Our results suggest that the N47K and R58Q mutations may act through similar mechanisms, leading to compensatory hypertrophy of the functionally compromised myocardium, but the malignant R58Q phenotype is most likely associated with more severe alterations in cardiac performance manifested as impaired relaxation and global diastolic dysfunction. At the molecular level, we suggest that by reducing the phosphorylation of RLC, the R58Q mutation decreases the kinetics of myosin cross-bridges, leading to an increased myofilament calcium sensitivity and to overall changes in intracellular Ca(2+) homeostasis.

ObjectiveThis study was designed to examine the utility of two-dimensional strain (2DS) or speckle tracking imaging to typify functional adaptations of the left ventricle in variant forms of left ventricular hypertrophy (LVH).DesignCross-sectional study.SettingUrban tertiary care academic medical centres.ParticipantsA total of 129 subjects, 56 with hypertrophic cardiomyopathy (HCM), 34 with hypertensive left ventricular hypertrophy (H-LVH), 27 professional athletes with LVH (AT-LVH) and 12 healthy controls in sinus rhythm with preserved left ventricular systolic function.MethodsConventional echocardiographic and tissue Doppler examinations were performed in all study subjects. Bi-dimensional acquisitions were analysed to map longitudinal systolic strain (automated function imaging, AFI, GE Healthcare, Waukesha, Wisconsin, USA) from apical views.ResultsSubjects with HCM had significantly lower regional and average global peak longitudinal systolic strain (GLS-avg) compared with controls and other forms of LVH. Strain dispersion index, a measure of regional contractile heterogeneity, was higher in HCM compared with the rest of the groups. On receiver operator characteristics analysis, GLS-avg had excellent discriminatory ability to distinguish HCM from H-LVH area under curve (AUC) (0.893, p<0.001) or AT-LVH AUC (0.920, p<0.001). Tissue Doppler and LV morphological parameters were better suited to differentiate the athlete heart from HCM.Conclusions2DS (AFI) allows rapid characterisation of regional and global systolic function and may have the potential to differentiate HCM from variant forms of LVH.

A lethal and extensively characterized familial form of hypertrophic cardiomyopathy (HC) is due to a point mutation (Arg403Gln) in the cardiac β-myosin heavy-chain (MHC) gene. Although this is associated with abnormal energy metabolism and progression to heart failure in an animal model, in vivo cardiac energetic shave not been characterized in patients with this mutation. Noninvasive phosphorus saturation transfer magnetic resonance spectroscopy was used to measure the adenosine triphosphate (ATP)supplied by the creatine kinase (CK) reaction and phosphocreatine (PCr), the heart’s primary energy reserve, in 9 of 10 patients from a single kindred with HC caused by Arg403GIn mutation, and 17 age-matched healthy controls. Systolic and diastolic function was assessed by echocardiography in all 10 HC patients. HC patients had impairment of diastolic function as well as mild systolic dysfunction, when assessed using global systolic longitudinal strain. Myocardial [PCr] was significantly decreased by 24% in patients (7.1±2.3μmol/g) compared to controls (9.4±1.2μmol/g; p=0.003). The pseudo-first-order CK rate-constant was 26% lower (0.28±0.15 vs. 0.38±0.07s−1, p=0.035) and the forward CK flux was 44% lower (2.0±1.4 vs3.6±0.9 μmol/g/s, p=0.001) than controls. The contractile abnormalities did not correlate with metabolic indices. In conclusion, myocardial PCr and CK ATP delivery are significantly reduced in patients with HC due to Arg403Gln mutation, akin to prior results from mice with the same mutation. Lack of a relation between energetic and contractile abnormalities suggests the former are due to the sarcomeric mutation and not a late consequence of mechanical dysfunction.

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Background Presence of delayed enhancement (DE) on magnetic resonance (CMR) is associated with worse clinical outcomes in hypertrophic cardiomyopathy (HCM). We investigated the relationship between DE on CMR, and myocardial ischemia in HCM. Methods and Results HCM patients (n=47) underwent CMR for assessment of DE and vasodilator stress ammonia positron emission tomography (PET) to quantify myocardial blood flow (MBF) and coronary flow reserve (CFR). The summed difference score (SDS) for regional myocardial perfusion (rMP) was also assessed. Patients in the DE-group (n=35) had greater LV wall thickness (2.09 ± 0.44 vs. 1.78 ± 0.34 cm; P 0.03). Stress MBF (2.25 ± 0.46 vs. 1.78 ± 0.43 ml/min/g, P = 0.01), and CFR (2.78 ± 0.32 vs. 2.01 ± 0.52, P < 0.001) were significantly lower in DE-positive patients. SDS (7.3 ± 6.6 vs. 0.9 ± 1.4, P < 0.0001) was significantly higher in patients with DE. A CFR < 2.00 was seen in 18 patients (51%) with DE, but in none of the DE-negative patients (P <0.0001). CMR and PET showed visually concordant DE and rMP abnormalities in 31 patients and absence of DE and perfusion defects in 9 patients. Four DE-positive patients demonstrated normal rMP, and 3 DE-negative patients had (apical) rMP abnormalities. Conclusions We found a close relationship between DE by CMR and microvascular function in the majority of the patients studied. However, a small proportion of patients had DE in the absence of perfusion abnormalities, suggesting that microvascular dysfunction and ischemia are not the sole causes of DE in HCM patients.

