HCM Patients Research Articles

P1245In a prospective randomized study in familial hypertrophic cardiomyopathy, metoprolol maintains exercise-performance, with lower myocardial oxygen-cost, and prevents deterioration in exercise-ability

Abstract Background Hypertrophic cardiomyopathy (HCM) is an inherited disorder with a prevalence of 0.2% in young adults, with a significant risk of sudden death. Another feature of the disease is progressive fibrosis causing late heart failure. International guidelines suggest beta-blocker therapy for symptomatic patients, but that symptom-free patients need not be treated. Cohort studies on pediatric HCM-patients have suggested that beta-blocker therapy has a dose-related protective effect on the risk for sudden death, suggesting prophylactic beta-blocker therapy might benefit symptom-free patients. Purpose As prophylactic beta-blocker therapy is presumed to have a negative effect on exercise-ability, we assessed the effect of selective beta-blocker therapy on exercise hemodynamics and exercise performance in asymptomatic HCM patients. Methods Previously un-diagnosed cases of HCM were identified by family screening; those without symptoms and risk-factors were randomized to either life-style advice only (Obs-group; n=15), or to advice plus metoprolol therapy (Bbl-group; n=12). Patients performed bicycle ergometer testing before randomization, and yearly during follow-up. Performance in Watt was related to predicted normal for age, body size and sex; heart rate and blood pressure was recorded every minute during exercise terminated by patient tolerance. Results Median age was 18 [IQR 14–26]yrs, with a median follow-up of 6.0 [2.0–8.0]yrs. In the Obs-group the exercise-ability had deteriorated after two years (median 80% predicted vs. initial 88%, p=0.021), and remained lower at last follow-up, 78% (p=0.0017). Patients in the Bbl-group received a median final dose of 325mg metoprolol/day, corresponding to 3.8 [3.5–4.3]mg/kg, and had a reduction in maximal heart rate, 134 vs. 182 bpm (p=0.ehz748.02033], and systolic blood pressure 164 vs. 182 mmHg (p=0.0077), at maximal work load compared to Obs-group. In spite of reduction in maximal heart rate there was no reduction in maximal work capacity in Bbl-group (p=0.33 two year, p=0.50 last follow-up), with within patient change 2% of predicted [−3 to +5]% vs. −6% [−14 to −3]% in Obs-group (p=0.0039). Last visit work capacity was 180 [170–190]Watt in Obs-group and 205 [185–210]Watt in Bbl-group (p=0.015). Rate-pressure product (RPP) was 29% lower, and Watt/RPP was improved by 42% in Bbl-group compared to Obs-group (0.0084 vs. 0.0059; p=0.ehz748.02032). Conclusions Untreated patients with asymptomatic HCM show a slow deterioration in exercise-ability over follow-up, whereas patients treated with metoprolol do not decrease exercise performance compared with pre-treatment values, and do not deteriorate on medium-term follow-up. As myocardial oxygen consumption is linearly related to RPP, Bbl-group achieves a good exercise performance with substantially lower myocardial oxygen consumption than the Obs-group, which may have relevance for subendocardial ischaemia on exercise and future development of myocardial fibrosis. Acknowledgement/Funding Swedish Heart-Lung Fundation grant nr 20080510, Gothenburg University ALF grant nr ALFgbg-544981

P1244Survival after septal myectomy in male and female patients with hypertrophic obstructive cardiomyopathy

Abstract In recent years, studies have debated the impact of gender on the presentation and clinical course of HCM, with research showing that at time of myectomy, women are older, have worse diastolic function and more advanced cardiac remodeling. The clinical impact of these differences is unknown. We included 221 HCM patients (57% men) who underwent septal myectomy and are followed in our center. Time to treatment was calculated in relation to symptom onset. Pre- and post-operative clinical and echocardiographic data were collected. Gender differences were assessed at baseline and in survival analyses for the composite endpoint of all-cause mortality, cardiac transplantation, re-intervention and aborted sudden cardiac death. Women were older at time of myectomy, but time until treatment was similar (table). Pre-operative echocardiographic indices were comparable among groups, but were significantly higher in women when correcting for body surface area. At three months, no differences were found in clinical and echocardiographic results. After 6.1 [2.9–10.1] years, 24% of women and 23% of men had reached the composite endpoint (p=0.30, figure). Gender comparison pre- and post-myectomy Men (n=125) Women (n=96) p value Age 49±14 54±17 0.02 Maximal wall thickness, mm 19.9±4.7 19.8±5.8 0.97 Indexed maximal wall thickness, mm/m2 9.8±2.5 11.5±4.5 0.001 Left atrial diameter, mm 48.1±7.3 45.9±7.3 0.06 Indexed left atrial diameter, mm/m2 23.5±3.5 26.5±7.5 0.002 LV end-diastolic diameter, mm 45.4±7.6 42.8±5.6 0.04 Indexed LV end-diastolic diameter, mm/m2 22.1±3.7 23.6±3.0 0.02 Gradient reduction, %* 75.1±25.0 72.9±28.6 0.63 Improvement in symptoms*† 97 (95%) 64 (89%) 0.34 MWT = maximal wall thickness; LV = left ventricle. *At three months follow-up; †Defined as a reduction of ≥1 NYHA class, measured in 102 men and 72 women. Survival after myectomy Although women present later in life and seem to have more advanced disease at time of myectomy, time to treatment is similar and survival after myectomy is excellent for both men and women.

