Ommen, Steve R.

Backgrounds: Left ventricular torsion (LVtor) is an integral part of systole and untwisting plays an important role in diastole. The aim of this study was to characterize LVtor and untwisting in different grades of diastolic dysfunction. Methods: We studied 135 patients with normal LV EF with various grades of diastolic dysfunction (40 group1:mild,42 group 2:moderate,and 22 group 3:severe dysfunction) and 31 controls with normal diastolic function. Apical and basal short axis rotations were measured by 2D STE. LVtor was defined as net difference between apical and basal rotation. Results: Age, gender, and EF were similar in 3 groups and control. Mitral annulus early diastolic velocity was reduced in all 3 groups (see table ). Peak LVtor was significantly greater in group 1 compared with control, group 2 and group 3. The time from peak LVtor to Mitral valve opening, and to peak early diastolic velocity were significantly delayed in group 1 compared to control (p=0.0030 and 0.0409, respectively). The twisting rate and untwisting rate were found to be highest in group 1. Conclusions: Systolic torsion and diastolic untwisting are significantly increased in patients with mild diastolic dysfunction. In patients with advanced diastolic dysfunction with increased filling pressure, torsion and untwisting are normalized. Hence, vigorous LV torsion appears to be a compensatory mechanism during an early stage of diastolic dysfunction to maintain normal filling in the setting of reduced longitudinal myocardial motion.

Background: Exercise normally enhances LV relaxation with minimal change in filling pressure (P). We hypothesize that exercise in hypertensive (HTN) patients increases LV diastolic P through a direct effect on relaxation and ventricular-vascular coupling. Methods: Patients (n=21) with HTN, normal EF, and no coronary disease underwent simultaneous micromanometer LV P and echo-Doppler measurements at rest and with low level supine exercise (12 bicycle; 9 arm weight). Continuous volume (V) was obtained from mitral Doppler inflow and end-diastolic (ED) and end-systolic (ES) V from 2-D echo. Relaxation-corrected LV diastolic P was used for PV relationship P = α.e β*V ; to account for covariance in α and β, LV capacitance (EDV 20 = Ln[20mmHg/α]/β) was reported. Single beat method was used for LV ES elastance (Ees). Group 1 did not increase mean LV diastolic P (mDP) with exercise, Group 2 increased mDP >6mmHg. Results: LV diastolic P and arterial and LV ES elastance increased with exercise; EDV was stable; EDV 20 decreased. Compared to Group 1, Group 2 had a greater exercise-induced increase in afterload, associated with increase in LV minimal P and impaired augmentation of relaxation rate (Table & Figure ). Conclusions: In patients with HTN, impairment of ventricular relaxation plays a major role in causing LV filling P increase with exercise, which is related to ventricular-vascular coupling.

Background: Myocardial late gadolinium enhancement (LGE) on Contrast-Enhanced Magnetic Resonance Imaging (CE-MRI) of patients (pts) with hypertrophic cardiomyopathy (HCM) may indicate intra-myocardial fibrosis. We explored whether the presence and extent of LGE on CE-MRI among pts with HCM predicted ventricular arrhythmogenicity, and decreased survival. Methods: 424 HCM pts [age = 55 ± 16 years (range 2 – 90), 41% females], without prior history of septal ablation/myectomy, underwent CE-MRI (GE 1.5T) during a 6-year period. We compared the presence and amount of LGE with degree of ventricular ectopy on Holter ECG (available in 220 pts) recorded during the same time period of the CE-MRI. All cause death and appropriate, VF-terminating ICD therapies were then recorded during a mean follow-up of 34 ± 14 months (range 7 – 85). Results: 239 pts (56%) had LGE ranging from 0.4 – 65% of the myocardium. LGE -positive pts were more likely to have non-sustained ventricular tachycardia on Holter ECG [34/126 (27%) vs 8/94 (8.5%), p < 0.001], and had more total ventricular extrasystoles/24 hours (700 ± 2080 vs 103 ± 460, p < 0.001). During follow-up, 7 pts died and 4 received appropriate ICD discharges (9.7% of 41 pts with ICD). All 11 pts were LGE-positive. Event free survival was excellent (100%) in pts without LGE, and lower (95.4%) in pts with LGE (log rank, p < 0.002). Multivariate analysis (adjusting for age, gender, morphologic and functional data, and comorbidities) identified LGE involving ≥ 5% of LV mass (p=0.03, present in 7/11 pts with events), septal thickness≥30mm (p=0.03), and atrial fibrillation (p=0.02) as independent predictors of death or appropriate ICD discharges. Conclusions : In pts with HCM, LGE by CE-MRI was strongly associated with surrogates of arrhythmia and was independently associated with subsequent death and/or ICD discharge. If replicated, LGE may be considered a major risk for sudden death in HCM.

