Safety profile and utility of treadmill exercise in patients with high-gradient hypertrophic cardiomyopathy.

BACKGROUND: Exercise echocardiography in the evaluation of hypertrophic cardiomyopathy (HCM) provides valuable information for risk stratification, selection of optimal treatment, and prognostication. However, HCM patients with left ventricular outflow tract gradients ≥30mm Hg are often excluded from exercise testing because of safety considerations. We examined the safety and utility of exercise testing in patients with high-gradient HCM. METHODS: We evaluated clinical characteristics, hemodynamics, and imaging variables in 499 consecutive patients with HCM who performed 959 exercise tests. Patients were divided based on peak left ventricular outflow tract gradients using a 30-mm Hg threshold into the following: obstructive (n=152), labile-obstructive (n=178), and nonobstructive (n=169) groups. RESULTS: There were no deaths during exercise testing. We noted 20 complications (2.1% of tests) including 3 serious ventricular arrhythmias (0.3% of tests). There was no difference in complication rate between groups. Patients with obstructive HCM had a higher frequency of abnormal blood pressure response (obstructive: 53% vs labile: obstructive: 41% and nonobstructive: 37%; P=.008). Obstructive patients also displayed a lower work capacity (obstructive: 8.4±3.4 vs labile obstructive: 10.9±4.2 and nonobstructive: 10.2±4.0, metabolic equivalent; P<.001). Exercise testing provided incremental information regarding sudden cardiac death risk in 19% of patients with high-gradient HCM, and we found a poor correlation between patient-reported functional class and work capacity. CONCLUSION: Our results suggest that exercise testing in HCM is safe, and serious adverse events are rare. Although numbers are limited, exercise testing in high-gradient HCM appears to confer no significant additional safety hazard in our selected cohort and could potentially provide valuable information.

Structural and Functional Correlates of Myocardial T1 Mapping in 321 Patients With Hypertrophic Cardiomyopathy.

OBJECTIVE: The aim of this study was to evaluate the structural and functional correlates of T1 mapping in 321 patients with hypertrophic cardiomyopathy (HCM). METHODS: Three hundred twenty-one patients with HCM who underwent cardiac magnetic resonance from 2003 to 2013 were retrospectively identified from our institution's HCM registry. Left ventricular volume, function, late gadolinium enhancement (LGE), and Look-Locker T1 time were quantified. T1 time was normalized to blood pool to calculate T1 ratio. Correlations between LGE%, T1 ratio, and structural and functional features were performed using Pearson correlation coefficient. RESULTS: Late gadolinium enhancement showed stronger correlation with left ventricular mass index (r = 0.41, P < 0.001) compared with T1 ratio (r = -0.17, P = 0.004). Both LGE% and T1 ratio correlated with ejection fraction (r = -0.18 and P = 0.002 vs r = 0.21 and P < 0.001, respectively). E/e' showed correlation with LGE% but not with T1 ratio. CONCLUSIONS: Late gadolinium enhancement was more strongly correlated with the phenotypic expression of HCM compared with T1 ratio.

Apparent left ventricular cavity dilatation during PET/CT in hypertrophic cardiomyopathy: Clinical predictors and potential mechanisms.

BACKGROUND: Apparent left ventricular cavity dilatation (LVCD) in patients with hypertrophic cardiomyopathy (HCM) is an incompletely understood phenomenon. We aimed at investigating its clinical predictors and potential mechanisms. METHODS: Sixty one HCM patients underwent N-13-ammonia PET for visual evaluation of LVCD, transient ischemic dilatation (TID) index, myocardial blood flow (MBF), coronary flow reserve (CFR), and regional myocardial perfusion (rMP). TID index was also derived at 2-4 and 15-20 minutes. RESULTS: Visual LVCD and quantitative TID (>1.13 abnormal) agreement were excellent (k 0.91; P < .0001). LVCD-positive (n = 32) patients had greater LV thickness (2.26 ± 0.59 vs 1.92 ± 0.41 cm; P = .005), but lower stress MBF (1.66 ± 0.42 vs 2.07 ± 0.46 mL/minute/g; P < .0001), and CFR (1.90 ± 0.46 vs 2.46 ± 0.69; P < .0001) than LVCD-negative (n = 29) patients. Abnormal rMP was present in 31/32 LVCD-positive but only 12/29 (P < .0001) LVCD-negative. TID index was higher at 2-4 (1.30 ± 0.13) than at 15-20 minutes (1.27 ± 0.12; P = .001) in LVCD-positive, whereas it was the same (1.04 ± 0.07 vs 1.04 ± 0.07; P = .9) in LVCD-negative. In multivariate analysis, global peak MBF, abnormal rMP, and LV thickness were the best predictors of LVCD. CONCLUSION: Apparent LVCD is a common finding in HCM, intimately related to abnormal myocardial perfusion, globally impaired vasodilator flow reserve, and degree of hypertrophy. In addition to regional and/or diffuse subendocardial ischemia, some degree of true LV chamber dilatation may also contribute to the occurrence of apparent LVCD in HCM.