3151The prognostic meaning of a reduced reserve of left ventricular force during exercise in hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) patients with blunted force-frequency relationship assessed with pacing during cardiac catheterization are at greater risk of adverse events. Left ventricular contractile reserve (LVCR) based on force can be obtained noninvasively during exercise stress echocardiography (ESE). Purpose To evaluate the prognostic correlates of force-based LVCR during ESE in HCM. Methods We enrolled 332 HCM patients (age 51±15 years, 193 males, New York Heart Association, NYHA, Class I-III, EF 68±9%, maximal wall thickness 20±5 mm, left ventricular outflow tract gradient, LVOTG, present at rest in 34 pts, 10%) referred for ESE in 7 quality-controlled labs. SE assessment included LVOTG (mm Hg), LV Force (systolic blood pressure by cuff sphygmomanometer + LVOTG/LV end-systolic volume assessed with 2-D, mmHg/ml) and LVCR (peak/rest ratio of LV Force). LV volumes were measured from apical biplane (4- and 2-chamber) views with Simpson method when feasible (n=290) or with linear Teichholz (T) method from parasternal (long- or short-axis) view (n=42). All patients were followed-up. Results Force values were 8.5±6.7 at rest and 15.0±13.7 mmHg/mL at peak stress (P<0.001). During a median follow-up time of 58 months, 50 patients experienced at least one event: 19 deaths (10 cardiac), 9 hospitalizations for acute heart failure, 16 myotomy/myectomy and 22 atrial fibrillations. The event-free survival was lower in the 195 patients with LVCR <1.77 (identified with Receiver-Operator Characteristic analysis) compared to the 137 with LVCR ≥1.77: see figure. Multivariate analysis identified LVCR (Hazard ratio, HR, 2.032, 95% confidence intervals, CI, 1.042–3.964, P=0.037), age (HR, 1.033, 95% CI 1.009–1.058, P=0.007) and NYHA class (HR 2.204, 95% CI 1.161–4.185, P<0.016) as independent predictors of events. Figure 1. HCM-LVCR Conclusion A non-invasive evaluation of LVOTG, systolic blood pressure and LV end-systolic volume during ESE allows to assess force-based LVCR in HCM. Lower LVCR is associated with greater risk of events at follow-up.

P6575Evaluation of arrhythmias using an insertable cardiac monitor in patients with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease associated with arrhythmias. Life-threatening ventricular tachycardia (VT) or fibrillation is the main cause of sudden cardiac death (SCD) in HCM, even though bradycardia does occur. An implantable cardioverter-defibrillator effectively prevents SCD. Non-sustained VT is a risk factor for SCD and part of current risk stratification. Furthermore, atrial fibrillation (AF) is believed to be common in HCM and increases the risk of stroke. Notably, novel oral anticoagulant (NOAC) is recommended in HCM with AF, even in the absence of other risk factors. Routinely, arrhythmias are evaluated by 24–48 hours of ambulatory monitoring occasionally. Thus, the true burden of arrhythmia is unknown but may be elucidated by an insertable cardiac monitor (ICM). Purpose The purpose of this study was to ascertain the incidence of NSVT, AF, and significant bradycardia in unselected HCM patients by use of an ICM. Methods In total, 30 adults with HCM had an ICM Confirm Rx implanted subcutaneously at the level of the fourth rib on the left side. None had a cardiac device implanted previously since they were considered to be at low risk for SCD according to ESC risk score. The application for monitoring was installed in the patients' phone which also allowed for patient activation in case of symptoms. The ICM was programmed as follows: VT ≥160 beats per minute (bpm) during ≥8 intervals, AF ≥2minute of duration, and bradycardia ≤40 bpm or pause ≥3.0 s. Clin Trial Reg: NCT03259113. Results In total, 29 patients, mean age 51.2±12.3 years, 24 (82.8%) males, completed the monitoring and 1 had the phone disconnected the vast majority of time and was excluded for analyses. During a follow-up of 14–18 months, 9 patients (31.0%) had AF and were started on NOAC and potential dose-adjustment of beta-blocker. One of these patients had syncope due to rapidly conducted AF. One of the patients with AF also had episodes of atrial flutter. At least one episode of NSVT was detected in 6 patients (20.7%). In 11 patients (37.9%), sino-atrial block/sinus arrest were seen, typically 30–40 bpm. In 9 patients (31.0%) no significant arrhythmia were detected. Conclusion In this first study of ICM in HCM, evaluation of arrhythmia burden in low risk patients with HCM, yielded 31.0% AF, 20.7% NSVT, and 37.9% sino-atrial block/arrest. Acknowledgement/Funding Abbott

