Left Ventricular Chamber Size Research Articles

Pediatric Hypertrophic Cardiomyopathy: Survival and Prognostic Indicators in the Current Era

Purpose Our objective was to provide a contemporary analysis of a pediatric hypertrophic cardiomyopathy (HCM) cohort and determine risk factors independently associated with death or heart transplantation. Methods A retrospective review of patients aged 0-18 years who were diagnosed with HCM at our tertiary-level institution between January 1, 2001 and July 1, 2017 was conducted. Survival analysis using Cox proportional hazard models was used to identify risk factors associated with a combined primary end-point of death or transplantation. Results Of 177 patients with HCM, 120 (68%) were males and 101 (57%) had genetic or familial HCM. The median age at diagnosis was 6.3 years (IQR 0.3-12.8) and at follow-up was 13.1 years (IQR 4.3-17.3). Left ventricular (LV) outflow tract obstruction was observed in 65 patients (37%), cardiac surgery was performed in 21 (12%) after diagnosis, and 20 (11%) received an implantable cardioverter defibrillator (ICD). There were 18 (10%) deaths and 5 (3%) transplants with an overall 10-year transplant-free survival of 81% (95% CI 77-85%). Independent risk factors for death or transplantation included chromosomal abnormalities, smaller baseline LV end-diastolic dimension (EDD), and presenting with Stage C or D heart failure on diagnosis (Table 1). Conclusion Pediatric HCM patients have a relatively high rate of interventions as well as death and/or transplantation. Risk factors for death or transplantation include chromosomal abnormalities, a small LV chamber size, and advanced heart failure on initial presentation. Our objective was to provide a contemporary analysis of a pediatric hypertrophic cardiomyopathy (HCM) cohort and determine risk factors independently associated with death or heart transplantation. A retrospective review of patients aged 0-18 years who were diagnosed with HCM at our tertiary-level institution between January 1, 2001 and July 1, 2017 was conducted. Survival analysis using Cox proportional hazard models was used to identify risk factors associated with a combined primary end-point of death or transplantation. Of 177 patients with HCM, 120 (68%) were males and 101 (57%) had genetic or familial HCM. The median age at diagnosis was 6.3 years (IQR 0.3-12.8) and at follow-up was 13.1 years (IQR 4.3-17.3). Left ventricular (LV) outflow tract obstruction was observed in 65 patients (37%), cardiac surgery was performed in 21 (12%) after diagnosis, and 20 (11%) received an implantable cardioverter defibrillator (ICD). There were 18 (10%) deaths and 5 (3%) transplants with an overall 10-year transplant-free survival of 81% (95% CI 77-85%). Independent risk factors for death or transplantation included chromosomal abnormalities, smaller baseline LV end-diastolic dimension (EDD), and presenting with Stage C or D heart failure on diagnosis (Table 1). Pediatric HCM patients have a relatively high rate of interventions as well as death and/or transplantation. Risk factors for death or transplantation include chromosomal abnormalities, a small LV chamber size, and advanced heart failure on initial presentation.

Cardiac remodeling in aortic and mitral valve disease: a simulation study with clinical validation.

Remodeling is an important long-term determinant of cardiac function throughout the progression of heart disease. Numerous biomolecular pathways for mechanosensing and transduction are involved. However, we hypothesize that biomechanical factors alone can explain changes in myocardial volume and chamber size in valve disease. A validated model of the human vasculature and the four cardiac chambers was used to simulate aortic stenosis, mitral regurgitation, and aortic regurgitation. Remodeling was simulated with adaptive feedback preserving myocardial fiber stress and wall shear stress in all four cardiac chambers. Briefly, the model used myocardial fiber stress to determine wall thickness and cardiac chamber wall shear stress to determine chamber volume. Aortic stenosis resulted in the development of concentric left ventricular hypertrophy. Aortic and mitral regurgitation resulted in eccentric remodeling and eccentric hypertrophy, with more pronounced hypertrophy for aortic regurgitation. Comparisons with published clinical data showed the same direction and similar magnitudes of changes in end-diastolic volume index and left ventricular diameters. Changes in myocardial wall volume and wall thickness were within a realistic range in both stenotic and regurgitant valvular disease. Simulations of remodeling in left-sided valvular disease support, in both a qualitative and quantitative manner, that left ventricular chamber size and hypertrophy are primarily determined by preservation of wall shear stress and myocardial fiber stress. NEW & NOTEWORTHY Cardiovascular simulations with adaptive feedback that normalizes wall shear stress and fiber stress in the cardiac chambers could predict, in a quantitative and qualitative manner, remodeling patterns seen in patients with left-sided valvular disease. This highlights how mechanical stress remains a fundamental aspect of cardiac remodeling. This in silico study validated with clinical data paves the way for future patient-specific predictions of remodeling in valvular disease.

