Iraklis Pozios

Relationship of Delayed Enhancement by Magnetic Resonance to Myocardial Perfusion by Positron Emission Tomography in Hypertrophic Cardiomyopathy

Background— Presence of delayed enhancement (DE) on cardiac magnetic resonance (CMR) is associated with worse clinical outcomes in hypertrophic cardiomyopathy. We investigated the relationship between DE on CMR and myocardial ischemia in hypertrophic cardiomyopathy. Methods and Results— Hypertrophic cardiomyopathy patients (n=47) underwent CMR for assessment of DE and vasodilator stress ammonia positron emission tomography to quantify myocardial blood flow and coronary flow reserve. The summed difference score for regional myocardial perfusion was also assessed. Patients in the DE group (n=35) had greater left ventricular wall thickness (2.09±0.44 versus 1.78±0.34 cm; P=0.03). Stress myocardial blood flow (2.25±0.46 versus 1.78±0.43 mL/min per gram; P=0.01) and coronary flow reserve (2.78±0.32 versus 2.01±0.52; P<0.001) were significantly lower in DE-positive patients. Summed difference score (median, 5 versus 0; P<0.0001) was significantly higher in patients with DE. A coronary flow reserve <2.00 was seen in 18 patients (51%) with DE but in none of the DE-negative patients (P<0.0001). CMR and positron emission tomography showed visually concordant DE and regional myocardial perfusion abnormalities in 31 patients and absence of DE and perfusion defects in 9 patients. Four DE-positive patients demonstrated normal regional myocardial perfusion, and 3 DE-negative patients had (apical) regional myocardial perfusion abnormalities. Conclusions— We found a close relationship between DE by CMR and microvascular function in most 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 hypertrophic cardiomyopathy patients.

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.

Comparison and effectiveness of regadenoson versus dipyridamole on stress electrocardiographic changes during positron emission tomography evaluation of patients with hypertrophic cardiomyopathy

Dipyridamole is the most common vasodilator used with positron emission tomography for the evaluation of patients with hypertrophic cardiomyopathy (HC). The aim of this study was to evaluate whether positron emission tomographic quantification of regional myocardial perfusion (rMP), myocardial blood flow (MBF), and coronary flow reserve are comparable between dipyridamole and the newer vasodilator regadenoson in HC. An additional aim was to evaluate the association between vasodilator-induced ST-segment depression on electrocardiography and myocardial flow in HC. Nitrogen-13 ammonia positron emission tomography was performed in 57 patients with symptomatic HC at rest and during vasodilator stress (peak) with either dipyridamole (0.56 mg/kg during 4-minute infusion) or regadenoson (0.4 mg fixed bolus dose) for assessment of electrocardiographic findings, rMP (17-segment American Heart Association summed difference score), MBF, and coronary flow reserve. The dipyridamole and regadenoson groups consisted of 28 and 29 patients respectively. Baseline characteristics, including rest MBF (0.92 ± 0.22 vs 0.89 ± 0.23 ml/min/g, p = 0.60), were similar between the 2 groups. During stress, the presence and severity of abnormal rMP (summed difference score 5.5 ± 5.5 vs 5.8 ± 6.7, p = 0.80), peak MBF (1.81 ± 0.44 vs 1.82 ± 0.50 ml/min/g, p = 0.90), and coronary flow reserve (2.02 ± 0.53 vs 2.12 ± 0.12, p = 0.50) were comparable between the dipyridamole and regadenoson groups. Fewer patients exhibited side effects with regadenoson (2 vs 7, p = 0.06). Vasodilator-induced ST-segment depression showed high specificity (about 92%) but low sensitivity (about 34%) to predict abnormal rMP (summed difference score ≥2). In conclusion, measurement of rMP and quantitative flow with positron emission tomography is similar between regadenoson and dipyridamole in patients with symptomatic HC. Regadenoson is tolerated better than dipyridamole and is easier to administer. Vasodilator-induced ST-segment depression is a specific but nonsensitive marker for the prediction of abnormal rMP in patients with 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.