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.

Afterload-induced left ventricular diastolic dysfunction during myocardial ischaemia and reperfusion.

NEW FINDINGS: What is the central question of this study? While the load dependence of the diastolic function is established for the normal heart, little is known about the response of the acutely ischaemic and reperfused myocardium to alterations in afterload. What is the main finding and its importance? Using a model that simulates the clinical scenario of acute ischaemia-reperfusion, we show that increased afterload aggravates diastolic dysfunction during both acute ischaemia and reperfusion. In addition, increased afterload induces diastolic dyssynchrony, which might be the underlying mechanism of the diastolic dysfunction of the ischaemic myocardium. These findings provide us with new information regarding how better to manage patients who undergo revascularization therapy after acute myocardial infarction. The effects of changes in left ventricular (LV) afterload on diastolic function of acutely ischaemic and reperfused myocardium have not been studied in depth. We examined the following factors: (i) the consequences of increasing the LV afterload on LV diastolic function during acute ischaemia and reperfusion; (ii) whether the myocardial response to afterload elevation is stable throughout a 2 h reperfusion period; and (iii) the role of LV wall synchrony in the development of afterload-induced diastolic dysfunction. We instrumented 12 anaesthetized, open-chest pigs with Millar pressure catheters and piezoelectric crystals before ligating mid-left anterior descending coronary artery for 1 h, followed by reperfusion for 2 h. Six of the animals survived throughout the 2 h of reperfusion, and their data were used for comparisons across the different experimental phases. Left ventricular afterload was increased by inflating an intra-aortic balloon. Data were recorded at baseline, after 20 min of coronary occlusion and at 30 and 90 min of myocardial reperfusion. The increased afterload for 2 min lengthened the isovolumic relaxation during ischaemia and during early and late reperfusion but had no significant effect on isovolumic relaxation before coronary artery occlusion. Increasing the afterload aggravated LV diastolic dyssynchrony during coronary artery occlusion, but not during reperfusion. The afterload-induced prolongation of isovolumic relaxation was positively correlated with afterload-induced diastolic dyssynchrony. These observations indicate that, during myocardial ischaemia and throughout reperfusion, LV diastolic function is afterload dependent. Afterload-induced diastolic dyssynchrony might be an underlying mechanism of diastolic dysfunction during acute ischaemia.

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.

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

ß-myosin heavy chain mutations are the most frequently identified basis for hypertrophic cardiomyopathy (HCM). A transgenic mouse model (αMHC(403)) 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 αMHC(403) transgenic mice (at t-5 weeks, -12 weeks, and -24 weeks) and 10 HCM patients from the same family with a ß-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 (αMHC(403)) 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(-1) vs. 1.3±0.2 s-1, P=0.01) were significantly worse in the older generation. In ß-myosin heavy chain mutations, transgenic mice and humans have similar progression in morphologic and functional abnormalities. The αMHC(403) transgenic mouse model closely recapitulates human disease.

Electro-Mechanical Alterations in Atrial Fibrillation: Structural, Electrical, and Functional Correlates.