Mixed lineage kinase-3 prevents cardiac dysfunction and structural remodeling with pressure overload.

Myocardial hypertrophy is an independent risk factor for heart failure (HF), yet the mechanisms underlying pathological cardiomyocyte growth are incompletely understood. The c-Jun NH2-terminal kinase (JNK) signaling cascade modulates cardiac hypertrophic remodeling, but the upstream factors regulating myocardial JNK activity remain unclear. In this study, we sought to identify JNK-activating molecules as novel regulators of cardiac remodeling in HF. We investigated mixed lineage kinase-3 (MLK3), a master regulator of upstream JNK-activating kinases, whose role in the remodeling process had not previously been studied. We observed increased MLK3 protein expression in myocardium from patients with nonischemic and hypertrophic cardiomyopathy and in hearts of mice subjected to transverse aortic constriction (TAC). Mice with genetic deletion of MLK3 (MLK3-/-) exhibited baseline cardiac hypertrophy with preserved cardiac function. MLK3-/- mice subjected to chronic left ventricular (LV) pressure overload (TAC, 4 wk) developed worsened cardiac dysfunction and increased LV chamber size compared with MLK3+/+ littermates ( n = 8). LV mass, pathological markers of hypertrophy ( Nppa, Nppb), and cardiomyocyte size were elevated in MLK3-/- TAC hearts. Phosphorylation of JNK, but not other MAPK pathways, was selectively impaired in MLK3-/- TAC hearts. In adult rat cardiomyocytes, pharmacological MLK3 kinase inhibition using URMC-099 blocked JNK phosphorylation induced by neurohormonal agents and oxidants. Sustained URMC-099 exposure induced cardiomyocyte hypertrophy. These data demonstrate that MLK3 prevents adverse cardiac remodeling in the setting of pressure overload. Mechanistically, MLK3 activates JNK, which in turn opposes cardiomyocyte hypertrophy. These results support modulation of MLK3 as a potential therapeutic approach in HF. NEW & NOTEWORTHY Here, we identified a role for mixed lineage kinase-3 (MLK3) as a novel antihypertrophic and antiremodeling molecule in response to cardiac pressure overload. MLK3 regulates phosphorylation of the stress-responsive JNK kinase in response to pressure overload and in cultured cardiomyocytes stimulated with hypertrophic agonists and oxidants. This study reveals MLK3-JNK signaling as a novel cardioprotective signaling axis in the setting of pressure overload.

High risk HLHS: hybrid approach yes, but how does it work?

The majority of newborns with duct-dependent systemic blood flow are related to a hypoplastic left heart syndrome (HLHS), accounting for 2–3.5% of congenital heart defects (1). HLHS is anatomically subdivided in defects with stenosis or atresia of the mitral and aortic valve; consecutively left ventricular chamber size varies between fully diminished to almost normal dimensions in case of an associated VSD.

Spinal cord injury-induced cardiomyocyte atrophy and impaired cardiac function are severity dependent.