Strain Echocardiography Parameters Correlate With Disease Severity in Children and Infants With Sepsis.

Objectives: In the progression of severe sepsis, sepsis-induced myocardial dysfunction contributes to severity of illness and ultimate mortality. Identification of sepsis-induced myocardial dysfunction causing depressed cardiac function during critical illness has implications for ongoing patient management. However, assessing pediatric cardiac function traditionally relies on echocardiographic qualitative assessment and measurement of left ventricular ejection fraction or fractional shortening. These metrics are often insensitive for detecting early or regional myocardial dysfunction. Strain echocardiography is a contemporary echocardiographic modality that may be more sensitive to perturbations in cardiac function. This investigation hypothesizes that strain echocardiography metrics correlate with severity of illness in pediatric sepsis despite normal fractional shortening. Design: Single-center retrospective observational study. Setting: Tertiary 36-bed medical/surgical PICU. Patients: Pediatric patients admitted with sepsis. Interventions: None. Measurements and Main Results: Twenty-three children with sepsis received an echocardiogram in the study period. Patients with sepsis demonstrated abnormal peak systolic longitudinal strain for age (mean = –0.13 ± 0.07; p < 0.01) and low normal peak systolic circumferential strain (mean = –0.17 ± 0.14; p = 0.02) compared with internal controls as well as previously published normal values. Depressed strain was demonstrated in the septic patients despite having normal fractional shortening (mean = 0.41; 95% CI, 0.38–0.43). On initial echocardiographic imaging, worsening peak systolic longitudinal strain was associated with increasing lactate (p = 0.04). Conclusions: Pediatric patients with sepsis demonstrate evidence of depressed strain echocardiography parameters not shown by fractional shortening that correlate with clinical indices of sepsis severity. Whether strain echocardiography could eventually assist in grading pediatric sepsis severity and affect management is an area for potential future investigation.

Distinguishing ventricular septal bulge versus hypertrophic cardiomyopathy in the elderly

The burgeoning evidence of patients diagnosed with sigmoidal hypertrophic cardiomyopathy (HCM) later in life has revived the quest for distinctive features that may help discriminate it from more benign forms of isolated septal hypertrophy often labelled ventricular septal bulge (VSB). HCM is diagnosed less frequently than VSB at older ages, with a reversed female predominance. Most patients diagnosed with HCM at older ages suffer from hypertension, similar to those with VSB. A positive family history of HCM and/or sudden cardiac death and the presence of exertional symptoms usually support HCM, though they are less likely in older patients with HCM, and poorly investigated in individuals with VSB. A more severe hypertrophy and the presence of left ventricular outflow obstruction are considered diagnostic of HCM, though stress echocardiography has not been consistently used in VSB. Mitral annulus calcification is very prevalent in both conditions, whereas a restrictive filling pattern is found in a minority of older patients with HCM. Genetic testing has low applicability in this differential diagnosis at the current time, given that a causative mutation is found in less than 10% of elderly patients with suspected HCM. Emerging imaging modalities that allow non-invasive detection of myocardial fibrosis and disarray may help, but have not been fully investigated. Nonetheless, there remains a considerable morphological overlap between the two conditions. Comprehensive studies, particularly imaging based, are warranted to offer a more evidence-based approach to elderly patients with focal septal thickening.

Pacemaker-induced transient asynchrony suppresses heart failure progression.