Atrial fibrillation is the most common arrhythmia encountered in clinical practice affecting both patients' survival and well-being. Apart from aging, many cardiovascular risk factors may cause structural remodeling of the atrial myocardium leading to atrial fibrillation development. Structural remodelling refers to the development of atrial fibrosis, as well as to alterations in atrial size and cellular ultrastructure. The latter includes myolysis, the development of glycogen accumulation, altered Connexin expression, subcellular changes, and sinus rhythm alterations. The structural remodeling of the atrial myocardium is commonly associated with the presence of interatrial block. On the other hand, prolongation of the interatrial conduction time is encountered when atrial pressure is acutely increased. Electrical correlates of conduction disturbances include alterations in P wave parameters, such as partial or advanced interatrial block, alterations in P wave axis, voltage, area, morphology, or abnormal electrophysiological characteristics, such as alterations in bipolar or unipolar voltage mapping, electrogram fractionation, endo-epicardial asynchrony of the atrial wall, or slower cardiac conduction velocity. Functional correlates of conduction disturbances may incorporate alterations in left atrial diameter, volume, or strain. Echocardiography or cardiac magnetic resonance imaging (MRI) is commonly used to assess these parameters. Finally, the echocardiography-derived total atrial conduction time (PA-TDI duration) may reflect both atrial electrical and structural alterations.

Prevalence and prognostic implications of hypertensive response to exercise in patients with hypertrophic cardiomyopathy.

Objective: Hypertensive response to exercise (HRE) is observed in patients with hypertrophic cardiomyopathy (HCM) with normal resting blood pressure (BP). However, the prevalence or prognostic implications of HRE in HCM remain unclear. Methods: In this study, normotensive HCM subjects were enrolled. HRE was defined as systolic BP > 210 mmHg in men or >190 mmHg in women, or diastolic BP > 90 mmHg, or an increase in diastolic BP > 10 mmHg during treadmill exercise. All participants were followed for subsequent development of hypertension, atrial fibrillation (AF), heart failure (HF), sustained ventricular tachycardia/fibrillation (VT/VF), and all-cause death. Six hundred and eighty HCM patients were screened. Results: 347 patients had baseline hypertension, and 333 patients were baseline normotensive. 132 (40%) of the 333 patients had HRE. HRE was associated with female sex, lower body mass index and milder left ventricular outflow tract obstruction. Exercise duration and metabolic equivalents were similar between patients with or without HRE, but the HRE group had higher peak heart rate (HR), better chronotropic response and more rapid HR recovery. Conversely, non-HRE patients were more likely to exhibit chronotropic incompetence and hypotensive response to exercise. After a mean follow-up of 3.4 years, patients with and without HRE had similar risks of progression to hypertension, AF, HF, sustained VT/VF or death. Conclusion: HRE is common in normotensive HCM patients during exercise. HRE did not carry higher risks of future hypertension or cardiovascular adverse outcomes. Conversely, the absence of HRE was associated with chronotropic incompetence and hypotensive response to exercise.

Clinical Outcomes in Patients With Nonobstructive, Labile, and Obstructive Hypertrophic Cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease characterized by varying degrees of left ventricular outflow tract obstruction. In a large cohort, we compare the outcomes among 3 different hemodynamic groups. METHODS AND RESULTS: We prospectively enrolled patients fulfilling standard diagnostic criteria for HCM from January 2005 to June 2015. Detailed phenotypic characterization, including peak left ventricular outflow tract pressure gradients at rest and after provocation, was measured by echocardiography. The primary outcome was a composite cardiovascular end point, which included new-onset atrial fibrillation, new sustained ventricular tachycardia/ventricular fibrillation, new or worsening heart failure, and death. The mean follow-up was 3.4±2.8 years. Among the 705 patients with HCM (mean age, 52±15 years; 62% men), 230 with obstructive HCM were older and had a higher body mass index and New York Heart Association class. The 214 patients with nonobstructive HCM were more likely to have a history of sustained ventricular tachycardia/ventricular fibrillation and implantable cardioverter defibrillator implantation. During follow-up, 121 patients experienced a composite cardiovascular end point. Atrial fibrillation occurred most frequently in the obstructive group. Patients with nonobstructive HCM had more frequent sustained ventricular tachycardia/ventricular fibrillation events. In multivariate analysis, obstructive (hazard ratio, 2.80; 95% confidence interval, 1.64-4.80) and nonobstructive (hazard ratio, 1.94; 95% confidence interval, 1.09-3.45) HCM were associated with more adverse events compared with labile HCM. CONCLUSIONS: Nonobstructive HCM carries notable morbidity, including a higher arrhythmic risk than the other HCM groups. Patients with labile HCM have a relatively benign clinical course. Our data suggest detailed sudden cardiac death risk stratification in nonobstructive HCM and monitoring with less aggressive management in labile HCM.