Background: Atrial fibrillation (AF) is common in HCM yet the mechanisms are poorly understood but are likely secondary to either the consequences of left atrial structural remodeling (LASR) or myopathy, or triggers arising from pulmonary and other thoracic veins. The presence and severity of LASR as characterized by left atrial strain (LA ϵ), and its relationship to AF in HCM, has not been determined. Therefore, we measured LA ϵ and strain rate (SR) in Pts with HCM both with (AF+) and without (AF−) prior AF and compared these measures to those in age and gender matched controls without HCM or AF. Methods: Two-dimensional speckle-derived LA longitudinal peak ϵ, SR during systole (SR S ), early (SR E ) and late diastole (SR A ) were measured at the basal and mid portions of the lateral, septal, and posterior LA walls using Vector Velocity Imaging during sinus rhythm and were averaged. Results: Mean age of Pts in each of the matched groups was 56 ± 2 years (16 males; 59%). Significant left ventricular outflow tract obstruction was present in all Pts with HCM. Diastolic dysfunction was similar in both HCM groups and worse when compared to controls. Peak LA 3 , SR S , SR E , and SR A for each group is shown (table 1 ). HCM was associated with significantly lower LA ϵ and SR compared to controls. Although LA size was increased in Pts with HCM when compared to controls there was no correlation between LA size and ϵ or SR (p>0.05 for all). No differences in LA ϵ and SR were found between AF+ versus AF− Pts. Conclusion: HCM is associated with LASR as determined by decreased LA ϵ and SR. However, LA ϵ and SR were similar in AF+ versus AF− Pts suggesting that the occurrence of AF in HCM is not due to LASR alone. Table 1. Left Atrial Strain and Strain Rate in Hypertrophic Cardiomyopathy

Background: Contrast enhanced magnetic resonance imaging (CE-MRI) is a useful tool to define cardiac morphology, systolic function, and the presence of late gadolinium enhancement (LGE). In patients (pts) with hypertrophic cardiomyopathy (HCM), LGE may represent intra-myocardial fibrosis. We explored the association between left ventricular (LV) morphology and function to the presence and amount of LGE in pts with HCM. Methods: 424 HCM pts (age = 55 ± 16 years, 41% females), without prior history of septal ablation/myectomy, underwent CE-MRI (GE 1.5T) during a 6-year period. LV volumes, diameter, ejection fraction (EF), septal shape and thickness, and the presence of obstructive physiology were assessed from standard steady state free precession pulse sequences. The presence and amount of LGE were traced from a dynamic post contrast inversion recovery pulse sequence. Morphologic and functional findings were then compared with presence and amount of LGE. Results: Over half of the pts [239/424 (56%)] had LGE, most commonly localizing to RV insertion points [174/239 pts, (73%)]. The extent of LGE ranged from 0.4–65% of LV mass. Univariate (morphologic) predictors of LGE were: reverse curve septal shape [OR = 7.8, (95% CI, 3.9–15.6)], septal thickness ≥ 16 mm (OR = 4.5, 2.4–8.2), LV mass ≥ 150 grams (OR = 2.6, 1.7–3.8)], LVEF<50% (OR = 4.6, 1.3–16), and presence of obstructive physiology (OR = 1.8, 1.02–3). The percentage of LV mass involved with LGE increased with higher LV mass, increased septal wall thickness, and decreasing LVEF (Spearman rank = 0.2– 0.4, p<0.0001 for all). Multivariate analysis (adjusting for all morphologic and functional parameters) showed that septal thickness ≥ 16mm (p = 0.0001), LV mass ≥ 150 grams (p = 0.01) and LVEF < 50% (p = 0.02) were independent predictors of LGE on CE-MRI. Conclusions: LGE, as determined by CE-MRI, was seen in over half of the patients with HCM. Decreased LVEF, increased septal thickness, and increased LV mass were associated with the presence of LGE. The clinical and prognostic impact of these morphological features warrants further investigation.

Background: Mutations in MYBPC3 -encoded myosin binding protein C underlie the most common genotype in hypertrophic cardiomyopathy (HCM). Compared to most HCM-associated mutations which are primarily missense mutations, MYBPC3-HCM is often caused by insertions, deletions, nonsense mutations or mutations involving the canonical splice site. However, the effects of most mutations that prematurely truncate MYBPC3 are unknown. Access to cardiac specific mRNA and tissue has permitted a molecular and cellular elucidation of the consequences of two splice site mutations. Methods: Mutational analysis of MYBPC3 revealed 2 HCM-susceptibility mutations involving the splice donor sites of exons 7 and 30. Reverse transcription was performed on cDNA generated from RNA extracted from cardiac tissue obtained following surgical myectomy. Western blot analysis and immunohistochemistry (IHC) of the myofilaments were performed to further assess the impact of the splice-site mutations. Results: Both splice donor mutations produced abnormal RNA splicing of MYBPC3. The c.821+1 g>a mutation in the splice donor site of exon 7 generated two alternatively-spliced mutant transcripts resulting in two frame-shifted, premature truncations (H257 fs/37 and H257 fs/15). The c.3330+2 t>g mutation in exon 30’s splice donor site produced a single alternatively-spliced mutant transcript that translated into a frame-shifted premature truncation (V1063 fs/37). Expression levels of wild type myosin binding protein C were decreased in the myectomy specimen from the patient with the exon 7 splice donor site mutation. By IHC, the spatial organization of myosin binding protein C was disrupted severely in both patients. Conclusions: This study provides the first molecular and cellular characterization of HCM-causing mutations involving canonical splice-site motifs within the intron. Loss of function of the splice site resulted in exon skipping and generation of frame-shifted and prematurely truncated myosin binding protein C and disruption of the distribution and organization of myosin binding protein C in the heart tissue. This research has received full or partial funding support from the American Heart Association, AHA Midwest Affiliate (Illinois, Indiana, Iowa, Kansas, Michigan, Minnesota, Missouri, Nebraska, North Dakota, South Dakota & Wisconsin).

