Pathological Left Ventricular Hypertrophy Research Articles

Benefits of 4-tiered classification of exercise-induced left ventricular hypertrophy in adolescent athletes

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Innovation and Technology Ministry Hungary - National Research, Development and Innovation Office (Innovációs és Technológiai Minisztérium - Nemzeti Kutatási, Fejlesztési és Innovációs Hivatal Hungary. Introduction Exercise-induced left ventricular hypertrophy (LVH) is widely investigated in adolescent athletes characterized by 2-tiered classification (2TC). Though, the differentiation of normal adaptive changes from pathological LVH can be challenging. 4-tiered classification (4TC) may discriminate better different forms of exercise-induced LVH providing three-dimensional information of the left ventricle (LV). Purpose, methods The main objective of our study was to distinguish alterations between 2TC and 4TC examining 121 adolescent athletes with echocardiography. Moreover, these results were also compared to the matched LV parameters of 114 adult athletes. Results Examining the 4TC allocation representing parameters (LV mass, LV mass/BSA, LV end-diastolic volume/BSA, concentricity) of the adolescent and adult athletes we identified significant differences (p< 0,05) between the different LVH groups and normal geometry, suggesting that the applied classification provides proper group distinguishing power. There were no significant differences between the cumulative training times of the different LVH groups (p >0,05). Furthermore, the BSA corrected LV parameters did not show any correlation with training time. Totally 25 athletes (22%) were reclassified in 4TC into completely different groups, highlighted the 6 athletes (5%) reclassified from normal geometry to concentric LVH and the 11 adolescent (9%) reclassified from normal to eccentric LVH. The reclassifications rate showed similar pattern in adult athletes. Conclusion Based on all these data we assume that training time has no significant impact on the classification. Cardiac remodeling develops already in young age, and further training time has less impact on the adaptive changes. We prefer to apply 4TC in the routine echocardiographic examination of endurance athletes to specify a more sensitive and distinct screening method.

Diagnosing Hypertrophic Cardiomyopathy in Athletes

Sudden cardiac death (SCD) in a young asymptomatic individual is a devastating, unpredictable event, with a widespread impact on the public health system. Hypertrophic cardiomyopathy (HCM) is the most common form of genetic heart disease, and considered one of the leading causes of SCD affecting young and frequently asymptomatic patients. A diagnosis of HCM is challenging particularly in young athletes due to overlapping clinical phenotypesbetween pathological left ventricular hypertrophy (LVH) and exercise-induced physiological LVH. Severalinvestigational tools have been used to differentiate these two distinct entities. This review article focuses upon the diagnosis of HCM in young athletes, SCD risk assessment, and current recommendations for exercise in athletic individuals with HCM.

Utility of advanced echocardiographic deformation measures to delineate cause of pathological left ventricular hypertrophy: value of a multiparametric approach

Abstract Background Early diagnosis of cardiac amyloidosis (CA) is warranted to initiate specific treatment and improve outcomes. Conventional echocardiography is unable to reliably differentiate CA from other causes of increased left ventricular (LV) wall thickness. Purpose To demonstrate the value of a multiparametric approach utilising both standard and advanced echocardiographic measures to distinguish CA from other pathological causes of increased LV wall thickness. Results Patients with HCM had the highest septal thickness, maximum LV wall thickness, septum/posterior wall (Sep/PW) thickness ratio and left ventricular outflow tract (LVOT) gradient and lowest PW thickness (p<0.0001) among all groups. Patients with CA had the lowest global longitudinal strain (GLS), tissue Doppler-derived myocardial systolic and diastolic velocities and LV ejection fraction (EF) (p<0.0001). EF strain ratio (EFSR=LVEF/GLS) and LV longitudinal strain (apex/base) ratio were highest (largest number) in CA patients (p<0.0001). Multivariate linear regression identified 5 independent predictors (PW thickness, Sep/PW thickness ratio, LVOT gradient, LV longitudinal strain (apex/base) ratio and GLS) that discriminated CA from other causes of increased LV wall thickness. A regression equation (using multivariate linear regression) {CA prediction value = (0.230*LS apex/base) − (0.002*LVOT gradient) − [0.068*(Sep/PW ratio)] + (0.007*PW thickness) + (0.022*GLS) + 0.189; r=0.667)} was derived which allowed reliable distinction of CA with a sensitivity of 92.3% and specificity of 91.2% at the optimal cut-off. Conclusion PW thickness, Sep/PW thickness ratio, LVOT gradient, LV longitudinal strain (apex/base) ratio and GLS are independent predictors of CA. We developed a multiparametric regression equation which allowed discrimination of CA from other causes of increased LV wall thickness. Future studies involving larger cohorts are required to validate these findings. Funding Acknowledgement Type of funding sources: None.