P3361Pathophysiology measured with positron emission tomography is equally impaired in hypertrophic and non-hypertrophic regions in hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is a heterogeneous disease with regard to clinical manifestations. It is characterized by an asymmetric pattern of hypertrophy of the left ventricle. However, less is known about pathophysiological distribution of the abnormalities. Positron emission tomography (PET) provides quantitative assessment of myocardial blood flow (MBF), oxidative metabolism, and sympathetic innervation using the following tracers: 15O-water, 11C-acetate, and 11C-HED. Purpose The purpose of the present study was to investigate if physiological parameters measured with PET are more impaired in hypertrophic regions compared to non-hypertrophic regions. Methods We examined 25 HCM patients using a Discovery MI PET/CT with 15O-water, 11C-acetate, and 11C-HED. Wall thickness (WT) was calculated from the 11C-acetate scan for basal and mid segments (n=12) in the 17-segment model and hypertrophic regions were defined as segments >15 mm. 15O-water PET was performed during rest and adenosine induced stress. Quantification of MBF, oxygen consumption (MVO2) and retention index of 11C-HED (RIHED) was done in aQuant software. Comparison of parameters in hypertrophic regions to non-hypertrophic regions was done using Mann-Whitney U- test and Bland-Altman analysis with repeatability coefficient defined as 2 times the standard-deviation of differences. Results One patient had all segments >15mm and one patient had all segments <15mm and were therefore excluded from analysis. WT was 18.2±1.9 mm in hypertrophic regions and 12.2±1.5 mm in non-hypertrophic regions. None of the PET-parameters showed a significant difference between hypertrophic and non-hypertrophic regions, see table 1. Table 1 MBFREST MBFSTRESS MVO2 RIHED Hypertrophic segments (mm) 0.70±0.20 1.74±0.92 0.092±0.026 0.12±0.037 Non-hypertrophic segments (mm) 0.68±0.18 1.71±0.87 0.094±0.025 0.12±0.036 p-value 0.767 0.851 0.956 0.684 Repeatability coefficient (%) 25.4 35.4 13.3 16.2 Mean ± standard deviation for PET-parameters in hypertrophic and non-hypertrophic segments. Relative repeatability coefficient (%) between regions and p-value for Mann-Whitney U-test. Conclusion Pathophysiology in terms of myocardial blood flow at rest and stress, oxygen consumption and sympathetic innervation are not significantly different in hypertrophic segments compared to non-hypertrophic segments in patients with HCM. Thus, the disease is not confined to hypertrophied areas but spread throughout the left ventricle. Acknowledgement/Funding Selanders stiftelse, Regionala forskningsrådet

P5554Follow the light - The prognostic value of late gadolinium enhancement in hypertrophic cardiomyopathy

