Lars Sorensen

Comparison of Outcomes in Patients With Nonobstructive, Labile-Obstructive, and Chronically Obstructive Hypertrophic Cardiomyopathy

Patients with nonobstructive hypertrophic cardiomyopathy (HC) are considered low risk, generally not requiring aggressive intervention. However, nonobstructive and labile-obstructive HC have been traditionally classified together, and it is unknown if these 2 subgroups have distinct risk profiles. We compared cardiovascular outcomes in 293 patients HC (96 nonobstructive, 114 labile-obstructive, and 83 obstructive) referred for exercise echocardiography and magnetic resonance imaging and followed for 3.3 ± 3.6 years. A subgroup (34 nonobstructive, 28 labile-obstructive, 21 obstructive) underwent positron emission tomography. The mean number of sudden cardiac death risk factors was similar among groups (nonobstructive: 1.4 vs labile-obstructive: 1.2 vs obstructive: 1.4 risk factors, p = 0.2). Prevalence of late gadolinium enhancement (LGE) was similar across groups but more non-obstructive patients had late gadolinium enhancement ≥20% of myocardial mass (23 [30%] vs 19 [18%] labile-obstructive and 8 [11%] obstructive, p = 0.01]. Fewer labile-obstructive patients had regional positron emission tomography perfusion abnormalities (12 [46%] vs nonobstructive 30 [81%] and obstructive 17 [85%], p = 0.003]. During follow-up, 60 events were recorded (36 ventricular tachycardia/ventricular fibrillation, including 30 defibrillator discharges, 12 heart failure worsening, and 2 deaths). Nonobstructive patients were at greater risk of VT/VF at follow-up, compared to labile obstructive (hazed ratio 0.18, 95% confidence interval 0.04 to 0.84, p = 0.03) and the risk persisted after adjusting for age, gender, syncope, family history of sudden cardiac death, abnormal blood pressure response, and septum ≥3 cm (p = 0.04). Appropriate defibrillator discharges were more frequent in nonobstructive (8 [18%]) compared to labile-obstructive (0 [0%], p = 0.02) patients. In conclusion, nonobstructive hemodynamics is associated with more pronounced fibrosis and ischemia than labile-obstructive and is an independent predictor of VT/VF in HC.

Hypertrophic cardiomyopathy associated Lys104Glu mutation in the myosin regulatory light chain causes diastolic disturbance in mice

We have examined, for the first time, the effects of the familial hypertrophic cardiomyopathy (HCM)-associated Lys104Glu mutation in the myosin regulatory light chain (RLC). Transgenic mice expressing the Lys104Glu substitution (Tg-MUT) were generated and the results were compared to Tg-WT (wild-type human ventricular RLC) mice. Echocardiography with pulse wave Doppler in 6month-old Tg-MUT showed early signs of diastolic disturbance with significantly reduced E/A transmitral velocities ratio. Invasive hemodynamics in 6month-old Tg-MUT mice also demonstrated a borderline significant prolonged isovolumic relaxation time (Tau) and a tendency for slower rate of pressure decline, suggesting alterations in diastolic function in Tg-MUT. Six month-old mutant animals had no LV hypertrophy; however, at >13months they displayed significant hypertrophy and fibrosis. In skinned papillary muscles from 5 to 6month-old mice a mutation induced reduction in maximal tension and slower muscle relaxation rates were observed. Mutated cross-bridges showed increased rates of binding to the thin filaments and a faster rate of the power stroke. In addition, ~2-fold lower level of RLC phosphorylation was observed in the mutant compared to Tg-WT. In line with the higher mitochondrial content seen in Tg-MUT hearts, the MUT-myosin ATPase activity was significantly higher than WT-myosin, indicating increased energy consumption. In the in vitro motility assay, MUT-myosin produced higher actin sliding velocity under zero load, but the velocity drastically decreased with applied load in the MUT vs. WT myosin. Our results suggest that diastolic disturbance (impaired muscle relaxation, lower E/A) and inefficiency of energy use (reduced contractile force and faster ATP consumption) may underlie the Lys104Glu-mediated HCM phenotype.

Late gadolinium enhancement confined to the right ventricular insertion points in hypertrophic cardiomyopathy: an intermediate stage phenotype?