Alterations of Lipid Metabolism in the Heart in Spontaneously Hypertensive Rats Precedes Left Ventricular Hypertrophy and Cardiac Dysfunction.

Disturbances in cardiac lipid metabolism are associated with the development of cardiac hypertrophy and heart failure. Spontaneously hypertensive rats (SHRs), a genetic model of primary hypertension and pathological left ventricular (LV) hypertrophy, have high levels of diacylglycerols in cardiomyocytes early in development. However, the exact effect of lipids and pathways that are involved in their metabolism on the development of cardiac dysfunction in SHRs is unknown. Therefore, we used SHRs and Wistar Kyoto (WKY) rats at 6 and 18 weeks of age to analyze the impact of perturbations of processes that are involved in lipid synthesis and degradation in the development of LV hypertrophy in SHRs with age. Triglyceride levels were higher, whereas free fatty acid (FA) content was lower in the LV in SHRs compared with WKY rats. The expression of de novo FA synthesis proteins was lower in cardiomyocytes in SHRs compared with corresponding WKY controls. The higher expression of genes that are involved in TG synthesis in 6-week-old SHRs may explain the higher TG content in these rats. Adenosine monophosphate-activated protein kinase phosphorylation and peroxisome proliferator-activated receptor α protein content were lower in cardiomyocytes in 18-week-old SHRs, suggesting a lower rate of β-oxidation. The decreased protein content of α/β-hydrolase domain-containing 5, adipose triglyceride lipase (ATGL) activator, and increased content of G0/G1 switch protein 2, ATGL inhibitor, indicating a lower rate of lipolysis in the heart in SHRs. In conclusion, the present study showed that the development of LV hypertrophy and myocardial dysfunction in SHRs is associated with triglyceride accumulation, attributable to a lower rate of lipolysis and β-oxidation in cardiomyocytes.

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.

Global longitudinal strain differentiates physiological hypertrophy from maladaptive remodeling.

AimsDifferentiation of left ventricular (LV) hypertrophy in healthy athletes from pathological LV hypertrophy in heart disease is often difficult. We explored whether extended echocardiographic measurements such as E/e’ and global longitudinal strain (GLS) distinguish physiologic from maladaptive hypertrophy in hypertrophic cardiomyopathy, excessively trained athletes’ hearts and normal hearts.MethodsSeventy-eight professional athletes (cyclists n = 37, soccer players n = 29, handball players n = 21) were compared with patients (n = 88) with pathological LV hypertrophy (hypertrophic obstructive cardiomyopathy (HOCM, n = 17), hypertensive heart disease (HHD, n = 36), severe aortic valve stenosis (AVS, n = 35) and with sedentary healthy individuals as controls (n = 37).ResultsLV ejection fraction (LVEF) was ≥50% in all patients, athletes (median age 26 years, all male) and the controls (97% male, median age 32 years). LV mass index (LVMI) and septal wall thickness was in normal range in controls, but elevated in cyclists and patients with pathological hypertrophy (p < 0.001 for both). E/e’ was elevated in all patients with maladaptive hypertrophy but normal in controls and athletes (p < 0.001 vs. pathological hypertrophy). Furthermore GLS was reduced in patients with pathological hypertrophy compared with athletes and controls (for both p < 0.001). In subjects with septal wall thickness >11 mm, GLS (≥−18%) has a specificity of 79% to distinguish between physiological and pathological hypertrophy.ConclusionGLS and E/e’ are reliable parameters unlike left ventricular mass or LV ejection fraction to distinguish pathological and physiological hypertrophy.