Expression of phosphorylated estrogen receptor beta is an independent negative prognostic factor for pancreatic ductal adenocarcinoma.

PURPOSE: The role of estrogen receptor beta (ER-ß) expression in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. Ligand-independent phosphorylation and activation of ER-ß may play a relevant role in the IL-6/STAT3 signaling pathway and, as a result, in tumor progression. Here, we examined the effect of ER-ß, phosphorylated ER-ß (pER-ß), STAT3, phosphorylated STAT3 (pSTAT3) and IL-6 expression on the overall and recurrence-free survival in a cohort of patients with resected PDAC. METHODS: We identified 175 patients who underwent pancreatic resection for PDAC. Tissue microarrays were constructed from the archival tumor specimens. These were stained with specific antibodies for the above molecules. The expression of the markers was then correlated with clinicopathological parameters and survival analysis was performed. RESULTS: High nuclear expression of ER-ß was found in 61.7% and pER-ß in 80.6% of the tumors. STAT3 was expressed in 54.3% of the tumor samples, pSTAT3 in 68% and IL-6 in 76.6%. The median overall survival for patients with low pER-ß expression was 29 months, whereas for patients with high pER-ß expression was 15.1 months (p = 0.016). Multivariate analysis revealed that pER-ß expression was an independent factor correlating with shorter overall survival (hazard ratio 1.9; p = 0.013) and disease-free survival (hazard ratio 1.9; p = 0.029). CONCLUSIONS: Expression of pER-ß constitutes an independent prognostic marker for PDAC and is correlated with poor prognosis. These data may help in identifying novel drug targets in PDAC and patients who could benefit from additional therapeutic regimens, including selective estrogen receptor modulators.

E/e' ratio and outcome prediction in hypertrophic cardiomyopathy: the influence of outflow tract obstruction.

Aims: Diastolic dysfunction is thought to be an important pathophysiologic component of hypertrophic cardiomyopathy (HCM). However, there are conflicting data on the potential value of the mitral E/e' ratio. We examined whether left ventricular outflow tract (LVOT) obstruction influences the value of E/e' in predicting outcomes in HCM. Methods and results: Patients who met diagnostic criteria for HCM were enrolled. Diastolic function was assessed with complete two-dimensional and Doppler echocardiography. A composite clinical outcome including new onset atrial fibrillation, sustained ventricular tachycardia/fibrillation, heart failure, transplantation, and death was examined over a mean follow-up period of 4.2 years. Among 604 patients, 206 patients had an E/e' level ≥20. Patients with higher septal E/e' level were older, with more severe NYHA class, and more severe LVOT obstruction. Higher E/e' was associated with worse event-free survival in non-obstructive group and total HCM cohort. In addition, E/e' and LVOT pressure gradient were highly correlated in non-obstructive and total HCM, but not in labile or obstructive group. During follow-up period, 95 patients underwent myectomy. Post-op E/e' correlated significantly with LVOT pressure gradient (R = 0.306, P = 0.004). In these patients, post-op E/e' was associated with worse event-free survival (log-rank P = 0.030). Conclusion: Assessment of E/e' is useful for risk stratification in HCM patients. Nevertheless, the predictive power is confounded by dynamic LVOT obstruction. Higher E/e' predicts worse clinical outcomes in non-obstructive HCM and in labile/obstructive after myectomy.

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.

Role of Global Longitudinal Strain in Predicting Outcomes in Hypertrophic Cardiomyopathy.

Global longitudinal strain (GLS) is a sensitive indicator of global left ventricular function particularly in those with normal ejection fraction. We examined the potential value of GLS in predicting outcomes in hypertrophic cardiomyopathy (HC). Conventional and strain echocardiography was performed in 400 patients with HC followed for a median 3.1 years (interquartile range 1.2 to 5.6). Peak systolic strain from 3 apical views was averaged to calculate GLS. Patients were divided based on a previously published cutoff value of -16%. Additionally, we identified 4 HC subgroups based on GLS: GLS ≤ -20%, -20% < GLS ≤ -16%, -16% < GLS ≤ -10%, and GLS > -10%. The primary end point was a composite of new-onset sustained ventricular tachycardia/fibrillation, heart failure, cardiac transplantation, and all-cause death. Patients with GLS > -16% had significantly more events (17% vs 7%, p = 0.002). In the 4-group analysis, event rates increased with worsening GLS (5%, 7%, 14%, and 33%, respectively, p = 0.001). Event-free survival was significantly superior in those with GLS ≤ -16% versus GLS > -16% (p = 0.004); similarly, GLS > -10% portended a significantly worse event-free survival compared with each of the other 3 groups (p <0.01 for all pairwise comparisons). By univariate and multivariate Cox regression analysis, GLS remained significantly associated with the composite end point. GLS > -10% had 4 times the risk of events compared with GLS ≤ -16% (p = 0.006). In conclusion, echo-based GLS is independently associated with outcomes in HC. Patients with GLS > -10% have significantly higher event rates.