Transient asynchrony induced by an implanted pacemaker improves pathobiology of heart failure in large animals. Disruptive technology Healthy and the majority of failing hearts beat synchronously. However, some hearts contract with poor coordination and if they are weak, this worsens clinical outcomes. Pacemakers used to reset a heart’s rhythm can also change the synchrony of contraction, making it better or worse, and current therapy called resynchronization makes it better. Perhaps counterintuitively, Kirk et al. demonstrate that using a pacemaker to purposely induce dyssynchrony—but only for part of each day—makes the synchronous failing heart better. In their process, pacemaker-induced transient asynchrony (PITA), the heart’s right ventricle is paced to induce a 6-hour period of dyssynchrony each day, followed by atrial pacing to resynchronize the heart for the remaining 18 hours. In dogs with heart failure, PITA halted chamber dilation and negative remodeling of the heart tissue, improved cellular signaling and force generation, and resulted in normal muscle fiber structure and function, similar to healthy controls. PITA may help the majority of patients with heart failure who have synchronous contraction and thus are not treated with standard resynchronization pacemakers. Uncoordinated contraction from electromechanical delay worsens heart failure pathophysiology and prognosis, but restoring coordination with biventricular pacing, known as cardiac resynchronization therapy (CRT), improves both. However, not every patient qualifies for CRT. We show that heart failure with synchronous contraction is improved by inducing dyssynchrony for 6 hours daily by right ventricular pacing using an intracardiac pacing device, in a process we call pacemaker-induced transient asynchrony (PITA). In dogs with heart failure induced by 6 weeks of atrial tachypacing, PITA (starting on week 3) suppressed progressive cardiac dilation as well as chamber and myocyte dysfunction. PITA enhanced β-adrenergic responsiveness in vivo and normalized it in myocytes. Myofilament calcium response declined in dogs with synchronous heart failure, which was accompanied by sarcomere disarray and generation of myofibers with severely reduced function, and these changes were absent in PITA-treated hearts. The benefits of PITA were not replicated when the same number of right ventricular paced beats was randomly distributed throughout the day, indicating that continuity of dyssynchrony exposure is necessary to trigger the beneficial biological response upon resynchronization. These results suggest that PITA could bring the benefits of CRT to the many heart failure patients with synchronous contraction who are not CRT candidates.

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.

Neuroticism personality trait is associated with Quality of Life in patients with Chronic Heart Failure

AIM To evaluate Quality of life (QoL) in chronic heart failure (CHF) in relation to Neuroticism personality trait and CHF severity. METHODS Thirty six consecutive, outpatients with Chronic Heart Failure (6 females and 30 males, mean age: 54 ± 12 years), with a left ventricular ejection fraction ≤ 45% at optimal medical treatment at the time of inclusion, were asked to answer the Kansas City Cardiomyopathy Questionnaire (KCCQ) for Quality of Life assessment and the NEO Five-Factor Personality Inventory for personality assessment. All patients underwent a symptom limited cardiopulmonary exercise testing on a cycle-ergometer, in order to access CHF severity. A multivariate linear regression analysis using simultaneous entry of predictors was performed to examine which of the CHF variables and of the personality variables were correlated independently to QoL scores in the two summary scales of the KCCQ, namely the Overall Summary Scale and the Clinical Summary Scale. RESULTS The Neuroticism personality trait score had a significant inverse correlation with the Clinical Summary Score and Overall Summary Score of the KCCQ (r = -0.621, P < 0.05 and r = -0.543, P < 0.001, respectively). KCCQ summary scales did not show significant correlations with the personality traits of Extraversion, Openness, Conscientiousness and Agreeableness. Multivariate linear regression analysis using simultaneous entry of predictors was also conducted to determine the best linear combination of statistically significant univariate predictors such as Neuroticism, VE/VCO2 slope and VO2 peak, for predicting KCCQ Clinical Summary Score. The results show Neuroticism (β = -0.37, P < 0.05), VE/VCO2 slope (β = -0.31, P < 0.05) and VO2 peak (β = 0.37, P < 0.05) to be independent predictors of QoL. In multivariate regression analysis Neuroticism (b = -0.37, P < 0.05), the slope of ventilatory equivalent for carbon dioxide output during exercise, (VE/VCO2 slope) (b = -0.31, P < 0.05) and peak oxygen uptake (VO2 peak), (b = 0.37, P < 0.05) were independent predictors of QoL (adjusted R2 = 0.64; F = 18.89, P < 0.001). CONCLUSION Neuroticism is independently associated with QoL in CHF. QoL in CHF is not only determined by disease severity but also by the Neuroticism personality trait.

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.