Piezo1 and TRPM4 work in tandem to initiate cardiac hypertrophic signalling in response to pressure overload

Pathological left ventricular hypertrophy (LVH) occurs in response to an increased cardiac workload or injury and remains the single most important clinical predictor of cardiac mortality. Two very common clinical conditions, essential hypertension, and aortic valve stenosis leading to LVH are currently treated by medications that lower blood pressure or replacement of the stenotic aortic valve, respectively. Nonetheless, they do not completely reverse the pathological effects on the myocardium once LVH is established.

C19. Cardiac Amyloidosis: A Great Pretender of Left Ventricular Hypertrophy with Systemic Manifestation

Abstract Background Systemic amyloidosis encompasses an underdiagnosed disorder characterized by the extracellular deposition of amyloid in one or more organs, including the heart. The therapeutic strategy depends on the characterization of amyloid protein type and the extent of the disease. When founding a pathological left ventricular hypertrophy, initial clues provided by electrocardiography and echocardiography combined with other clinical manifestations could support a suspicion of cardiac amyloidosis. Case Summary A 54-year-old male patient was repeatedly admitted to a local hospital for recurrent heart failure and refractory bilateral pleural effusions of unknown cause. There was intolerance of any heart failure medications and repeated thoracocentesis failed to control the pleural effusion. The echocardiogram revealed severely impaired left ventricular function with phenotypic overlap between hypertrophic and restrictive cardiomyopathy. In contrast, we found a low voltage electrocardiogram. After an extensive diagnostic workup, including speckle tracking echocardiography, cardiac magnetic resonance, serum immunofixation and free light chain, bone marrow biopsy, and also Congo Red staining for amyloid, the final diagnosis was light chain (AL) amyloidosis. Discussion Cardiac involvement in systemic amyloidosis is the leading cause of morbidity and mortality. Frequently, myocardial wall thickening is incorrectly referred to as hypertrophy which may potentially lead to the wrong diagnosis and therapy. However, a need remains for improved awareness and expertise, while a multidisciplinary approach is important in making the correct diagnosis and management of this debilitating disease.

C19. Cardiac Amyloidosis: A Great Pretender of Left Ventricular Hypertrophy with Systemic Manifestation

Abstract Background Systemic amyloidosis encompasses an underdiagnosed disorder characterized by the extracellular deposition of amyloid in one or more organs, including the heart. The therapeutic strategy depends on the characterization of amyloid protein type and the extent of the disease. When founding a pathological left ventricular hypertrophy, initial clues provided by electrocardiography and echocardiography combined with other clinical manifestations could support a suspicion of cardiac amyloidosis. Case Summary A 54-year-old male patient was repeatedly admitted to a local hospital for recurrent heart failure and refractory bilateral pleural effusions of unknown cause. There was intolerance of any heart failure medications and repeated thoracocentesis failed to control the pleural effusion. The echocardiogram revealed severely impaired left ventricular function with phenotypic overlap between hypertrophic and restrictive cardiomyopathy. In contrast, we found a low voltage electrocardiogram. After an extensive diagnostic workup, including speckle tracking echocardiography, cardiac magnetic resonance, serum immunofixation and free light chain, bone marrow biopsy, and also Congo Red staining for amyloid, the final diagnosis was light chain (AL) amyloidosis. Discussion Cardiac involvement in systemic amyloidosis is the leading cause of morbidity and mortality. Frequently, myocardial wall thickening is incorrectly referred to as hypertrophy which may potentially lead to the wrong diagnosis and therapy. However, a need remains for improved awareness and expertise, while a multidisciplinary approach is important in making the correct diagnosis and management of this debilitating disease.

Replication Stress Response Modifies Sarcomeric Cardiomyopathy Remodeling.