Abstract Background and aim Hypertrophic cardiomyopathy (HCM) is a genetic based cardiomyopathy with heterogeneous phenotypic expression. Since it is one of the most common cause of sudden cardiac death (SCD) in the young different risk score have been proposed to properly identify the patients that would benefit from a primary prevention with an implantable cardioverter-defibrillator (ICD). ESC guidelines on HCM suggest to estimate the risk of SCD considering clinical and echocardiographic parameters and mention the use of cardiac magnetic resonance (CMR) only in the case of poor echo windows. The aim of the present study-level meta-analysis was to explore the prognostic value of late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) for adverse fatal events. Methods We searched PubMed and EMBASE for studies that investigated the prognostic value of LGE in patients with HCM. The outcomes of interest were SCD or aborted SCD, all-cause mortality and cardiovascular (CV) mortality. Random-effects Odds Ratios (ORs) were estimated using a DerSimonian-Laird method with a person-year approach. Moreover, an univariate meta-regression was performed to assess the moderator effect of mean age, LGE % of left ventricle (LV) and gender (expressed as male percentage). Results A total of 7 studies (n=3351) were included in the analysis. Mean follow-up was 3±0.63 years. Mean age was 47.7±14.6 years and 56.9% were male. LGE was detected in 1845 (55%) patients with a mean LGE percentage of LV of 7%. The presence of LGE was associated with an increased incidence of SCD or aborted SCD (OR 3.44; 95% CI 2.02–5.86; p<0.001- Figure), all-cause mortality (OR 1.92; 95% CI 1.31–2.81; p<0.001) and CV mortality (OR 3.16; 95% CI 1.77–5.64; p<0.001) compared with the absence of LGE at CMR. The LGE percentage of LV, mean age and gender did not have any moderator effect on the outcomes of interest. However, LGE % of LV was reported only in 4 studies and the absence of any moderator effect of this parameter could be due to a type II error. Prognostic value of LGE for SCD Conclusions The presence of LGE at CMR in patients with HCM exhibited a substantial prognostic value in fatal events and, in particular, in the prediction of SCD. LGE assessment is an effective tool to stratify the arrhythmic risk in HCM. Therefore, it should be considered, especially in borderline cases, to improve the identification of HCM patients who could benefit from ICD implantation.

Performance and validation of R-CHA2DS2VASc score for thromboembolism in patients with hypertrophic cardiomyopathy

ObjectiveTo validate the modified R-CHA2DS2VASc score as a predictor of thromboembolism in HCM patients. MethodsA total of 446 HCM patients were enrolled in our study, thirty-one (6.95%) patients experienced thromboembolic events during the follow-up time of 1786.7 person-years. The association between R-CHA2DS2VASc score and risk of thromboembolism was assessed by Cox’s proportional hazard analysis. The discriminatory power of R-CHA2DS2VASc score for thromboembolism prediction was assessed by Harrell’s C-statistic and validated internally by bootstrapping methods. Calibration plot was plotted by observed versus expected probabilities of thromboembolism. ResultsThe R-CHA2DS2VASc score was well calibrated with 0.84 thromboembolic events per 100 person-years in the predefined low risk (R-CHA2DS2VASc score ≤2) group, 1.84 in the low to moderate risk (R-CHA2DS2VASc score 3-4) group, 4.67 in the moderate to high risk (R-CHA2DS2VASc score 5-7) group, and 17.54 in the high risk (R-CHA2DS2VASc score ≥8) group. Hazard ratios for thromboembolism were 2.88 (95%CI: 1.06-7.82, P=0.038) for low to moderate versus low risk group, 5.30 (95%CI: 2.14-13.12, P=0.0003) for moderate to high versus low risk group, and 16.57 5.30 (95%CI: 4.96-55.33, P<0.0001) for high versus low risk group after adjusting left atria size. The Harrell’s C statistic was 0.7737 (95% CI: 0.65-0.89) for R-CHA2DS2VASc score. ConclusionThe R-CHA2DS2VASc score has shown good calibration and discriminative power in the prediction of thromboembolism for HCM patients. It should be considered as a potential decision support tool for HCM patients during clinical practice.

Abstract 237: Identifying the Transcriptome Signature of Calcium Channel Blocker in Human iPSC-Derived Cardiomyocytes

Calcium channel blockers (CCBs) are important in treating cardiovascular diseases and the acute pharmacological actions of CCBs in the hearts have been extensively studied. However, we lack the knowledge of the drug-specific effect on human cardiomyocyte transcriptome and potential physiological change after long-term exposure as patients are usually prescribed with these medications for their lifetime after diagnosis. Thus, we aimed to simulate chronic CCB treatment in human cardiomyocytes and subsequently examine both the functional and transcriptomic alterations. We differentiated cardiomyocytes from three human induced pluripotent stem cell (iPSC) lines and exposed them to four different CCBs—nifedipine, amlodipine, diltiazem, and verapamil—at their physiological serum concentrations for two weeks. Without inducing cell death and damage to myofilament structure, CCBs elicited line specific inhibition on calcium kinetics and contractility. While all four CCBs exerted comparable inhibition on calcium kinetics, verapamil applied the strongest inhibition on cardiomyocyte contractile function. By examining cardiomyocyte transcriptome after treatment, we identified little overlap in their transcriptome signatures. Verapamil is the only inhibitor that reduced the expression of contraction related genes, such as myosin heavy chain and troponin I, consistent with its depressive effects on contractile function. Moreover, the alterations in these gene may help explain how HCM patients respond to verapamil in relieving outflow tract obstruction. In conclusion, we identified the distinct transcriptome signatures of different CCBs in human cardiomyocytes, suggesting that although the four inhibitors act on the same target, they may have distinct effects on normal cardiac cell physiology. The application of iPSC platform and transcriptomic findings may allow us to identify responders to verapamil treatment.