What is the central question of this study? How does the severity of spinal cord injury affect left ventricular mechanics, function and the underlying cardiomyocyte morphology? What is the main finding and its importance? Here, we show that severe, but not moderate, spinal cord injury causes cardiomyocyte atrophy, altered left ventricular mechanics and impaired cardiac function. The principal aim of the present study was to assess how the severity of spinal cord injury (SCI) affects left ventricular (LV) mechanics, function and underlying cardiomyocyte morphology. Here, we used different severities of T3 spinal cord contusions (MODERATE, 200kdyn contusion; SEVERE, 400kdyn contusion; SHAM) and combined standard echocardiography with speckle tracking analyses to investigate in vivo cardiac function and deformation (contractility) after experimental SCI in the Wistar rat. In addition, we investigated changes in the intrinsic structure of cardiac myocytes ex vivo. We demonstrate that SEVERE SCI induces a characteristic decline in LV chamber size and a reduction in in vivo LV deformation (i.e. radial strain) throughout the entire systolic portion of the cardiac cycle [25.6±3.0 versus 44.5±8.1% (Pre-injury); P=0.0029]. SEVERE SCI also caused structural changes in cardiomyocytes, including decreased length [115.6±7.63 versus 125.8±6.75μm (SHAM); P=0.0458], decreased width [7.78±0.71 versus 10.78±1.08μm (SHAM); P=0.0015] and an increase in the length/width ratio [14.88±0.66 versus 11.74±0.89 (SHAM); P=0.0018], which was significantly correlated with LV flow-generating capacity after SCI (i.e. stroke volume, R2 =0.659; P=0.0013). Rats with MODERATE SCI exhibited no changes in any metric versus SHAM. This is the first study to demonstrate that the severity of SCI determines the course of changes in the intrinsic structure of cardiomyocytes, which are directly related to contractile function of the LV.

VEGF-C-mediated cardiac lymphangiogenesis in high salt intake accelerated progression of left ventricular remodeling in spontaneously hypertensive rats

ABSTRACTHigh salt (HS) diet can accelerate the progress of hypertensive left ventricular (LV) remodeling. But the detailed mechanism remains poorly understood. We hypothesized HS intake could impact cardiac lymphangiogenesis through tonicity-responsive enhancer binding protein (TonEBP)/vascular endothelial growth factor-C (VEGF-C) signaling pathway which might play an important role in HS intake accelerated LV remodeling. Eight-week-old male spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were randomized to 0.5% NaCl (Low salt, LS) and 8% NaCl (high salt, HS) diets for 12 weeks. LV remodeling was determined by echocardiography. LV invasive hemodynamic analysis and morphologic staining (cardiomyocyte hypertrophy, collagen deposition, TonEBP expression, macrophage infiltration and lymphatic density) were performed at the time of sacrifice. The blood pressure of SHR-HS group was significantly increased compared to SHR-LS and WKY groups. Meanwhile, The LV chamber size was markedly enlargement, LV function apparently compromised accompanied with a severe macrophage infiltration, and fibrosis in the perivascular and interstitium of LV compared with SHR-LS group. Furthermore, the expression levels of VEGF-C, TonEBP, and lymphatic markers in SHR-HS group were significantly increased parallel with apparent lymphangiogenesis compared with SHR-LS group. Our work indicates that TonEBP/VEGF-C signaling pathway was up-regulated in HS intake accelerated hypertensive LV remodeling process that may be valuable for further investigation.