BackgroundSarcomere gene mutations lead to cardiomyocyte hypertrophy and pathological myocardial remodeling. However, there is considerable phenotypic heterogeneity at both the cellular and the organ level, suggesting modifiers regulate the effects of these mutations. We hypothesized that sarcomere dysfunction leads to cardiomyocyte genotoxic stress, and this modifies pathological ventricular remodeling.Methods and ResultsUsing a murine model deficient in the sarcomere protein, Mybpc3−/− (cardiac myosin‐binding protein 3), we discovered that there was a surge in cardiomyocyte nuclear DNA damage during the earliest stages of cardiomyopathy. This was accompanied by a selective increase in ataxia telangiectasia and rad3‐related phosphorylation and increased p53 protein accumulation. The cause of the DNA damage and DNA damage pathway activation was dysregulated cardiomyocyte DNA synthesis, leading to replication stress. We discovered that selective inhibition of ataxia telangiectasia and rad3 related or cardiomyocyte deletion of p53 reduced pathological left ventricular remodeling and cardiomyocyte hypertrophy in Mybpc3−/− animals. Mice and humans harboring other types of sarcomere gene mutations also had evidence of activation of the replication stress response, and this was associated with cardiomyocyte aneuploidy in all models studied.ConclusionsCollectively, our results show that sarcomere mutations lead to activation of the cardiomyocyte replication stress response, which modifies pathological myocardial remodeling in sarcomeric cardiomyopathy.

The Ca2+-activated cation channel TRPM4 is a positive regulator of pressure overload-induced cardiac hypertrophy.

Pathological left ventricular hypertrophy (LVH) occurs in response to pressure overload and remains the single most important clinical predictor of cardiac mortality. The molecular pathways in the induction of pressure overload LVH are potential targets for therapeutic intervention. Current treatments aim to remove the pressure overload stimulus for LVH, but do not completely reverse adverse cardiac remodelling. Although numerous molecular signalling steps in the induction of LVH have been identified, the initial step by which mechanical stretch associated with cardiac pressure overload is converted into a chemical signal that initiates hypertrophic signalling remains unresolved. In this study, we show that selective deletion of transient receptor potential melastatin 4 (TRPM4) channels in mouse cardiomyocytes results in an approximately 50% reduction in the LVH induced by transverse aortic constriction. Our results suggest that TRPM4 channel is an important component of the mechanosensory signalling pathway that induces LVH in response to pressure overload and represents a potential novel therapeutic target for the prevention of pathological LVH.

Maxacalcitol (22-Oxacalcitriol (OCT)) Retards Progression of Left Ventricular Hypertrophy with Renal Dysfunction Through Inhibition of Calcineurin-NFAT Activity

Left ventricular hypertrophy (LVH) is a cardiovascular complication highly prevalent in patients with chronic kidney disease (CKD). Previous studies analyzing 1α-hydroxylase or vitamin D receptor (Vdr) knockout mice revealed active vitamin D as a promising agent inhibiting LVH progression. Paricalcitol, an active vitamin D analog, failed to suppress the progression of LV mass index (LVMI) in pre-dialysis patients with CKD. As target genes of activated VDR differ depending on its agonists, we examined the effects of maxacalcitol (22-oxacalcitriol: OCT), a less calcemic active vitamin D analog, on LVH in hemodialysis patients and animal LVH models with renal insufficiency. In retrospective cohort study, patients treated with OCT who underwent hemodialysis were enrolled. Using cardiac echocardiography, LV mass was evaluated by the area-length method. In animal study, angiotensin II (Ang II)-infused Wister rats with heminephrectomy or Ang II-stimulated neonatal rat ventricular myocytes (NRVM) were treated with OCT. OCT significantly inhibited the progression of LVMI in hemodialysis patients. In Ang II-infused heminephrectomized rats, OCT suppressed the progression of LVH in a blood pressure-independent manner. OCT also suppressed the activity of calcineurin in the left ventricle of model rats. Specifically, OCT reduced the protein levels of calcineurin A, but not the mRNA levels of Ppp3ca (calcineurin Aα). Luciferase assays showed that OCT increased the promoter activity of Fbxo32 (atrogin1), an E3 ubiquitin ligase targeting calcineurin A. Finally, OCT promoted ubiquitination and degradation of calcineurin A. Our works indicated that OCT retards progression of LVH through calcineurin-NFAT pathway, which reveal a novel aspect of OCT in attenuating pathological LVH.