Implantable cardioverter defibrillators in patients with electrical heart disease and hypertrophic cardiomyopathy: data from the German device registry

Implantable cardioverter- defibrillator (ICD) therapy is established for the prevention of sudden cardiac death (SCD) in different entities. However, data from large patient cohorts with electrical heart disease are rare. Therefore, we investigated these patients as well as patients with hypertrophic cardiomyopathy by analyzing registry data from a multi-center 'real-life' registry. The German Device Registry (DEVICE) is a nationwide, prospective registry with one-year follow-up investigating 5450 patients receiving device implantations in 50 German centers. The present analysis of DEVICE focussed on patients with electrical heart disease or HCM who received an ICD for primary or secondary prevention. 174 patients with HCM and 112 patients with electrical heart disease (long-QT syndrome, Brugada syndrome and arrhythmogenic right ventricular cardiomyopathy) were compared with 5164 other ICD patients. Median follow-up was 17.0months. Patients in the control group were significantly older. Of note, overall mortality after 1year was 1.8% in HCM patients, 6.6% in patients with electrical heart disease and 7.3% in the control group. Patients in the control group presented significantly more severe comorbidities. In contrast to HCM patients and the control group where primary prevention was the major indication for ICD implantation, 77.5% of patients with electrical heart disease received an ICD for secondary prevention. The number of surgical revisions was higher in patients with electrical heart disease. Data from the present registry display a surprisingly high mortality in patients with electrical heart disease equivalent to the control group. A high proportion of patients who received an ICD for secondary prevention may be regarded as a major determinant for these results, while severe comorbidities such as diabetes, hypertension, and renal failure are major determinants for mortality in the control cohort.

Burden and trends of arrhythmias in hypertrophic cardiomyopathy and its impact of mortality and resource utilization.

BackgroundHypertrophic cardiomyopathy (HCM) accounts for significant morbidity and mortality worldwide. Arrhythmias are considered the main cause of mortality, however, there is paucity of data relating to trends of arrhythmia and associated outcomes in HCM patients.MethodsNationwide Inpatient Sample from 2003 to 2014 was analyzed. HCM related hospitalizations were identified using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD9‐CM) code 425.1 and 425.11 in all diagnosis fields.ResultsOverall, there was an increase in number of hospitalizations related to arrhythmias among HCM patients from 7784 in 2003 to 8380 in 2014 (relative increase 10.5%, P < 0.001). The increase was most significant in patients ≥ 80 years and those with higher comorbidity burden. Atrial fibrillation (AF) was the most frequently occurring arrhythmia however atrial flutter (AFL) witnessed the highest rise during the study period. In general, there was a down trend in mortality with the greatest reduction occurring in patients with ventricular fibrillation/flutter (VF/VFL). The mean length of stay was higher if patients had arrhythmia, which led to increased cost of care from $16105 in 2003 to $19310 in 2014 (relative increase 22.9%, P < 0.001).ConclusionThere is overall decline in HCM related hospitalizations but rise in hospitalization among HCM patients with arrhythmias. HCM with arrhythmia accounts for significant inpatient mortality coupled with prolonged hospital stay and increased cost of care. However, there is an encouraging downtrend in the mortality most likely because of improved clinical practice, cardiac screening and primary and secondary prevention strategies.

PERFUSION SCINTIGRAPHY OF THE MYOCARDIUM IN VARIOUS FORMS OF CARDIAC PATHOLOGY IN CHILDREN

Perfusion scintigraphy of the myocardium was carried out with the help of the Millennium MG gamma camera (USA) in synchronization with the ECG in 141 patients aged of from 5 to 15 years. Patients were divided into four groups: 30 chronic myocarditis (CM) patients, 30 hypertrophic cardiomyopathy (HCMP) patients, 30 dilated cardiomyopathy (DCMP) cases and 21noncompact cardiomyopathy (NCMP) patients. The left ventricular (LV) ejection fraction was established to be preserved in CM and HCMC patients (in cases without signs of obstruction), a significant reduction in the ejection fraction was found in NKMP and DCMP patients. The thickness of the myocardium of the LV significantly increased only in HCM patients. The expansion of the LV cavity was detected in all patients, but its decrease was present only in HCM cases. The contractility of the myocardium was impaired in all the patients examined. Disturbances of the myocardial perfusion were the most pronounced in NKMP and DCMP patients. Signs of fibrosis were detected in most patients, but HCM patients. In 40% of CM patients, scintigraphic signs of inflammation were determined. In 17% of all examinations there was noted hyperperfusion of the right ventricular myocardium. The authors believe myocardial tomoscintigraphy to be the unique method for analyzing myocardial viability in various forms of cardiac pathology that can be used for the evaluation of the effectiveness of the treatment.