15 Metal-on-metal hip replacements and subclinical evidence of myocardial dysfunction

Introduction Over 1 million metal-on-metal (MOM) hip replacements were performed between 2003 and 2010. These prostheses were intended to be more durable than previous models, but have been associated with a higher failure rate. There have also been isolated cases of fulminant cardiomyopathy in patients with very high serum cobalt levels. We screened a cohort of asymptomatic patients with these prostheses for subclinical cardiac abnormalities. Methods All patients with MOM hip replacements at our centre undergo regular follow-up in the orthopaedic clinic with serum cobalt and chromium levels, and periodic magnetic resonance scanning of the affected joint. We recruited consecutive asymptomatic patients to receive echocardiography and recorded demographic data including age, height, weight, serum cobalt and chromium levels, and date of prosthesis implantation. Echocardiographers were blinded to medical history and laboratory results. The cohort was split into quartiles of serum cobalt. ANOVA, Kruksall-Wallis H test and Chi-squared tests were used to evaluate the differences between groups. Results Baseline characteristics between each quartile were similar (table 1). Mean duration of implant increased with quartile, but serum cobalt was not correlated with duration of prosthesis (r=0.135, p=0.162). Patients in the highest quartile of serum cobalt levels had larger left ventricular end-diastolic and end-systolic dimensions (50.8 vs. 44.7 mm, p=0.018; 31.6 vs. 25.8 mm, p=0.014 respectively) and indexed end-diastolic and end-systolic volumes by Simpsons method (42.0 vs. 32.8 ml/m2, p Conclusions Subjects with the highest serum cobalt levels have larger left ventricular and left atrial chamber sizes than those with the lowest serum levels. However, no difference in even sensitive markers of systolic or diastolic function were found. Left ventricular measurements are part of a range and therefore it is not possible to specify a cut-off for abnormality in these people. Whilst our findings do not suggest a clear relationship between serum ion levels and basic echocardiographic parameters of left ventricular systolic and diastolic dysfunction, we cannot exclude an idiosyncratic response as described in isolated case reports. We therefore advise that patients with MOM hip replacements undergo serial cardiology follow up.

Intramyocardial Injection of Stem Cells in Pig Myocardial Infarction Model: The First Trial in Korea.

Although cell therapy is emerged for cardiac repair, its efficacy is modest by intracoronary infusion. Therefore, we established the intramyocardial delivery technique using a left ventricular (LV) mapping system (NOGA® XP) using 18 pigs. After adipose tissue-derived mesenchymal stem cells (ATSCs) were delivered intramyocardially to porcine infarcted heart, LV ejection fraction (EF) was increased, and LV chamber size was decreased. We proved the therapeutic effect of intramyocardial injection of ATSC through a LV mapping system in the porcine model for the first time in Korea. The adoption of this technique may accelerate the translation into a clinical application in the near future.

A systematic review of randomised controlled trials examining the therapeutic effects of adult bone marrow-derived stem cells for non-ischaemic dilated cardiomyopathy.

BackgroundCertain early-phase clinical trials have suggested that bone marrow-derived stem cell transplantation might improve left ventricular function in patients with non-ischaemic dilated cardiomyopathy (NIDCM), whereas others trials have revealed no benefit from this approach. We sought to evaluate the therapeutic effects of bone marrow-derived stem cell therapy on NIDCM.MethodsWe searched the PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases (through February 2016) for randomised controlled clinical trials that reported on bone marrow-derived stem cell transplantation for patients with NIDCM with a follow-up period ≥12 months. The co-primary endpoints were changes in mortality rate and left ventricular ejection fraction (LVEF); the secondary endpoints were changes in the 6-minute-walk test (6MWT) and left ventricular chamber size. Seven trials involving bone marrow-derived stem cell therapy that included 482 patients satisfied the inclusion and exclusion criteria.ResultsSubjects who received bone marrow-derived stem cell therapy exhibited a significant reduction in mortality rate (19.7% in the cell group vs. 27.1% in the control group; 95% confidence interval (CI) –0.16 to –0.00, I 2 = 52%, p = 0.04). Bone marrow-derived stem cell therapy tended to produce LVEF improvement within 6 months (1.83% increase; 95% CI –0.27 to 3.94, I 2 = 74%, p = 0.09) and significantly improved LVEF after mid-term (6–12 months) follow-up (3.53% increase; 95% CI 0.76 to 6.29, I 2 = 88%, p = 0.01). However, this therapy produced no significant benefit in the 6MWT (p = 0.18). Finally, the transplantation of increased numbers of stem cells resulted in no observable additional benefit with respect to LVEF.ConclusionsBone marrow-derived stem cell therapy might have improved prognoses and appeared to provide moderate benefits in cardiac systolic function at mid-term follow-up. However, this therapy produced no observed improvement in exercise tolerance.