Obesity is independently associated with left ventricular (LV) hypertrophy and thus may be an important modifier of the hypertrophic cardiomyopathy (HC) phenotype. We examined if obesity modifies the clinical presentation, LV morphology, outflow hemodynamics and exercise tolerance in HC. In this cross-sectional study, 88 obese (body mass index, BMI≥30 kg/m2) and 154 non-obese (BMI<30 kg/m2) patients from the Johns Hopkins HC clinic were compared with respect to a variety of clinical and LV echocardiographic measurements. Obese patients (36.4%) were more likely to report exertional dyspnea (p=0.04) and chest pain (p=0.002), and had higher prevalence of hypertension (p=0.008). LV posterior wall thickness (p=0.01) but not the septal wall (p≥0.21) was significantly higher in obese patients, resulting in an increased LV mass index (p=0.003). No significant differences in LV systolic and diastolic function were observed, but obesity was associated with higher LV stroke volume (p=0.03), inducible LV outflow tract gradients (p=0.045) and chance of developing LV outflow tract obstruction during stress (p=0.035). In multivariate analysis, BMI was associated with increased posterior (but not septal) wall thickness (β=0.15, p=0.02) and LV mass index (β=0.18, p=0.005), particularly in those with hypertension. Obesity was also associated with reduced exercise time and functional capacity, and BMI independently correlated with reduced exercise tolerance. In conclusion, obesity is associated with larger LV mass, worse symptoms, lower exercise tolerance and labile obstructive hemodynamics in HC. The association with increased outflow tract gradients has particular importance as contribution of obesity to the pressure gradients may influence clinical decisions in labile obstructive HC.

Background Cardiosphere-derived cell (CDC) transplantation can improve global left ventricle ejection fraction (LVEF) post-infarction (MI). Here, we examined the effects of CDC transplantation on regional function and dyssynchrony post-MI. Methods Two million rat CDCs(n=7) or saline(PBS;n=7) were injected into the infarct region of WK rats. Infarct size and CDC localization were evaluated by positron emission tomography (PET; n=7). Two dimensional and strain echocardiography were performed at 1&4 weeks post-MI. LVEF, circumferential strain and time to peak circumferential strain were measured in the basal and apical short axis views. Dyssynchrony was defined as max difference of time to peak circumferential strain of opposing segments in each short axis view. Engraftment was measured by quantitative polymerase chain reaction(PCR). Results PET revealed that infarct size was 15.4 ±3.6% of the LV and CDCs were localized to the infarct and border-zone. CDC transplantation improved LVEF (45±8 to 52±7%,p=0.02), mean circumferential strain (−7±2 to −10±1%,p=0.02) and dyssynchrony (45±10 to 28±11ms,p=0.04) of the infarct/peri-infarct zone from 1 to 4weeks post-MI, despite CDC engraftment of only 2.4±3%. In contrast, LVEF (48±5 to 40±4%,p=0.03) and mean circumferential strain (−8±2 to −7±1%, p=0.02) of the infarcted region deteriorated, with no significant change in dyssynchrony (42±12 vs. 46±13ms,p=0.6) in the PBS group during the same time period. Change in LVEF correlated with change in circumferential strain (r=−0.8,p=0.002) and dyssynchrony (r=0.6,p=0.02) of the infarct/peri-infarct region at 4weeks post-MI. Conclusion CDC therapy enhanced LVEF by improving circumferential strain and decreasing dyssynchrony of the infarct/peri-infarct region at 4 weeks, but not 1 week post-MI. Cellular resynchronization therapy (CRT) using CDCs may be an alternative to traditional electrical CRT in post-MI dyssynchrony.

Non-obstructive hypertrophic cardiomyopathy (HC) patients are considered low-risk, generally not requiring aggressive intervention. However, non- and labile-obstructive HC have been traditionally classified together and it is unknown if these 2 sub-groups have distinct risk profiles. We compared cardiovascular outcomes in 293 HC patients (96 non-obstructive, 114 labile-obstructive and 83 obstructive) referred for exercise echocardiography and magnetic resonance imaging and followed for 3.3±3.6 years. A sub-group (34 non-obstructive, 28 labile-obstructive, 21 obstructive) underwent positron emission tomography (PET). The mean number of sudden cardiac death risk factors was similar among groups (non-obstructive: 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 LGE≥20% of myocardial mass [23(30%) vs. 19(18%) labile-obstructive and 8(11%) obstructive, p=0.01]. Fewer labile-obstructive patients had regional PET perfusion abnormalities [12(46%) vs. non-obstructive 30(81%) and obstructive 17(85%), p=0.003]. During follow-up, 60 events were recorded (36 VT/VF, including 30 defibrillator discharges, 12 heart failure worsening and 2 deaths). Non-obstructive patients were at higher risk of VT/VF at follow-up, when compared to labile-obstructive (HR 0.18, 95%CI 0.04–0.84, 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≥3cm (p=0.04). Appropriate defibrillator discharges were more frequent in non-obstructive [8(18%)] compared to labile-obstructive [0(0%), p=0.02] patients. In conclusion, non-obstructive hemodynamics is associated with more pronounced fibrosis and ischemia than labile-obstructive and is an independent predictor of VT/VF in HC.