Novel Trans-Septal Left Atrial VAD Cannulation Technique for Hypertrophic/Restrictive Cardiomyopathy

Purpose Left ventricular assist device (LVAD) outcomes for hypertrophic (HCM) or restrictive cardiomyopathy (RCM) with a small LV are unsatisfactory due to difficulty draining via an LV apical cannula. We developed a new transeptal cannulation technique to decompress the left atrium where the atrial septum is cannulated via the right atrium. Methods Retrospective review of our institutional experience with LVAD/BiVAD implantation in HCM or RCM patients from October 2016 to Aug 2018. Outcomes following implantation were analyzed, including subsequent interventions, quality of VAD output, and patient outcomes. Results In total, 5 patients underwent LVAD implantation with trans-septal left-atrial cannulation techniques (HCM = 4 patients, RCM =1). Two patients received Berlin Heart BiVADs, 1 received a Berlin Heart LVAD, 1 patient received PediMag BiVADs, and 1 patient received a Heartware LVAD. Total support days were 485 days. Three patients underwent successful heart transplant after 275, 111 and 62 days of support. One neonate with HCM died from sepsis 27 days after PediMag BiVAD placement. One RCM patient died 10 days after Berlin Heart BiVAD placement following extracorporeal membrane oxygenation due to ARDS. Total survival rate is 60%. All three survivors did not develop any neurological deficits or complications related to thrombus and were discharged home after heart transplant. Conclusion This novel trans-septal left-atrial LVAD cannulation strategy is a viable alternative cannulation technique for HCM or RCM patients with a small left ventricular cavity. This technique can be applied to a variety of pediatric and adult devices in children ranging from infants to adults.

The demanding grey zone: Sport indices by cardiac magnetic resonance imaging differentiate hypertrophic cardiomyopathy from athlete's heart.

BackgroundWe aimed to characterize gender specific left ventricular hypertrophy using a novel, accurate and less time demanding cardiac magnetic resonance (CMR) quantification method to differentiate physiological hypertrophy and hypertrophic cardiomyopathy based on a large population of highly trained athletes and hypertrophic cardiomyopathy patients.MethodsElite athletes (n = 150,>18 training hours/week), HCM patients (n = 194) and athletes with hypertrophic cardiomyopathy (n = 10) were examined by CMR. CMR based sport indices such as maximal end-diastolic wall thickness to left ventricular end-diastolic volume index ratio (EDWT/LVEDVi) and left ventricular mass to left ventricular end-diastolic volume ratio (LVM/LVEDV) were calculated, established using both conventional and threshold-based quantification method.ResultsWhereas 47.5% of male athletes, only 4.1% of female athletes were in the grey zone of hypertrophy (EDWT 13-16mm). EDWT/LVEDVi discriminated between physiological and pathological left ventricular hypertrophy with excellent diagnostic accuracy (AUCCQ:0.998, AUCTQ:0.999). Cut-off value for LVM/LVEDVCQ<0.82 mm×m2/ml and for EDWT/LVEDViTQ<1.27 discriminated between physiological and pathological left ventricular hypertrophy with a sensitivity of 77.8% and 89.2%, a specificity of 86.7% and 91.3%, respectively. LVM/LVEDV evaluated using threshold-based quantification performed significantly better than conventional quantification even in the male subgroup with EDWT between 13-16mm (p<0.001).ConclusionsAlmost 50% of male highly trained athletes can reach EDWT of 13 mm. CMR based sport indices provide an important tool to distinguish hypertrophic cardiomyopathy from athlete’s heart, especially in highly trained athletes in the grey zone of hypertrophy.