Abstract 221: Sam68 Interacts With mTORC1 and Contributes to Myocardial Hypertrophy

Introduction: The Src-associated in mitosis 68 kDa (Sam68) belongs to the STAR (signal transducer and activator of RNA) family of RNA-binding proteins. Our recent work revealed its critical role in the regulation of adipose thermogenesis. However, whether Sam68 regulates cardiomyocyte biology and heart disease is currently unknown. Methods and Results: Echocardiography analyses were performed in Sam68 -/- mice and WT littermates; the baseline left-ventricular wall thickness (LVPWs and LVPWd), chamber size (LVDs and LVDd), and contractility (LVEF and FS) are similar between the 2 groups of animals. However, after transverse aortic constriction (TAC) for 2 and 4 weeks, Sam68 -/- mice exhibited a significantly lesser increase in LV wall thickness (at 2 and 4 weeks), a closer to normal LV chamber size (at 4 weeks), and a lower heart-weight (HW)/body-weight (BW) ratio (at 4 weeks), as compared to WT controls. Consistently, after continuous administration of angiotensin II (by subcutaneous osmotic minipumps) for 2 weeks, Sam68 -/- mice displayed a similarly ameliorated LV wall thickness, chamber size, and HW/BW ratio. The attenuated hypertrophic responses of Sam68 -/- mice to both TAC and Ang II treatment was supported by a lowered expression of fetal genes (β-myosin heavy chain, atrial and brain natriuretic peptides) in the heart (qRT-PCR) and excitingly, by the decreased activity of mTORC1, as indicated by the lowered levels of phosphorylated S6K1 and 4E-BP1 (Western blotting). The cardiomyocyte-specific role of Sam68 was further confirmed in cultured H9c2 cells with lentivirus-mediated Sam68 knockdown, which confirmed the reduction of mTORC1 activity. Furthermore, co- immunoprecipitation assays revealed that the endogenous Sam68 protein interacts Raptor and mTOR, but not Rictor, in the mTOR complex. Experiments are underway to establish the functional significance of the Sam68-mTOR pathway in cardiac hypertrophy and failure in vivo. Conclusion: Collectively, our data suggest that Sam68 is a novel cofactor of mTORC1. It interacts with Raptor to augment mTOR signaling and contribute to the development of cardiac hypertrophy.

Characterization of an investigative safety pharmacology model to assess comprehensive cardiac function and structure in chronically instrumented conscious beagle dogs

IntroductionThere has been an increasing need to conduct investigative safety pharmacology studies to complement regulatory-required studies, particularly as it applies to a comprehensive assessment of cardiovascular (CV) risk. MethodsWe describe refined methodology using a combination of telemetry and direct signal acquisition to record concomitant peripheral hemodynamics, ECG, and left ventricular (LV) structure (LV chamber size and LV wall thickness) and function, including LV pressure-volume (PV) loops to determine load independent measures of contractility (end systolic elastance, Ees, and preload recruitable stroke work, PRSW) in conscious beagle dogs. Following baseline characterization, 28days of chronic rapid ventricular pacing (RVP) was performed and cardiac function monitored: both as a way to compare measures during development of dysfunction and to characterize feasibility of a model to assess CV safety in animals with underlying cardiac dysfunction. ResultsWhile ±dP/dT decreased within a few days of RVP and remained stable, more comprehensive cardiac function measurements, including Ees and PRSW, provided a more sensitive assessment confirming the value of such endpoints for a more clear functional assessment. After 28days of RVP, the inodilator pimobendan was administered to further demonstrate the ability to detect changes in cardiac function. Expectedly pimobendan caused a leftward shift in the PV loop, improved ejection fraction (EF) and significantly improved Ees and PRSW. DiscussionIn summary, the data show the feasibility and importance in measuring enhanced cardiac functional parameters in conscious normal beagle dogs and further describe a relatively stable cardiac dysfunction model that could be used as an investigative safety pharmacology risk assessment tool.

Normal values of left ventricular mass and cardiac chamber volumes assessed by 320-detector computed tomography angiography in the Copenhagen General Population Study.