Myocardial oxidative stress correlates with left ventricular dysfunction on strain echocardiography in a rodent model of sepsis.

BACKGROUND: Recognition of cardiomyopathy in sepsis can be challenging due to the limitations of conventional measures such as ejection fraction (EF) and fractional shortening (FS) in the context of variable preload and afterload conditions. This study correlates myocardial function using strain echocardiography (SE) with cardiomyocyte oxidative stress in a murine model of sepsis. METHODS: C57BL/6J mice were randomized into control (n = 10), sham (n = 25), and a cecal ligation and puncture (CLP) (n = 33) model of sepsis. Echocardiography was performed pre-, 12, 24, and 48 h post-injury. Cardiac pro-inflammatory cytokines and mitochondrial redox scavenger expression were evaluated in a subset of each arm. To evaluate the influence of redox scavenger upregulation on oxidative injury and cardiac function, CLP was performed on mitochondrial catalase-upregulated C57BL/6J MCAT+/+ mice (n = 12) and wild-type (WT) animals for comparison. RESULTS: Septic C57BL/6J mice exhibited depressed longitudinal strain (LS) when compared to sham and control at 24 h (p < 0.01) and 48 h (p = 0.04) post-CLP despite having a preserved EF. Furthermore, there was a significant association between increased odds of mortality and depressed LS (OR = 1.23, p = 0.04). Septic C57BL/6J mice concomitantly demonstrated increased expression of cardiomyocyte pro-inflammatory cytokines and decreased expression of redox scavengers at 24 and 48 h. When comparing C57Bl/6 MCAT +/+ mice and C57BL/6J WT mice, a significant decrease in LS was identified in the WT mice at 24 h (MCAT = -23 ± 5% vs. WT = -15 ± 4% p < 0.01) and 48 h (MCAT = -23 ± 7% vs. WT = -15 ± 4.3% p = 0.04) post-CLP which correlated with significant increase in the level of cardiac oxidative stress following CLP. CONCLUSIONS: In this sepsis model, SE identified cardiomyopathy despite normal EF. SE depression temporally coincides with upregulation of inflammatory cytokines and decreases expression of key mitochondrial ROS scavengers. Upregulation of redox scavenger (CAT) abrogates oxidative stress and cardiac dysfunction in this sepsis model.

Impact of peak provoked left ventricular outflow tract gradients on clinical outcomes in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is traditionally classified based on a left ventricular outflow tract (LVOT) pressure gradient of 30mmHg at rest or with provocation. There are no data on whether 30mmHg is the most informative cut-off value and whether provoked gradients offer any information regarding outcomes. METHODS: Resting and provoked peak LVOT pressure gradients were measured by Doppler echocardiography in patients fulfilling guidelines criteria for HCM. A composite clinical outcome including new onset atrial fibrillation, ventricular tachycardia/fibrillation, heart failure, transplantation, and death was examined over a median follow-up period of 2.1years. RESULTS: Among 536 patients, 131 patients had resting LVOT gradients greater than 30mmHg. Subjects with higher resting gradients were older with more cardiovascular events. For provoked gradients, a bi-modal risk distribution was found. Patients with provoked gradients >90mmHg (HR 3.92, 95% CI 1.97-7.79) or <30mmHg (HR 2.15, 95% CI 1.08-4.29) have more events compared to those with gradients between 30 and 89mmHg in multivariable analysis. The introduction of two cut-off points for provoked gradients allowed HCM to be reclassified into four groups: patients with "benign" latent HCM (provoked gradient 30-89mmHg) had the best prognosis, whereas those with persistent obstructive HCM had the worst outcome. CONCLUSIONS: Provoked LVOT pressure gradients offer additional information regarding clinical outcomes in HCM. Applying cut-off points at 30 and 90mmHg to provoked LVOT pressure gradients further classifies HCM patients into low-, intermediate- and high-risk groups.

