause mortality in CA patients.

Multi-Omic Architecture of Obstructive Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy. Currently, hypertrophy pathways responsible for HCM have not been fully elucidated. Their identification could serve as a nidus for the generation of novel therapeutics aimed at halting disease development or progression. Herein, we performed a comprehensive multi-omic characterization of hypertrophy pathways in HCM. Flash-frozen cardiac tissues were collected from genotyped HCM patients (n=97) undergoing surgical myectomy and tissue from 23 controls. RNA sequencing and mass spectrometry-enabled deep proteome and phosphoproteomic assessment were performed. Rigorous differential expression, gene set enrichment, and pathway analyses were performed to characterize HCM-mediated alterations with emphasis on hypertrophy pathways. We identified transcriptional dysregulation with 1246 (8%) differentially expressed genes and elucidated downregulation of 10 hypertrophy pathways. Deep proteomic analysis identified 411 proteins (9%) that differed between HCM and controls with strong dysregulation of metabolic pathways. Seven hypertrophy pathways were upregulated with antagonistic upregulation of 5 of 10 hypertrophy pathways shown to be downregulated in the transcriptome. Most upregulated hypertrophy pathways encompassed the rat sarcoma-mitogen-activated protein kinase signaling cascade. Phosphoproteomic analysis demonstrated hyperphosphorylation of the rat sarcoma-mitogen-activated protein kinase system suggesting activation of this signaling cascade. There was a common transcriptomic and proteomic profile regardless of genotype. At time of surgical myectomy, the ventricular proteome, independent of genotype, reveals widespread upregulation and activation of hypertrophy pathways, mainly involving the rat sarcoma-mitogen-activated protein kinase signaling cascade. In addition, there is a counterregulatory transcriptional downregulation of the same pathways. Rat sarcoma-mitogen-activated protein kinase activation may serve a crucial role in hypertrophy observed in HCM.

Prevalence, characteristics, and natural history of apical phenotype in a large cohort of patients with hypertrophic cardiomyopathy

BackgroundApical hypertrophic cardiomyopathy (ApHCM) is a variant of hypertrophic cardiomyopathy (HCM) with distinct imaging and clinical characteristics. Data on the prognosis of this HCM subgroup appear conflicting. Our study aims to clarify the natural history of ApHCM and identify predictors of outcomes. Materials and methodsA total of 856 patients with HCM were retrospectively examined. ApHCM was defined as asymmetric left ventricular hypertrophy confined predominantly at the apex, either isolated (pure ApHCM type) or with co-existent hypertrophy of the interventricular septum (mixed ApHCM). Echocardiographic, clinical, and survival data were compared between individuals with ApHCM and non-ApHCM. ResultsA total of 143 (16.7%) patients were diagnosed with ApHCM. Compared with non-ApHCM, subjects with apical HCM were diagnosed at an older age and had better echocardiographic indices and more comorbidities at baseline. Apical aneurysms were more prevalent among the ApHCM phenotype (6.3% vs. 1.7%, p = 0.003). During a mean follow-up of 6 ± 3 years, ApHCM was characterized by lower all-cause, cardiovascular, heart failure-related mortality, and ventricular arrhythmic events compared with non-ApHCM. Multivariate analysis identified atrial fibrillation and HCM risk-sudden cardiac death (SCD) as independent predictors of the composite outcome of overall mortality and hospitalizations for cardiovascular reasons (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.9-9.5 for atrial fibrillation and HR 1.2, 95% CI 1.02-1.3 for HCM risk-SCD) in ApHCM. ConclusionsApHCM exhibited a lower rate of all-cause mortality and arrhythmic events in the middle-aged population of patients with HCM. Atrial fibrillation and HCM risk-sudden cardiac death were independent predictors of a composite of overall mortality and cardiovascular hospitalizations among those with ApHCM.

Cardiomiopatia Hipertrófica: Uma Revisão pelo Olhar da Ressonância Magnética

Hypertrophic cardiomyopathy, the most common genetic cardiopathy in the general population, is characterized by asymmetric left ventricular hypertrophy. However, the phenotypic changes in this cardiomyopathy extend beyond ventricular hypertrophy and include changes in the mitral valve apparatus, papillary muscles, and right ventricle. Due to the difficult differential diagnosis among multiple causes of hypertrophy, cardiac magnetic resonance has played a fundamental role in its diagnostic and prognostic evaluation; magnetic cine-resonance in defining the location and extent of hypertrophy; late enhancement, in the detection of areas of myocardial fibrosis; more recent techniques such as T1 mapping that assesses interstitial fibrosis and extracellular volume; and finally tissue tracking in the analysis of myocardial deformation.