Normal values of left ventricular mass (LVM) and cardiac chamber sizes are prerequisites for the diagnosis of individuals with heart disease. LVM and cardiac chamber sizes may be recorded during cardiac computed tomography angiography (CCTA), and thus modality specific normal values are needed. We studied 569 healthy subjects undergoing 320-detector CCTA as a part of the Copenhagen General Population Study. LVM as well as ventricular and atrial volumes was assessed with semi-automated software stratified by gender and age decades and indexed by body surface area (BSA). Mean age was 55 (range: 40-84) years, and 188 (33%) were men. BSA-indexed 97.5th percentile cut-off values: LVM = 80 and 65 gr/m(2), left ventricular volume = 97 and 83 mL/m(2), right ventricular volume = 120 and 102 mL/m(2), left atrial volume = 60 and 57 mL/m(2), and right atrial volume = 85 and 73 mL/m(2) for men and women, respectively. Men had greater absolute and indexed LVM and chamber volumes than women. For both genders, indexed ventricular volumes declined, whereas indexed atrial volumes increased in advancing age groups. For men, indexed LVM declined in advancing age groups. In multivariate analyses, gender, BSA, systolic blood pressure, and hard physical activity accounted for 63% of variance in LVM. In this cross-sectional general population study, men have greater indexed LVM and chamber volumes than women, and cardiac indexed volumes vary between age groups in both genders. These findings demonstrate the need for age- and gender-specific normal values for clinical diagnostic purposes.

In Patients with Light-Chain (AL) Amyloidosis Myocardial Contraction Fraction (MCF) Is a Simple, but Powerful Prognostic Measure That Can be Calculated from a Standard Echocardiogram (ECHO)

Background: Amyloidosis is a multisystem disease with extracellular deposition of pathological insoluble beta-fibrillar proteins. Involvement of the heart is seen in more than one-half of the patients with systemic AL amyloidosis and it is the most important determinant of clinical outcome. Cardiac amyloidosis is a restrictive infiltrative cardiomyopathy in which, despite declines in stroke volume that accompany disease progression, the ejection fraction (EF) often remains preserved even in advanced stages of the disease. King et al. proposed a novel index of myocardial function, the myocardial contraction fraction (MCF), defined as the ratio of stroke volume (SV) to myocardial volume (MV). MCF is a measure of myocardial shortening, which differentiated myocardial performance in patients with similar degrees of hypertrophy and in a recent small cohort of AL amyloidosis patients appeared superior to left ventricular ejection fraction (EF) in predicting overall survival (OS). It was our goal to assess the prognostic role of MCF in a large cohort of patients with AL amyloidosis in the context of other prognostic variables.Methods: Patients seen between 4/1/1999 and 2/1/2015 were eligible for this retrospective study if they had an ECHO at the Mayo Clinic, Rochester, MN within 30 days of their AL amyloidosis diagnosis with measurements of left ventricular chamber size and wall thickness needed to calculate MCF, EF, and the presence or absence of pericardial effusion. To capture the full cohort, modeling was done first excluding Mayo (2012) staging and global averaged left ventricular longitudinal peak systolic strain (LV strain) since limited numbers of patients had these studies, 342 and 294, respectively. Thresholds of continuous variables were chosen based on receiver operator curves targeting death at 1-year. Cox proportional hazards analysis was used to identify factors that were prognostic for OS. Statistical analyses were done using JMP 9.0 (SAS, Cary, NC).Results: Among the 722 patients satisfying entry criteria,median age was 64 years (range 32-94) and 66% were male. The best cutoff for MCF was 21% (sensitivity: 74%, specificity: 60%; AUC=0.699) and distinguished two groups with different OS (median 53 vs. 9 months, P<0.0001; Figure). On univariate analysis the baseline ECHO variables predicting OS were interventricular septum thickness (IVS) >12 mm (RR 1.8, P=0.0002), EF <60% (RR 1.7), MCF ≤21% (RR 2.1), and presence of pericardial effusion (RR 2.0), all with P<0.0001. On multivariate MCF ≤21% (RR 1.6, P <0.0001), EF <60% (RR 1.4, P=0.0007) and the presence of pericardial effusion (RR 1.3, P=0.002) were independent predictors of OS.Additional modeling was done with the subset of 342 patients who were assessable for Mayo (2012) staging, (i.e. measurements of immunoglobulin free light chain, NT-proBNP, and troponin T). On univariate analysis, patients with a Mayo (2012) stage ≥ 3 had a RR 2.1, p<0.0001. On multivariate, only MCF ≤21% (RR 1.5, P =0.01), Mayo (2012) stage ≥ 3 (RR 1.5, P=0.01) and EF<60% (RR 1.7, P=0.0006) were independent prognostic determinants.Finally, we addressed LV-strain among the 294 patients in whom the study was performed. There was a significant correlation between MCF and LV strain (rho =-0.86, P<0.0001). On univariate, LV-strain less negative than -13 generated a RR of 2.3, p<0.0001. In contrast to the model containing MCF, on LV-strain multivariate, EF was no longer significant, but LV-strain less negative than -13 (RR 2.0, P=0.008) and Mayo (2012) stage ≥ 3 (RR 2.0, P=0.008) predicted independently OS.Conclusions: MCF ≤21% identified a subgroup of patients with a high mortality risk, and it was independent of the Mayo (2012) staging but highly correlated with LV strain. An advantage of MCF, which is a novel volumetric measurement of the left ventricular chamber, is that, unlike LV-strain, MCF is simple to calculate from routine ECHO measures. [Display omitted] DisclosuresKumar:AbbVie: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Skyline, Noxxon: Honoraria; Celgene, Millenium, Sanofi, Skyline, BMS, Onyx, Noxxon,: Other: Consultant, no compensation,; Sanofi: Research Funding; Millenium/Takeda: Research Funding; Onyx: Research Funding.