Advanced Morpho-Functional Analysis on Ventricular and Atrial Tissue Reveals Cross-Bridge Kinetics Alterations and Sarcomere Energetic Impairment in Hcm Patients

Advanced Morpho-Functional Analysis on Ventricular and Atrial Tissue Reveals Cross-Bridge Kinetics Alterations and Sarcomere Energetic Impairment in Hcm Patients

Cardiovascular magnetic resonance T2* mapping for structural alterations in hypertrophic cardiomyopathy

PurposeHypertrophic cardiomyopathy (HCM) is characterized by a heterogeneous morphology and variable prognosis. A mismatch between left ventricular mass (LVM) and microvascular circulation with corresponding relative ischemia has been implicated to cause myocardial replacement fibrosis that deteriorates prognosis. Besides parametric T1 mapping, Cardiovascular Magnetic Resonance (CMR) T2* mapping is able to identify ischemia as well as fibrosis in cardiac and extracardiac diseases. Therefore, we aimed to investigate the value of T2* mapping to characterize structural alterations in patients with HCM. MethodsCMR was performed on a 1.5 T MR imaging system (Achieva, Philips, Best, Netherlands) using a 5-channel coil in patients with HCM (n = 103, 50.6 ± 16.4 years) and in age- and gender-matched controls (n = 20, 44.8 ± 16.9 years). T2* mapping (1 midventricular short axis slice) was acquired in addition to late gadolinium enhancement (LGE). T2* values were compared between patients with HCM and controls as well as between HCM patients with- and without fibrosis. ResultsHCM patients showed significantly decreased T2* values compared to controls (26.2 ± 4.6 vs. 31.3 ± 4.3 ms, p < 0.001). Especially patients with myocardial fibrosis presented with decreased T2* values in comparison to those without fibrosis (25.2 ± 4.0 vs. 28.7 ± 5.3 ms, p = 0.003). A regression model including maximum wall thickness, LVM and T2* values provided good overall diagnostic accuracy of 80% to diagnose HCM with and without fibrosis. ConclusionIn this study, parametric mapping identified lower T2* values in HCM patients compared to controls, especially in a sub-group of patients with myocardial fibrosis. As myocardial fibrosis has been suggested to influence prognosis of patients with HCM, T2* mapping may add information for identifying a higher risk sub-group of HCM patients.

Myocardial ischemia in patients with hypertrophic cardiomyopathy

Authors present is comprehensive clinical and instrumental evaluation of patients with HCM with myocardial ischemia. 104 patients (38.4% of men) with HCM were examined, mean age 58.2±14.7. The examination included risk factors assessment for CAD, ECG, Echo, stress ECG test, 24-hour ECG monitoring. In the presence of myocardial ischemia, CAG (n=66) and MSCT of the coronary arteries (CA) (n=4) were performed. All patients were split up on 2 groups: I - 70 HCM patients with myocardial ischemia, 67.3%, and II (the control group) - 34 HCM patients without myocardial ischemia, 32.7%. The group I was divided on 2 subgroups: 1 - 29 patients with coronary atherosclerosis (41.4%), 2 - 41 patient without coronary atherosclerosis (58.6%). Age (p=0.046), family history (p=0.037), higher systolic and diastolic arterial pressure, long-term arterial hypertension (p<0.05) were determined as significant risk factors for CAD. Smaller diameter of LAD (p=0.008), higher LV mass index, greater LV diastolic function disorder (p<0.05) were detected in group 2 compared to group II. The decrease in myocardial perfusion (MBG scale) was associated with high LV mass index and cardiac arrhythmias. The frequency of concomitant coronary atherosclerosis among HCM patients with myocardial ischemia was determined as 41.4%. Analysis of traditional risk factors for CAD in patients with HCM revealed the strong relation to age, aggravated by a family history of CAD, blood pressure level and duration of hypertension. Smaller diameter of LAD, higher LV mass index, greater LV diastolic function disorder were observed in HCM patients with myocardial ischemia without CAD.

Hypertrophic cardiomyopathy. Cardiomyocyte ultrastructure, the specific or stereotypic signs

To study cardiomyocyte (CMC) ultrastructural changes in the interventricular septum (IVS) of patients with HCM and evaluate their specificity for this pathology. IVS myocardial samples taken from 44 HCM patients aged 18-59 years at IVS myoectomy underwent an electron microscopic study. The diameter of CMCs and their nuclei was measured in semithin sections. A morphometric examination of the IVS myocardium in HCM patients revealed moderate hypertrophy of CMCs and their nuclei, the diameters of which averaged 23.7±4.4 and 5.2±0.9 μm, respectively. The IVS CMCs were characterized by the ultrastructural signs of hypertrophy: the larger size and number of structures ensuring contractile and synthetic functions; the myocytes contained higher amounts of myofibrils, intermyofibrillar mitochondria, granular endoplasmic reticulum cisterns, and free ribosomes. On the contrary, some CMCs had fewer myofibrils in the perinuclear region, which is an adaptive change under hemodynamic overload conditions. In addition, a number of myocytes displayed signs of dystrophic changes: the appearance of lipofuscin granules, myelin figures, phagosomes, lipid droplets, and vacuoles, which can fill all free sarcoplasmic zones. Ultrastructural changes characteristic of hypertrophy were found in IVS CMCs in HCM patients. In addition, there was partial myofibrillar loss and dystrophic changes in a number of myocytes, which are stereotypic compensatory-adaptive changes under hemodynamic overload conditions. All the above-mentioned changes in the CMC ultrastructure are characteristic of myocardial hypertrophy, but not specific for hypertrophic cardiomyopathy.

Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients.

ABSTRACTHypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. Gene mutations causing HCM have been found in about half of HCM patients, while the genetic etiology and pathogenesis remain unknown for many cases of HCM. To identify novel mechanisms underlying HCM pathogenesis, we generated a cardiovascular-mutant medaka fish, non-spring heart (nsh), which showed diastolic dysfunction and hypertrophic myocardium. The nsh homozygotes had fewer myofibrils, disrupted sarcomeres and expressed pathologically stiffer titin isoforms. In addition, the nsh heterozygotes showed M-line disassembly that is similar to the pathological changes found in HCM. Positional cloning revealed a missense mutation in an immunoglobulin (Ig) domain located in the M-line–A-band transition zone of titin. Screening of mutations in 96 unrelated patients with familial HCM, who had no previously implicated mutations in known sarcomeric gene candidates, identified two mutations in Ig domains close to the M-line region of titin. In vitro studies revealed that the mutations found both in medaka fish and in familial HCM increased binding of titin to muscle-specific ring finger protein 1 (MURF1) and enhanced titin degradation by ubiquitination. These findings implicate an impaired interaction between titin and MURF1 as a novel mechanism underlying the pathogenesis of HCM.

Apical Hypertrophic Cardiomyopathy in an asymptomatic male

Apical Hypertrophic cardiomyopathy is a rare variant of HCM and has a prevalence of around ~ 15 % among HCM patients. As compared to other variants, it has a relatively benign prognosis. Predominantly prevalent in the Japanese population; it is characterized by localized hypertrophy of the LV apex as compared to other segments. It is usually silent in early stages and is manifested at an adult stage with typical ECG changes of giant T wave inversions in the precordial leads. Transthoracic echocardiography remains the mainstay of non – invasive diagnosis. We report a case of an asymptomatic elderly male who presented with the classical deep T wave inversion in ECG for which echocardiography revealed the apical variant of hypertrophic cardiomyopathy.

Pediatric cardiomyopathies: Assessment of genetic causes by next generation sequencing of cardiomyopathy genes and genotype-phenotype correlation

Cardiomyopathies (CM) are cardiac muscle diseases of the young adults. In 30–60% of cases, a genetic origin is observed with most often an autosomal dominant transmission. Except for syndromic and metabolic diseases, pediatric forms of primary cardiomyopathies remains poorly known regarding their genetic etiology, and frequently present a severe evolution. The aim of the work is to determine the genetic causes of a primary cardiomyopathy in a cohort of 57 children diagnosed under 15 years, sequenced on a custom panel of 52 cardiomyopathy genes and attempt to correlate the disease causing gene with the severity of the phenotype. This cohort was composed of 57 patients (31 males and 26 females) including 24 HCM, 20 DCM and 13 other sub-types (RCM, LVNC). The overall mutation rate was 61%. Age of onset was significantly earlier in the patients ( P = 0.02) with DCM (4 ± 3.5 years) and with others CM (3 ± 3.5 years) than in HCM patients (7 ± 5 years). In patients with DCM and other CMs, the mutation rate was higher (14/20, 70% and 8/13, 62%, respectively) than in patients with HCM (13/24, 54%). Similarly, the proportion of patients carrying 2 pathogenic variants was higher in patients with DCM (35%) and other CMs (62%) than in HCM patients (23%). The mutated genes were predominantly sarcomeric genes (13/21) (MYH7, MYCPB3, TNNC1 etc). A significant rate of de novo mutations (5/49, 10%) was observed in the cohort. We report a cohort of genotyped pediatric cardiomyopathies analyzed on a large panel of genes. We observed a molecular cause in 61% of patients including more than 23% of patients were carrier of two disease causing variants, suggesting that the early and severe phenotype could be explained by the cumulative effect of several pathogenic dominant variants. The predominance of sarcomeric gene supported the hypothesis of a common genetic origin between adult and pediatric cardiomyopathy cases. Our results support genetic testing in pediatric cardiomyopathies.