Diffuse interstitial fibrosis assessed by cardiac magnetic resonance is associated with dispersion of ventricular repolarization in patients with hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by myocyte hypertrophy, disarray, fibrosis, and increased risk for ventricular arrhythmias. Increased QT dispersion has been reported in patients with HCM, but the underlying mechanisms have not been completely elucidated. In this study, we examined the relationship between diffuse interstitial fibrosis, replacement fibrosis, QTc dispersion and ventricular arrhythmias in patients with HCM. We hypothesized that fibrosis would slow impulse propagation and increase dispersion of ventricular repolarization, resulting in increased QTc dispersion on surface electrocardiogram (ECG) and ventricular arrhythmias. METHODS: ECG and cardiac magnetic resonance (CMR) image analyses were performed retrospectively in 112 patients with a clinical diagnosis of HCM. Replacement fibrosis was assessed by measuring late gadolinium (Gd) enhancement (LGE), using a semi-automated threshold technique. Diffuse interstitial fibrosis was assessed by measuring T1 relaxation times after Gd administration, using the Look-Locker sequence. QTc dispersion was measured digitally in the septal/anterior (V1-V4), inferior (II, III, and aVF), and lateral (I, aVL, V5, and V6) lead groups on surface ECG. RESULTS: All patients had evidence of asymmetric septal hypertrophy. LGE was evident in 70 (63%) patients; the median T1 relaxation time was 411±38 ms. An inverse correlation was observed between T1 relaxation time and QTc dispersion in leads V1-V4 (p<0.001). Patients with HCM who developed sustained ventricular tachycardia had slightly higher probability of increased QTc dispersion in leads V1-V4 (odds ratio, 1.011 [1.004-1.0178, p=0.003). We found no correlation between presence and percentage of LGE and QTc dispersion. CONCLUSION: Diffuse interstitial fibrosis is associated with increased dispersion of ventricular repolarization in leads, reflecting electrical activity in the hypertrophied septum. Interstitial fibrosis combined with ion channel/gap junction remodeling in the septum could lead to inhomogeneity of ventricular refractoriness, resulting in increased QTc dispersion in leads V1-V4.

Effect of Elevated Reperfusion Pressure on "No Reflow" Area and Infarct Size in a Porcine Model of Ischemia-Reperfusion.

BACKGROUND: The "no reflow" phenomenon (microvascular obstruction despite restoration of epicardial blood flow) develops postreperfusion in acute myocardial infarction and is associated with poor prognosis. We hypothesized that increased reperfusion pressure may attenuate the no reflow phenomenon, as it could provide adequate flow to overcome the high resistance of the microvasculature within the no reflow zone. Thus, we investigated the effect of modestly elevated blood pressure during reperfusion on the extent of no reflow area and infarct size in a porcine model of ischemia-reperfusion. METHODS: Eighteen farm pigs underwent acute myocardial infarction by occlusion of the anterior descending coronary artery for 1 hour, followed by 2 hours of reperfusion. Just prior to reperfusion, animals were randomized into 2 groups: in group 1 (control group, n = 9), no intervention was performed. In group 2 (n = 9), aortic pressure was increased by ∼20% (compared to ischemia) by partial clamping of the ascending aorta during reperfusion. Following 2 hours of reperfusion, animals were euthanized to measure area at risk, infarct size, and area of no reflow. RESULTS: Partial clamping of the ascending aorta resulted in modest elevation of blood pressure during reperfusion. The area at risk did not differ between the 2 groups. The no reflow area was significantly increased in group 2 compared to control animals (50% ± 13% vs 37% ± 9% of the area at risk; P = .04). The infarcted area was significantly increased in group 2 compared to control animals (75% ± 17% vs 52% ± 23% of the area at risk; P = .03). Significant positive correlations were observed between systolic aortic pressure and no reflow area, between systolic aortic pressure and infarcted area and between infarcted area and no reflow area during reperfusion. CONCLUSIONS: Modestly elevated blood pressure during reperfusion is associated with an increase in no reflow area and in infarct size in a clinically relevant porcine model of ischemia-reperfusion.

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.