Electrocardiographic differences between Anderson-Fabry and sarcomeric hypertrophic cardiomyopathy and correlation with cardiac magnetic resonance

Abstract Background Differential diagnosis between Anderson-Fabry (AF) and sarcomeric hypertrophic cardiomyopathy (HCM) is often very challenging particularly in AF patients with late onset cardiac involvement. Purpose To gain new insights from standard electrocardiogram (ECG) in AF disease for differential diagnosis from sarcomeric HCM. Additionally, to better understand ECG features in AF patients, a correlation substudy ECG-cardiac magnetic resonance (CMR) has been performed. Methods From 162 patients with definite diagnosis of AF disease, 111 [65 males, median age 57 (51–67) years] with pathologic left ventricular hypertrophy (LVH) (Group A) were compared with 111 sarcomeric HCM patients (Group B) sex, age and maximal wall thickness matched by 1:1 propensity score. Results AF patients showed shorter PR interval [155 (140–180) vs 163 (149–184) msec; p=0.005) and wider QRS interval [110 (100–134) vs 100 (90–106) msec; p&amp;lt;0.0001). Additionally AF patients had a higher prevalence of complete (22% vs 3%; p&amp;lt;0.0001) and incomplete (13% vs 1%; p&amp;lt;0.0001) right bundle branch block (RBBB) and a higher percentage of ST segment depression (12% vs 1%; p=0.001) and inferior negative T waves (34% vs 19%; p=0.01). No differences in terms of Sokolow-Lyon and Cornell scores were found whereas total QRS score was higher in Group A [20 (16–27) vs 18 [14–22] mV; p=0.0004). Low QRS voltages and inferior Q waves were not present in AF patients. Among the 69 AF patients who underwent MRI, the 44 with late gadolinium enhancement (LGE) were older [59 (52–66) vs 53 (40–59) years; p=0.017] and had more frequently negative T waves on ECG, particularly in the inferior leads (64% vs 8%; p&amp;lt;0.0001), compared to the 25 without LGE. At multivariate analysis, age and negative T waves were independently associated to the presence of LGE on CMR. Conclusions Compared to matched sarcomeric HCM, AF patients had a shorter PR, wider QRS and a higher percentage of RBBB in relation to to the different aetiology (storage vs “pure” hypertrophy). The higher total QRS score and the absence of inferior Q waves could reflect the more frequent concentric distribution of LVH. Additionally negative T waves, especially in inferior leads, are related to the presence of LGE on CMR (often in the postero-lateral wall). Funding Acknowledgement Type of funding source: None

Differentiation between physiological sport adaptation and hypertrophic cardiomyopathy in highly trained athletes using cardiac magnetic resonance

Abstract Differentiation between hypertrophic cardiomyopathy (HCM) patients and healthy athletes (HA) is a common clinical conundrum. We aimed to analyze cardiac magnetic resonance (CMR) characteristics of HA, sedentary HCM and athletic HCM patients and to determine CMR parameters which can help to diagnose HCM in athletes. Male sedentary HCM patients with slightly elevated maximal end-diastolic wall thickness (EDWT 13–18 mm, n=40, 47.6±14.7y) and HA (n=30, 27.5±5.6y) were consecutively enrolled. Additionally, athletes with HCM were enrolled (n=16, 29.6±13.4 y), where a comprehensive investigation confirmed the diagnosis of HCM. We determined conventional CMR parameters (left ventricular (LV) ejection fraction (EF), end-diastolic (EDVi) and end-systolic volume index, mass index (Mi)), derived parameters such as EDWT/LVEDVi, LVM/LVEDV ratio and strain parameters such as global longitudinal (GLS), radial (GRS) and circumferential strain (GCS), SD of peak LS and CS using feature tracking. Presence of late gadolinium enhancement (LGE) was also determined. CMR parameters representing LV hypertrophy pattern or LV function were analyzed using a logistic regression to detect the best CMR parameters to predict HCM in athletes. To differentiate between HA and athletes with HCM optimal cut-off values for CMR parameters were calculated using receiver operating curve analysis. Comparing the three groups significant differences were found regarding conventional and derived CMR parameters and strain values. None of the HA showed LGE, 75% of athletic HCM and 82% of sedentary HCM patients showed LGE. The univariate regression model showed that LVEF, EDWT, EDWT/LVMi, LVM/LVEDV, GCS, GRS, SD of peak LS and CS are determinants of the diagnosis of HCM among athletes. Multivariate regression revealed that EDWT/LVMi and GCS are independent disease predictors in athletes (p&amp;lt;0.05). Cut-off value for GCS ≤−32.5 and for EDWT/LVEDVi &amp;gt;0.126 discriminate athletic HCM from HA with a sensitivity of 81.3 and 87.5% (AUC 0.93), and a specificity of 96.7 and 83.3% (AUC 0.95), respectively (Figure 1). CMR characteristics of sedentary and athletic HCM may differ, therefore establishing diagnostic parameters based on comparison between athletic HCM and HA is essential. CMR based strain and derived parameters may help to differentiate between physiological and pathological left ventricular hypertrophy in athletes. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Office of Hungary (NKFIA) and National Research, Development and Innovation Office (NFKIH) of Hungary.