Exercise-Induced Left Ventricular Remodeling Among Competitive Athletes

Background— Contemporary understanding of exercise-induced cardiac remodeling is based on cross-sectional data and relatively short duration longitudinal studies. Temporal progression of exercise-induced cardiac remodeling remains incompletely understood. Methods and Results— A longitudinal repeated-measures study design using 2-dimensional and speckle-tracking echocardiography was used to examine acute augmentation phase (AAP; 90 days) and more extended chronic maintenance phase (39 months) left ventricular (LV) structural and functional adaptations to endurance exercise training among competitive male rowers (n=12; age 18.6±0.5 years). LV mass was within normal limits at baseline (93±9 g/m 2 ), increased after AAP (105±7 g/m 2 ; P =0.001), and further increased after chronic maintenance phase (113±10 g/m 2 ; P &lt;0.001 for comparison to post-AAP). AAP LV hypertrophy was driven by LV dilation (ΔLV end-diastolic volume, 9±3 mL/m 2 ; P =0.004) with stable LV wall thickness (ΔLV wall thickness, 0.3±0.1 mm; P =0.63). In contrast, chronic maintenance phase LV hypertrophy was attributable to LV wall thickening (Δ LV wall thickness, 1.1±0.4 mm; P =0.004) with stable LV chamber volumes (ΔLV end-diastolic volume, 1±1 mL/m 2 ; P =0.48). Early diastolic peak tissue velocity increased during AAP (−11.7±1.9 versus −13.6±1.3 cm/s; P &lt;0.001) and remained similarly increased after chronic maintenance phase. Conclusions— In a small sample of competitive endurance athletes, exercise-induced cardiac remodeling follows a phasic response with increases in LV chamber size, early diastolic function, and systolic twist in an acute augmentation phase of exercise training. This is followed by a chronic phase of adaptation characterized by increasing wall thickness and regression in LV twist. Training duration is a determinant of exercise-induced cardiac remodeling and has implications for the assessment of myocardial structure and function in athletes.

Abstract 15554: Heart Failure-Related Hyperphosphorylation of Ser199 on Cardiac Troponin I Causes Divergent Effects on Cardiac Function at Baseline and During Ischemia-Reperfusion