786 SYSTOLIC ANTERIOR MOVEMENT OF MITRAL VALVE: NOT ONLY HYPERTROPHIC CARDIOMYOPATHY, BUT ALSO CARDIAC AMYLOIDOSIS

Abstract A 71 years-old man was diagnosed with lambda light chain multiple myeloma evolving from monoclonal gammopathy of unknown significance during hematological follow-up. Serum creatinine and blood urea were normal, but proteinuria was significant. A subsequent renal biopsy showed amyloid deposits in renal glomeruli. He had no comorbidities or previous cardiologic history. To provide a complete diagnostic work-up, an echocardiogram was performed, showing marked and asymmetric left ventricular hypertrophy (interventricular septum diastolic thickness IVSd 15 mm) with dynamic left ventricular outflow tract obstruction (LVOTO) due to an incomplete systolic anterior motion (SAM) of mitral valve. ECG showed sinus rhythm with 1st degree atrio-ventricular block; notably, there was no electrocardiographic sign of left ventricular hypertrophy. Therefore, a Cardiac Magnetic Resonance (CMR) was performed, showing left ventricular hypertrophy (interventricular septum thickness 15 mm) with normal contractility. Mild left atrial enlargement and thickening of the interatrial septum were found, together with mild circumferential pericardial effusion. No perfusion defects were recorded, but late gadolinium enhancement (LGE) pattern was not assessable because of difficult myocardial signal nulling point. These findings were consistent with cardiac amyloidosis (CA). By the time, histological demonstration of amyloid was mandatory, so an endomyocardial biopsy was performed. Amyloid deposits were found to be in the myocardial interstitial space and into the myocardial vessel walls. Immunohistochemical staining revealed diffuse and high reactivity for lambda free light chains and moderate reactivity for kappa chains. No transthyretin was found in the specimens. Finally, a diagnosis of AL amyloidosis with cardiac and renal involvement associated with lambda light chain multiple myeloma was made and chemotherapy with bortezomib, thalidomide and dexamethasone (VTD) was started. During the cardiologic follow-up, three syncope with prodromal symptoms have occurred. In all these circumstances, no arrhythmias were found at prolonged ECG Holter monitoring. Echocardiogram showed a progression of the dynamic outflow obstruction to 80 mmHg and increasing mitral regurgitation associated with complete systolic anterior motion of the valve. Given the echocardiographic features and the clinical events, we performed a genetic blood test which excluded sarcomeric genes mutations. Also, familial screening with ECG and echocardiogram was negative. A better management of pharmacological therapy, together with avoidance of hypovolemia and supportive treatment of anemia finally relieved patient's symptoms. Conclusions we presented this case to underline that, although rare, cardiac amyloidosis can resemble other hypertrophic cardiomyopathies with left ventricular outflow tract obstruction due to SAM of the mitral valve and irregular septal hypertrophy, caused by amyloid deposits. Most of these cases are seen in the senile transthyretin type, but sometimes they are observed in AL patients. Nowadays, it is crucial to diagnose these patients correctly as early treatment is critical for survival in this population.