Introduction: Impaired peak VO2 and obesity are known predictors of morbidity and mortality in Hypertrophic Cardiomyopathy (HCM). The purpose of this study is to determine the degree of exercise impairment due to excess weight in patients with HCM. Methods: Adult HCM patients who underwent cardiopulmonary treadmill testing at our tertiary referral center from 2006 - 2012 and had consented to research participation were identified retrospectively. Percent predicted peak VO2 was calculated by the Astrand formula for men and the Jones formula for women which adjust for age and gender. Baseline echocardiographic features obtained within 1 week of exercise testing and % predicted peak VO2 were compared among four groups of patients stratified by body mass index (BMI). Results: 510 patients were identified, with a mean age at diagnosis of 44.3 ± 16.1 years, 186 (36.5%) female. Mean BMI at the time of cardiopulmonary exercise testing was 29.7 ± 5.3 and 227 (44.6%) patients had a BMI ≥ 30. Overweight and obese patients were older and were more likely to be male than their normal weight peers. However, there was no significant difference in ejection fraction (EF), resting left ventricular outflow tract gradient, right ventricular systolic pressure (RVSP), or septal thickness among the groups. HCM patients show impaired peak VO2 across all BMI groups. While peak VO2 increased progressively across BMI groups consistent with greater O2 demand generated by higher body weight, the adjusted peak VO2 in mL/kg/min fell progressively, indicating progressively greater performance impairment with increasing BMI despite similar degrees of cardiac impairment (p <0.0001) (Table 1). Conclusion: Increased BMI is associated with reduced exercise performance in a graded manner in HCM patients independent of cardiac impairment identified on echocardiography.

Introduction: Idiopathic Dilated (DCM) and hypertrophic cardiomyopathies (HCM) are leading causes of sudden cardiac death. The incidence and prevalence of both DCM and HCM were originally estimated in Olmsted County, MN over 1975-1984. Incidence was 6.0 and prevalence was 36.5 per 100,000 person-years, for DCM; with incidence and prevalence rates of 2.5 and 19.7 per 100,000 person-years for HCM. This study aims to determine the incidence and mortality rates of individuals diagnosed with HCM and DCM in Olmsted County, MN from 1984 to 2016. Methods: The Rochester Epidemiology Project is a validated long term medical record linkage system that collects and links medical information for the approximately 145000 residents of Olmsted County, Minnesota. Using this database and the Electronic Health Record systems at Mayo Clinic and Olmsted Medical Center in Rochester, MN, we manually reviewed and validated the medical records of 4440 patients. This cohort includes all patients with any mention of a cardiomyopathy based on ICD and HICDA codes during the period 1984 to 2016. Data were summarized with mean and standard deviation, frequency and percentage and compared between groups using two sample t-test for continuous data and chi-square for proportions. Survival was computed using Kaplan-Meier methods and compared to expected survival based on age and gender. Incidence was computed using Olmsted County population numbers during the time period and adjusted to the US 1980 white population to allow for comparison with the previous study. Results: The calculated crude incidence rate for DCM and HCM are 10.1 and 7.8 per 100,000 respectively. Incidence rates adjusted for comparison to US 1980 white population (age and sex adjusted) are 10.4 (95% CI: 9.3-11.4) and 8.0 (95% CI: 7.1-8.8) per 100,000 person-years, respectively. The observed number of deaths in this cohort (HCM and DCM) was 420 vs 194 expected. Conclusions: Calculated incidence, both crude and adjusted rates are higher than previously estimated rates. The crude incidence rate for HCM is almost 4-fold higher than that for DCM is 2.4 times higher than the original estimate by Codd et al. Individuals with cardiomyopathies were found to have a higher overall mortality rate than the general population with an observed to expected hazard ratio of 1.73 (95% CI 1.49-2.01, p<0.001) for DCM and 1.44 (95% CI 1.21-1.71, p<0.001) for HCM. Our findings suggest that previous studies may have underestimated the true burden of HCM and DCM in the population which has important implications for healthcare provision and cost.