AIMS To investigate whether hypertrophic cardiomyopathy (HCM) patients with late gadolinium enhancement (LGE) confined to the right ventricular insertion points (RVIP) differ phenotypically from patients without LGE or intramural LGE in the left ventricle (LV). METHODS AND RESULTS Sixty-two HCM patients underwent cardiac magnetic resonance for quantification of LGE (% LV mass) and were classified as group (i) no-LGE (n = 18), group (ii) LGE-RVIP (n = 19), and group (iii) intramural LGE (n = 25). All patients also underwent vasodilator N-13 ammonia PET to quantify myocardial blood flow (MBF) and myocardial flow reserve (MFR), and echocardiography to measure longitudinal LV strain. LGE extent (17 ± 11% vs. 4 ± 4% vs. 0%; P < 0.001) and LV thickness (21.7 ± 3.4 vs. 18.8 ± 3.9 vs. 16.3 ± 2.8 mm; P < 0.001) were significantly greater in group 3, intermediate in group 2, and lower in group 1. In contrast, stress MBF (1.62 ± 0.44 vs. 1.90 ± 0.37 vs. 2.22 ± 0.48 mL/min/g; P < 0.001); MFR (1.92 ± 0.47 vs. 2.15 ± 0.52 vs. 2.71 ± 0.52; P < 0.001), and longitudinal LV strain (-11.4 ± 3.8 vs. -12.6 ± 3.2 vs. -14.4 ± 4.1%; P = 0.04) were lower in group 3, intermediate in group 2, and higher in group 1. CONCLUSIONS From an imaging viewpoint, patients with LGE confined to only the RVIP appear to represent an intermediate-stage phenotype between patients with no LGE and intramural LGE in the LV.

Risk Factors of Endocarditis in Patients With Enterococcus faecalis Bacteremia: External Validation of the NOVA Score

BACKGROUND The NOVA score is a recently developed diagnostic tool used to identify patients with increased risk of infective endocarditis (IE) among patients with Enterococcus faecalis bacteremia. We aimed to validate the NOVA score and to identify risk factors for IE. METHODS From 1 January 2010 to 31 December 2013, we included 647 consecutive patients with E. faecalis bacteremia. The NOVA score was used in a slightly adapted form; 2/2 positive blood cultures resulted in 5 points, unknown origin of infection in 4 points, prior valve disease in 2 points, and heart murmur in 1 point. RESULTS IE was diagnosed in 78 patients (12%). Monomicrobial E. faecalis bacteremia (hazard ratio [HR], 3.60; 95% confidence interval [CI], 1.6-8.0), prosthetic heart valve (HR, 6.2; 95% CI, 3.8-10.1), male sex (HR, 2.0; 95% CI, 1.1-3.8), and community acquisition (HR, 1.8; 95% CI, 1.1-2.9) were independently associated with IE. The adapted NOVA score was applied in the 240 patients examined by echocardiography. A low score (<4) was found in 40 patients (17%), implying a low likelihood of IE. Of the 78 patients with IE, 76 had a high score (≥4), resulting in a sensitivity of 97%, specificity of 23%, a negative predictive value of 95%, and a positive predictive value of 38%. CONCLUSIONS Monomicrobial E. faecalis bacteremia, community acquisition, prosthetic heart valve, and male sex are associated with increased risk of IE. In our retrospective cohort, the adapted NOVA score performed well, suggesting that it could be useful in guiding clinical decisions.

Electromechanical Relationship in Hypertrophic Cardiomyopathy

We examined whether there is a relationship between repolarization abnormalities on electrocardiography (EKG) and deformation abnormalities by echocardiography. Analysis of baseline EKGs and mechanical (echo-based deformation) changes was performed in 128 patients with a clinical diagnosis of hypertrophic cardiomyopathy (HCM). Patients with left ventricular hypertrophy (LVH) or repolarization abnormalities had higher septal thickness when compared to patients with normal EKG. Patients with EKG evidence of LVH or QTc prolongation had lower systolic velocity, systolic strain, systolic strain rate, late diastolic velocity, and late diastolic strain rate than patients with a normal EKG. Patients with strain pattern or ST depression/T-wave inversion had lower systolic velocity, systolic strain, systolic strain rate, early diastolic velocity, and late diastolic velocity when compared to patients with normal EKGs. LVH and repolarization abnormalities on surface EKG are markers of impaired systolic and diastolic mechanics in HCM.