313 BRUGADA SYNDROME MIMICRY: THE IMPORTANCE OF AN EXTENDED FOLLOW-UP

Abstract Introduction Brugada Syndrome (BrS) is a genetically inherited condition associated with the risk of fatal arrhythmias and sudden cardiac death (SCD) occurring in a structurally normal heart. This disorder was historically related to mutations in the SCN5A gene, but recent observations suggest a more complex genetic inter-play, highlighting the possible overlap with structural cardiomyopathies, including hypertrophic cardiomyopathy (HCM). Case Presentation In May 2005, an asymptomatic 56-year-old man with a family history of unexplained SCD was referred to our outpatient clinic. A 12-lead ECG showed a type 2 Brugada pattern whilst transthoracic echocardiogram (TTE) was normal. Ventricular fibrillation (VF) was induced during an elective electrophysiological study and a transvenous implantable cardioverter-defibrillator (ICD) was implanted for primary prevention. More than 10 years later, in March 2022, our patient was admitted to the hospital because of palpitations. The ECG revealed a typical atrial flutter with a high ventricular rate, successfully treated with catheter ablation. Post-procedural ECG showed the persistence of type 2 Brugada pattern in association with new-onset T wave inversion in inferolateral leads and signs of ventricular hypertrophy. TTE revealed asymmetric left ventricular hypertrophy, with left ventricular outflow tract (LVOT) obstruction determined by mitral systolic anterior motion and preserved LV systolic function. The patient was treated with optimal medical therapy with symptom improvement and reduction of LVOT obstruction at a 3-month follow-up TTE. Discussion The distinction between Brugada phenocopy and BrS electrocardiogram patterns is not obvious, and according to our experience a Brugada type 2 pattern could be an early ECG marker of a concealed HCM which became manifest over an extended follow-up. Brugada ECG phenocopies are clinical entities characterized by type 1 or type 2 Brugada patterns elicited by an underlying condition, the disappearance of the pattern with the resolution of the condition and the absence of classical symptoms. Several pathogenic variants involving other and different genes have been recently reported suggesting a possible overlap with structural cardiomyopathies. Recently, two other cases of incidental findings of a Brugada ECG pattern in the context of HCM were described. Both patients had a common pathogenetic splicing mutation in the MYBPC3 sarcomeric gene (encoding for the cardiac myosin-binding protein C) responsible for HCM with no genetic mutations associated with Brugada syndrome. This fact suggests that patients are not simultaneously affected by BrS and HCM but a clinically manifest HCM with a specific genetic background can lead to an early BrS electrical manifestation. Conclusion Our experience confirms that a Brugada type 2 ECG pattern could be a very early sign of a concealed HCM manifested over 10 years later. The importance of proper risk stratification and regular follow-up has thus crucial implications in patient clinical management. However, whether Brugada pattern associated with structural heart disease is linked to an increased risk of sudden cardiac death is still unknown and needs further investigations.

Hypertrophic cardiomyopathy and left ventricular non-compaction cardiomyopathy: two in one.

A 22-year-old asymptomatic Caucasian woman was referred because of an elevated NT-pro-BNP level (1225 ng/L, normal <125 ng/L) and a positive family history of unclear cardiomyopathy. Her electrocardiogram showed sinus rhythm, left axis deviation with signs of left ventricular (LV) hypertrophy, and repolarization abnormalities (Panel A). The transthoracic echocardiography revealed an asymmetrical LV hypertrophy without signs of left ventricular outflow tract obstruction at rest or under provocative Valsalva manoeuvre (Supplementary material online, Video S1). Imaging with cardiovascular magnetic resonance (CMR) confirmed asymmetrical LV hypertrophy with a maximum wall thickness of 18 mm. CMR also showed biventricular prominent trabeculation with multiple anterior, septal and inferior deep recesses (Panel B, Supplementary material online, Video S2) and a maximum ratio of non-compacted to compacted myocardium of 2.6 (Supplementary material online, Image). Biventricular volumes and global ejection fraction were normal with a mild hypokinesia of the hypertrophied LV segments. Late Gadolinium Enhancement and post-contrast T1 mapping demonstrated focal patchy fibrosis in the hypertrophied segments and at both right ventricular insertion points (Panel C, D).

Different mechanisms of mitral regurgitation in hypertrophic cardiomyopathy: A clinical case and literature review.

Abnormalities of the mitral valve (MV) apparatus are typical features of hypertrophic cardiomyopathy (HCM). These abnormalities include leaflet elongation, thick leaflets, displacement of papillary muscle, and systolic anterior motion (SAM) of the MV anterior leaflet. Mitral valve chordal rupture associated with HCM is a rare but serious issue capable of change the clinical apparence and the prognosis of the patient. A 57-year-old lady with a history of diabetes, dyslipidemia, and a previous single episode of atrial fibrillation (treated with pharmacological cardioversion), presented to the Emergency Department for worsening dyspnea (New York Heart Association Classification class IV). A trans-thoracic echocardiogram (TTE) showed a significant, septal, and asymmetric left ventricular hypertrophy (basal anteroseptal wall diastolic thickness of 19 mm) with normal left ventricle systolic function. A SAM of AML was evident together with a left ventricular outflow tract gradient of 56 mmHg at rest, rising to 136 mmHg during the Valsalva maneuver. In addition, there was evidence of moderate to severe mitral regurgitation (MR) with an anteriorly directed jet, not very typical of MR related to SAM. A 2D-3D trans-esophageal echocardiogram (2D-3D TEE) revealed a combined MR mechanism based on PML degenerative prolapse with P2-flail from ruptured chordae with related eccentric anteriorly directed regurgitant jet, together with a second regurgitant posteriorly directed jet, related to SAM of AML. The patient underwent MV repair together with septal myectomy, with a good final outcome. Pre-operative echocardiography (both TTE and 2D-3D TEE) is an essential tool in order to detect different MV abnormalities in patients with HCM. These types of patients should never be treated by septal reduction alone. Surgical MV repair or replacement, together with septal myectomy, may be the preferred approach.