Cardiac magnetic resonance T2 mapping and feature tracking in athlete\u2019s heart and HCM

ObjectivesDistinguishing hypertrophic cardiomyopathy (HCM) from left ventricular hypertrophy (LVH) due to systematic training (athlete’s heart, AH) from morphologic assessment remains challenging. The purpose of this study was to examine the role of T2 mapping and deformation imaging obtained by cardiovascular magnetic resonance (CMR) to discriminate AH from HCM with (HOCM) or without outflow tract obstruction (HNCM).MethodsThirty-three patients with HOCM, 9 with HNCM, 13 strength-trained athletes as well as individual age- and gender-matched controls received CMR. For T2 mapping, GRASE-derived multi-echo images were obtained and analyzed using dedicated software. Besides T2 mapping analyses, left ventricular (LV) dimensional and functional parameters were obtained including LV mass per body surface area (LVMi), interventricular septum thickness (IVS), and global longitudinal strain (GLS).ResultsWhile LVMi was not significantly different, IVS was thickened in HOCM patients compared to athlete’s. Absolute values of GLS were significantly increased in patients with HOCM/HNCM compared to AH. Median T2 values were elevated compared to controls except in athlete’s heart. ROC analysis revealed T2 values (AUC 0.78) and GLS (AUC 0.91) as good parameters to discriminate AH from overall HNCM/HOCM.ConclusionDiscrimination of pathologic from non-pathologic LVH has implications for risk assessment of competitive sports in athletes. Multiparametric CMR with parametric T2 mapping and deformation imaging may add information to distinguish AH from LVH due to HCM.Key Points• Structural analyses using T2 mapping cardiovascular magnetic resonance imaging (CMR) may help to further distinguish myocardial diseases.• To differentiate pathologic from non-pathologic left ventricular hypertrophy, CMR including T2 mapping was obtained in patients with hypertrophic obstructive/non-obstructive cardiomyopathy (HOCM/HNCM) as well as in strength-trained athletes.• Elevated median T2 values in HOCM/HNCM compared with athlete’s may add information to distinguish athlete’s heart from pathologic left ventricular hypertrophy.

Pathological left ventricular hypertrophy and outflow tract obstruction in an infant of a diabetic mother: A case report

<strong>Background:</strong> Infants of diabetic mothers (IDMs) are at increased risk of developing congenital anomalies including cardiac defects. Pathological left ventricular hypertrophy, asymmetrical septal hypertrophy and outflow tract obstruction is a rare but known cardiac comorbidity in infants of diabetic mothers. The severity of this condition in IDMs can vary from an incidental finding on echocardiography to an infant with severe symptoms of congestive heart failure and specific management of the condition varies.

Downregulation of miR-26b-5p, miR-204-5p, and miR-497-3p Expression Facilitates Exercise-Induced Physiological Cardiac Hypertrophy by Augmenting Autophagy in Rats.