Allele-specific differences in transcriptome, miRNome, and mitochondrial function in two hypertrophic cardiomyopathy mouse models

Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnosis, irrespective of genotype. In this study, we determined how two mouse models of HCM differ, with respect to cellular/mitochondrial function and molecular biosignatures, at an early stage of disease. We show that hearts from young R92W-TnT and R403Q-αMyHC mutation-bearing mice differ in their transcriptome, miRNome, intracellular redox environment, mitochondrial antioxidant defense mechanisms, and susceptibility to mitochondrial permeability transition pore opening. Pathway analysis of mRNA-sequencing data and microRNA profiles indicate that R92W-TnT mutants exhibit a biosignature consistent with activation of profibrotic TGF-β signaling. Our results suggest that the oxidative environment and mitochondrial impairment in young R92W-TnT mice promote activation of TGF-β signaling that foreshadows a pernicious phenotype in young individuals. Of the two mutations, R92W-TnT is more likely to benefit from anti-TGF-β signaling effects conferred by angiotensin receptor blockers and may be responsive to mitochondrial antioxidant strategies in the early stage of disease. Molecular and functional profiling may therefore serve as aids to guide precision therapy for HCM.

New Approach to Intracardiac Hemodynamic Measurements in Small Animals Echo-Guided Percutaneous Apical Puncture

Invasive measurements of intracardiac hemodynamics in animal models have allowed important advances in the understanding of cardiac disease. Currently they are performed either through a carotid arteriotomy or via a thoracotomy and apical insertion. Both of these techniques have disadvantages and are not conducive to repeated measurements. Therefore, the purpose of this study was to develop a new technique for measuring intracardiac hemodynamics.

Age-related changes in familial hypertrophic cardiomyopathy phenotype in transgenic mice and humans

Summaryβ-myosin heavy chain mutations are the most frequently identified basis for hypertrophic cardiomyopathy (HCM). A transgenic mouse model (αMHC403) has been extensively used to study various mechanistic aspects of HCM. There is general skepticism whether mouse and human disease features are similar. Herein we compare morphologic and functional characteristics, and disease evolution, in a transgenic mouse and a single family with a MHC mutation. Ten male αMHC403 transgenic mice (at t-5 weeks, −12 weeks, and −24 weeks) and 10 HCM patients from the same family with a β-myosin heavy chain mutation were enrolled. Morphometric, conventional echocardiographic, tissue Doppler and strain analytic characteristics of transgenic mice and HCM patients were assessed. Ten male transgenic mice (αMHC403) were examined at ages −5 weeks, −12 weeks, and −24 weeks. In the transgenic mice, aging was associated with a significant increase in septal (0.59±0.06 vs. 0.64±0.05 vs. 0.69±0.11 mm, P<0.01) and anterior wall thickness (0.58±0.1 vs. 0.62±0.07 vs. 0.80±0.16 mm, P<0.001), which was coincident with a significant decrease in circumferential strain (−22%±4% vs. −20%±3% vs. −19%±3%, P=0.03), global longitudinal strain (−19%±3% vs. −17%±2% vs. −16%±3%, P=0.001) and E/A ratio (1.9±0.3 vs. 1.7±0.3 vs. 1.4±0.3, P=0.01). The HCM patients were classified into 1st generation (n=6; mean age 53±6 years), and 2nd generation (n=4; mean age 32±8 years). Septal thickness (2.2±0.9 vs. 1.4±0.1 cm, P<0.05), left atrial (LA) volume (62±16 vs. 41±5 mL, P=0.03), E/A ratio (0.77±0.21 vs. 1.1±0.1, P=0.01), E/e’ ratio (25±10 vs. 12±2, P=0.03), global left ventricular (LV) strain (−14%±3% vs. −20%±3%, P=0.01) and global LV early diastolic strain rate (0.76±0.17 s−1vs. 1.3±0.2 s-1, P=0.01) were significantly worse in the older generation. In β-myosin heavy chain mutations, transgenic mice and humans have similar progression in morphologic and functional abnormalities. The αMHC403 transgenic mouse model closely recapitulates human disease.