Fabry disease and hypertrophic cardiomyopathy: similar albeit different

Abstract Background Fabry disease (FD) is a lysosomal storage disease that affects one or multiple organ systems and can cause left ventricular hypertrophy (LVH). FD can mimic hypertrophic cardiomyopathy (HCM), and clinicians occasionally miss the diagnosis of FD for HCM. The factors associated with FD-HCM misdiagnosis remain unclear. Purpose We sought to determine the prevalence of FD among patients with LVH and uncover the factors associated with FD-HCM misdiagnosis. Methods We searched online databases for all studies that performed a screening for FD in patients with LVH with reporting of a prevalence. We constructed a list of patients with LVH diagnosed with FD and collected their clinical, echocardiographic, and electrocardiographic characteristics and GLA gene mutation. We classified LVH as symmetric or asymmetric and GLA gene mutations as missense or non-missense. We calculated the prevalence of FD among patients with LVH adjusted for the founder effect. We later divided all FD patients into two groups depending on whether they were misdiagnosed for HCM (Group 1) or not misdiagnosed (Group 2). We used the chi-square and Student's t-test, respectively, to compare the quantitative and qualitative variables of Group 1 and Group 2. Results Thirty-one studies (n=11434 patients) met the inclusion criteria. There were 148 patients with LVH diagnosed with FD, and after adjusting for the founder effect, the prevalence of patients with LVH diagnosed with FD (n=117) was 1%. The number of FD patients misdiagnosed (Group 1) and not misdiagnosed (Group 2) for HCM was respectively 109 (73.6%) and 39 (26.4%). Patients in Group 1 were more likely to have an asymmetrical LVH, χ2(1, N=148)=18.6, p&amp;lt;0.001, a missense mutation, χ2(1, N=112)=7.8, p=0.0053 after adjusting for the founder effect, and a normal renal function, χ2(1, N=148)=16.2, p&amp;lt;0.001. The genetic results of five patients were missing. The maximal left ventricular wall thickness (LVWT) of Group 1 (M=19.84, SD=0.95) compared to Group 2 (M=17.58, SD=1.684) was significantly higher, t(109)=2.44, p=0.0165, and data were missing in 37 subjects. We did not find a significant difference in the following factors: age, nonclassic FD, angiokeratoma, acroparesthesia, stroke history, left ventricular outflow tract obstruction, history of syncope, atrioventricular block, history of tachyarrythmias, and history of pacemaker or defibrillator implantation. Conclusion FD is common among patients with LVH with a prevalence of 1%. Asymmetrical LVH and severe LVH are incorrectly thought to be uncommon in FD and tend to mislead clinicians in their diagnostic approach. FD patients with LVH and misdiagnosed HCM are more likely to have a missense mutation. FD patients with LVH and CKD are less likely to be misdiagnosed for HCM, and the most probable cause is that clinicians misdiagnosed some of these patients for CKD-related LVH. To conclude, we must increase awareness among clinicians on the red flags of FD. Funding Acknowledgement Type of funding sources: None.

Echocardiography in the Diagnosis of Cardiomyopathies: Current Status and Future Directions

Cardiomyopathies are a challenging pathology and echocardiography is essential for diagnosis and prognosis. The most frequent cardiomyopathies are the dilated cardiomyopathy (DCM) and the hypertrophic cardiomyopathy (HCM), followed by the less frequent restrictive (RCM) and arrhythmogenic right ventricle cardiomyopathies (ARVC). Echocardiography can identify diagnostic features, and guide further testing for a definitive diagnosis. Echographic parameters are involved in risk score computing and prognosis assessment. While the most prevalent hallmark of HCM is the asymmetric left ventricular hypertrophy and systolic anterior motion of the mitral valve with the obstructive phenotype, DCM shows dilated left ventricle with different degrees of systolic dysfunction, and RCM is usually characterized by undilated ventricles associated with atrial enlargement. The aim of this review is to display and compare the most frequent cardiomyopathies encountered in clinical practice and highlight their most characteristic features in a useful way for the practicing clinician.