Exercise-induced autophagy is associated with physiological left ventricular hypertrophy (LVH), and a growing body of evidence suggests that microRNAs (miRNAs) can regulate autophagy-related genes. However, the precise role of miRNAs in exercise induced autophagy in physiological LVH has not been fully defined. In this study, we investigated the microRNA–autophagy axis in physiological LVH and deciphered the underlying mechanism using a rat swimming exercise model. Rats were assigned to sedentary control (CON) and swimming exercise (EX) groups; those in the latter group completed a 10-week swimming exercise without any load. For in vitro studies, H9C2 cardiomyocyte cell line was stimulated with IGF-1 for hypertrophy. We found a significant increase in autophagy activity in the hearts of rats with exercise-induced physiological hypertrophy, and miRNAs showed a high score in the pathway enriched in autophagy. Moreover, the expression levels of miR-26b-5p, miR-204-5p, and miR-497-3p showed an obvious increase in rat hearts. Adenovirus-mediated overexpression of miR-26b-5p, miR-204-5p, and miR-497-3p markedly attenuated IGF-1-induced hypertrophy in H9C2 cells by suppressing autophagy. Furthermore, miR-26b-5p, miR-204-5p, and miR-497-3p attenuated autophagy in H9C2 cells through targeting ULK1, LC3B, and Beclin 1, respectively. Taken together, our results demonstrate that swimming exercise induced physiological LVH, at least in part, by modulating the microRNA–autophagy axis, and that miR-26b-5p, miR-204-5p, and miR-497-3p may help distinguish physiological and pathological LVH.

An Electrocardiographic System With Anthropometrics via Machine Learning to Screen Left Ventricular Hypertrophy among Young Adults.

The prevalence of physiological and pathological left ventricular hypertrophy (LVH) among young adults is about 5%. A use of electrocardiographic (ECG) voltage criteria and machine learning for the ECG parameters to identify the presence of LVH is estimated only 20-30% in the general population. The aim of this study is to develop an ECG system with anthropometric data using machine learning to increase the accuracy and sensitivity for a screen of LVH. In a large sample of 2,196 males, aged 17–45 years, the support vector machine (SVM) classifier is used as the machine learning method for 31 characteristics including age, body height and body weight in addition to 28 ECG parameters such as axes, intervals and voltages to link the output of LVH. The diagnosis of LVH is based on the echocardiographic criteria for young males to be 116 gram/meter2 (left ventricular mass (LVM)/body surface area) or 49 gram/meter2.7 (LVM/body height2.7). On the purpose of increasing sensitivity, the specificity is adjusted around 70-75% and all data tested in proposed model reveal high sensitivity to 86.7%. The area under curve (AUC) of the Precision-Recall (PR) curve is 0.308 in the proposed model which is better than 0.109 and 0.077 using Cornell and Sokolow-Lyon voltage criteria for LVH, respectively. Our system provides a novel screening tool using age, body height, body weight and ECG data to identify most of the LVH among young adults. It provides a fast, accurate and practical diagnosis tool to identify LVH.

P1607Epigenetic modifications via histone acetylation by p300 are changed during the transition from cardiac hypertrophy to heart failure