Rest and Stress Longitudinal Systolic Left Ventricular Mechanics in Hypertrophic Cardiomyopathy: Implications for Prognostication

Background Exercise intolerance is the most common symptom in hypertrophic cardiomyopathy (HCM). We examined whether inability to augment myocardial mechanics during exercise would influence functional performance and clinical outcomes in HCM. Methods Ninety‐five HCM patients (32 nonobstructive, 32 labile‐obstructive, 31 obstructive) and 26 controls of similar age and gender distribution were recruited prospectively. They underwent rest and treadmill stress strain echocardiography, and 61 of them underwent magnetic resonance imaging. Mechanical reserve (MRES) was defined as percent change in systolic strain rate (SR) immediately postexercise. Results Global strain and SR were significantly lower in HCM patients at rest (strain: nonobstructive, −15.6 ± 3.0; labile‐obstructive, −15.9 ± 3.0; obstructive, −13.8 ± 2.9; control, −17.7% ± 2.1%, P < .001; SR: nonobstructive, −0.92 ± 0.20; labile−obstructive, −0.94 ± 0.17; obstructive, −0.85 ± 0.18; control, −1.04 ± 0.14 s−1, P = .002); and immediately postexercise (strain: nonobstructive, −15.6 ± 3.0; labile‐obstructive, −17.6 ± 3.6; obstructive, −15.6 ± 3.6; control, −19.2 ± 3.1%; P = .001; SR: nonobstructive, −1.41 ± 0.37; labile‐obstructive, −1.64 ± 0.38; obstructive, −1.32 ± 0.29; control, −1.82 ± 0.29 s−1, P < .001). MRES was lower in nonobstructive and obstructive compared with labile‐obstructive and controls (51% ± 29%, 54% ± 31%, 78% ± 38%, 77% ± 30%, P = .001, respectively). Postexercise SR and MRES were associated with exercise capacity (r = 0.47 and 0.42, P < .001 both, respectively). When adjusted for age, gender, body mass index, E/e’, and resting peak instantaneous systolic gradient, postexercise SR best predicted exercise capacity (r = 0.74, P = .003). Postexercise SR was correlated with extent of late gadolinium enhancement (r = 0.34, P = .03). By Cox regression, exercise SR and MRES predicted ventricular tachycardia/ventricular fibrillation (VT/VF) even after adjustment for age, gender, family history of sudden cardiac death, septum ≥ 3 cm and abnormal blood pressure response (P = .04 and P = .046, respectively). Conclusions Nonobstructive and obstructive patients have reduced MRES compared with labile‐obstructive and controls. Postexercise SR correlates with LGE and exercise capacity. Exercise SR and MRES predict VT/VF. HighlightsReduced tolerance in HCM may be related to abnormal mechanical response to exercise.Peak exercise strain rate and mechanical reserve correlated with exercise capacity.Peak exercise strain rate and mechanical reserve predicted ventricular arrhythmias.Labile HCM hemodynamics was associated with normal mechanical reserve.

Two-dimensional global longitudinal strain is superior to left ventricular ejection fraction in prediction of outcome in patients with left-sided infective endocarditis

BACKGROUND Impaired cardiac function is the main predictor of poor outcome in infective endocarditis (IE). Global longitudinal strain (GLS) derived from two-dimensional strain echocardiography has proven superior in prediction of long-term outcome as compared to left ventricular ejection fraction (LVEF) in valvular disease and heart failure in general. Whether measurements of cardiac deformation can predict survival in patients with IE has not previously been investigated. METHODS The study included consecutive patients with Duke definite IE who underwent transthoracic and transesophageal echocardiography within 7 days. Clinical and echocardiographic markers associated with 1-year survival were identified using a Cox-proportional hazards model that included propensity adjustment for surgery. Reclassification statistics including receiver operating characteristic curves and net reclassification improvement were applied to LVEF and GLS, respectively. RESULTS A cohort of 190 patients met eligibility criteria. LVEF and GLS were both prognostic markers of mortality. Independent markers of 1-year mortality were S. aureus IE (HR:2.02; 95%CI 1.11-5.72, p = .022), diabetes (HR:2.05; 95%CI 1.12-3.75, p = .020), embolic stroke (HR:3.95; 95%CI 1.93-8.10, p < .001) and LVEF<45% (HR: 3.02; 95% CI 1.70-5.38, p < .001), GLS> -15.4% (HR:2.95; 95%CI 1.52-5.72, p < .001). Adding LVEF<45% to a model with known risk factors of IE did not significantly improve risk classification, whereas addition of GLS to the model resulted in significant increase (AUC = 0.763, p < .001). CONCLUSIONS When treatment was taken into account, LVEF<45% and GLS > -15.4% were both associated with adverse long-term outcome in left-sided IE. GLS >-15.4 % was significantly associated with 1-year mortality in the multivariate analysis. Further, GLS was superior to LVEF in risk prediction and risk discrimination of long-term outcome in patients with left-sided IE.