Abstract P2011: The Role Of A Novel Alpha-crystallin B Chain Variant In Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disorder affecting 1 in 500 people in the general population. Characterized by asymmetric left ventricular hypertrophy, cardiomyocyte disarray, cardiac fibrosis and increased risk of sudden cardiac death, HCM is in fact a highly complex disease with heterogenous clinical presentation, onset and complication. While mutations in the sarcomere gene can account for a substantial proportion of familial cases of HCM, up to 70% of HCM patients do not carry such sarcomere variants and the causal mutations for their diseases remain elusive. Recently, we identified a novel variant of the alpha-crystallin B chain (CRYAB R123W ) in a pair of monozygotic twins who developed concordant HCM phenotypes that manifested over a nearly identical time course. Yet, how CRYAB R123W promotes HCM phenotype remains unclear. Here, we generated mice carrying the Cryab R123W -knockin allele and demonstrated that hearts from these animals exhibit increased elastance, reduced end diastolic volume and increased E/E’ consistent with increased systolic and reduced diastolic function. Upon transverse aortic constriction, mice carrying the Cryab R123W allele developed pathological left ventricular hypertrophy with substantial cardiac fibrosis and progressively reduced ejection fraction. In contrast to another well-characterized CRYAB variant (R120G) which induced Desmin aggregation, no evidence of protein aggregation was observed in hearts expressing CRYAB R123W despite its potent effect on driving cellular hypertrophy. Unexpectedly, CRYAB R123W appears to enhance calcium signaling by promoting nuclear localization of NFAT through direct interaction with calcineurin. Mice also were more susceptible to ventricular tachycardia with programmed stimulation. Single nuclei RNA-sequencing of mouse hearts is underway and preliminarily reveals reduction in oxidative phosphorylation, consistent with known effects of Cryab on mitochondrial function. Thus, our data establishes the Cryab R123W allele as a novel genetic model of HCM and unveiled additional sarcomere-independent mechanisms of cardiomyocyte hypertrophy.

PO-704-01 CLINICAL COURSE OF PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY AWAY FROM TERTIARY REFERRAL CARE

Hypertrophic cardiomyopathy (HCM) is one of the most common genetic heart diseases characterized by asymmetric left ventricular hypertrophy (LVH). Advances in diagnosis and management have made HCM a manageable disease with reduced morbidity and mortality. The clinical course of HCM mainly derives from studies in tertiary HCM centers. However, these studies are limited due to gaps in follow-up between clinical encounters or loss of follow-up as local physicians resume care.

Electrocardiographic features of patients with hypertrophic cardiomyopathy

Introduction. Hypertrophic cardiomyopathy is a disorder of the myocardium characterized by asymmetric or symmetric left ventricular hypertrophy. It is often an inherited disorder with an autosomal dominant pattern. The aim of this study was to evaluate the electrocardiographic characteristics of patients with hypertrophic cardiomyopathy, as well as to assess the accuracy of current electrocardiographic criteria for left ventricular hypertrophy used as indicators of hypertrophic cardiomyopathy. Material and Methods. This retrospective study was conducted using hospital medical records of 42 patients with the diagnosis of hypertrophic cardiomyopathy. Detailed electrocardiography analysis, apart from all the usual parameters, included the calculation of indices used to diagnose left ventricular hypertrophy including Sokolow augmented vector left, Cornell voltage, Cornell product, and Sokolow-Lyon index. Results. Sinus rhythm was present in 95.2% of patients, while atrial fibrillation was found in 4.8%. The majority of patients presented with left axis deviation. A slight positive correlation was found between the Sokolow augmented vector left index and posterolateral wall thickness (r = 0.475; p &lt; 0.05), and also between the Cornell voltage index and posterolateral wall thickness (r = 0.368; p &lt; 0.05). A borderline positive correlation was found between the Cornell product index and posterolateral wall thickness (r = 0.290; p = 0.063). Interventricular septum thickness showed no significant correlation with any of the electrocardiographic indices of left ventricular hypertrophy. Conclusion. In patients with hypertrophic cardiomyopathy, the Sokolow augmented vector left and Cornell voltage indices were the best indicators of posterolateral wall hypertrophy, whereas none of the examined indices correlated well with the interventricular septum thickness.