Abstract Background An intrinsic histone acetyltransferase (HAT), p300, is required for acetylation and the transcriptional activity of GATA4, as well as pathological left ventricular hypertrophy (LVH) and the development of heart failure (HF) in vivo. Recently, studies of histone modification have been performed within the flexible tails, such as H3K9 and H3K14. Although most previously studied histone modifications are within the flexible tails of histones, H3K122 is reportedly a novel site of the histone globular domain acetylated by p300, and its acetylation activates gene transcriptions by destabilizing histone-DNA binding and increasing the accessibility of transactional factors to DNA. However, little is known about the extent histone modifications directly affect LVH and HF. Hypothesis We hypothesized that p300 could induce epigenetic changes by acetylation of the globular domain as well as tail domain of histone during the development of LVH and HF. Methods First, to investigate whether the acetylation of H3K122 in the globular domain of histones as well as those of H3K9 and H3K14 in the tail domain of histones increased in cardiomyocytes hypertrophy, western blotting and chromatin-immunoprecipitation (ChIP) assays were performed using neonatal rat cultured cardiomyocytes with phenylephrine (PE) stimulus. Second, neonatal rat cultured cardiomyocytes were treated with p300 knockdown by siRNA or curcumin, a p300-specific HAT inhibitor. Third, to investigate the role of p300 HAT activity in histone acetylation in vivo, we utilized mice overexpressing p300 in the heart, which induced LVH. Final, to investigate whether these acetylation changes during the development of LVH and HF, in vivo ChIP assay was performed using hypertensive heart disease model of Dahl salt-sensitive rats. Results Western blotting indicated that treatment with PE increased the acetylation of H3K122 as well as those of H3K9 and H3K14 in cardiomyocytes hypertrophy. ChIP assay demonstrated that PE increased the recruitment of acetylated H3K122 and H3K9 onto ANF and BNP promoters containing the GATA element and peaks of acetylation of these domains were 4 hours after PE stimulation. Next, these acetylations were significantly inhibited by p300 knockdown by siRNA or treatment with curcumin. Conversely, in vivo ChIP assays in mice overexpressing p300 indicated that p300 overexpression increased recruitment of acetylated H3K122 and H3K9 onto ANF and BNP promoters containing the GATA element. Next, in hypertensive heart disease model of Dahl salt-sensitive rats, in vivo ChIP assays reviled that acetylation of H3K9 was increased around ANF and BNP promoters containing the GATA element at the LVH stage but that of H3K122 was increased at the HF stage. Conclusion Our data indicate that acetylation of H3K122 in globular domain of histones by p300 is the key event of the transition from LVH to HF.

Selective Heart Irradiation Induces Cardiac Overexpression of the Pro-hypertrophic miR-212.

Background: A deleterious, late-onset side effect of thoracic radiotherapy is the development of radiation-induced heart disease (RIHD). It covers a spectrum of cardiac pathology including also heart failure with preserved ejection fraction (HFpEF) characterized by left ventricular hypertrophy (LVH) and diastolic dysfunction. MicroRNA-212 (miR-212) is a crucial regulator of pathologic LVH via FOXO3-mediated pathways in pressure-overload-induced heart failure. We aimed to investigate whether miR-212 and its selected hypertrophy-associated targets play a role in the development of RIHD.Methods: RIHD was induced by selective heart irradiation (50 Gy) in a clinically relevant rat model. One, three, and nineteen weeks after selective heart irradiation, transthoracic echocardiography was performed to monitor cardiac morphology and function. Cardiomyocyte hypertrophy and fibrosis were assessed by histology at week 19. qRT-PCR was performed to measure the gene expression changes of miR-212 and forkhead box O3 (FOXO3) in all follow-up time points. The cardiac transcript level of other selected hypertrophy-associated targets of miR-212 including extracellular signal-regulated kinase 2 (ERK2), myocyte enhancer factor 2a (MEF2a), AMP-activated protein kinase, (AMPK), heat shock protein 40 (HSP40), sirtuin 1, (SIRT1), calcineurin A-alpha and phosphatase and tensin homolog (PTEN) were also measured at week 19. Cardiac expression of FOXO3 and phospho-FOXO3 were investigated at the protein level by Western blot at week 19.Results: In RIHD, diastolic dysfunction was present at every time point. Septal hypertrophy developed at week 3 and a marked LVH with interstitial fibrosis developed at week 19 in the irradiated hearts. In RIHD, cardiac miR-212 was overexpressed at week 3 and 19, and FOXO3 was repressed at the mRNA level only at week 19. In contrast, the total FOXO3 protein level failed to decrease in response to heart irradiation at week 19. Other selected hypertrophy-associated target genes failed to change at the mRNA level in RIHD at week 19.Conclusions: LVH in RIHD was associated with cardiac overexpression of miR-212. However, miR-212 seems to play a role in the development of LVH via FOXO3-independent mechanisms in RIHD. As a central regulator of pathologic remodeling, miR-212 might become a novel target for RIHD-induced LVH and heart failure.