Background: Phosphorylation of cardiac troponin I (cTnI) on Ser199 is significantly increased in human heart failure (HF), however its cardiac impact in vivo remains unknown. In addition, selective proteolysis of cTnI is a marker of myocardial injury and contributes to cardiac dysfunction in ischemia/reperfusion (I/R), and Ser199 phosphorylation affects cTnI proteolysis in vitro, thus whether Ser199 phosphorylation affects cardiac performance during I/R is of great interest. Methods and Results: We generated transgenic mice (TgS200D) carrying cTnI S200D mutation to mimic the site-specific hyperphosphorylation of murine Ser200 (equivalent to human Ser199). Cardiac function was first assessed in vivo using echocardiography. TgS200D mice demonstrated unaltered ejection fraction (EF), significantly prolonged isovolumic relaxation time, and normal left ventricular (LV) chamber size and wall thickness (n=10). LV pressure-volume studies showed preserved dp/dtmax, significantly decreased -dp/dtmin and increased relaxation time constant in TgS200D when compared to non-transgenic (NTg) control group at baseline (n=10). With increasing heart rates, the two groups showed similar enhancement in both systolic and diastolic function, suggesting the positive force-frequency relation is preserved in TgS200D (n=5). After isoproterenol injection (i.v. 40ng/min/kg), although a comparable increase in dp/dtmax was observed in both groups, there was no enhancement of -dp/dtmin in TgS200D in contrast to 15% of increase in NTg (n=5, p=0.019). After ischemia (30 min)/reperfusion (60 min), LV developed pressure was recovered by ~90% in isolated TgS200D hearts but only ~40% in NTg (n=5, p=0.003). Immunoblotting detected cTnI cleavage only in NTg hearts. Conclusions: Our results indicate that hyperphosphorylation of cTnI Ser199 1) impairs basal diastolic function but preserves systolic function, without LV hypertrophy or dilation; 2) blunts cardiac lusitropic response to β-adrenergic stimulation with isoproterenol; 3) protects heart against I/R injury, likely via preventing cTnI degradation. We propose a dual role of cTnI Ser199 hyperphosphorylaiton: contributing to HF with preserved EF but protecting heart during I/R.

The role of muscle sympathetic nerve activity in limiting exercise capacity in heart failure.

The role of muscle sympathetic nerve activity in limiting exercise capacity in heart failure.

Relationship of exercise capacity and left ventricular dimensions in patients with a normal ejection fraction. An exploratory study.

ObjectivesExtreme endurance exercise is known to be associated with an enlargement of the left ventricular (LV) chamber, whereas inactivity results in inverse changes. It is unknown if these dimensional relationships exist in patients.MethodsWe analyzed the relationship of exercise capacity and LV dimension in a cohort of sequential patients with a normal ejection fraction undergoing stress echocardiography. In a total of 137 studies the following questions were addressed: (a) is there a difference in LV dimensions of patients with an excellent exercise capacity versus patients with a poor exercise capacity, (b) how is LV dimension and exercise capacity affected by LV wall thickness and (c) how do LV dimensions of patients who are unable to walk on a treadmill compare to the above groups.ResultsPatients with a poor exercise capacity or who are unable to physically exercise have a 34 percent smaller LV cavity size when compared to patients with an excellent exercise capacity (p<0.001). This reduction in LV chamber size is associated with concentric LV hypertrophy and a reciprocal increase in resting heart rate. In addition, cardiac output reserve is further blunted by chronotropic incompetence and a tachycardia-induced LV volume reduction. In conclusion the relationship of exercise capacity and cardiac dimensions described in extreme athletes also applies to patients. Our exploratory analysis suggests that patients who cannot sufficiently exercise have small LV cavities.

Combined therapy with shock wave and autologous bone marrow-derived mesenchymal stem cells alleviates left ventricular dysfunction and remodeling through inhibiting inflammatory stimuli, oxidative stress & enhancing angiogenesis in a swine myocardial infarction model

BackgroundWe hypothesized that combined therapy with shock wave (SW) and autologous bone marrow-derived mesenchymal stem cells (BMDMSCs) is superior to either therapy alone for alleviating left ventricular (LV) dysfunction. Methods and resultsMale mini-pigs (n=30) equally divided into group 1 (sham control), group 2 [acute myocardial infarction (AMI) by left coronary artery ligation], group 3 (AMI-SW), group 4 (AMI-BMDMSC), and group 5 (AMI-SW-BMDMSC) were sacrificed by day 60 and the hearts were collected for studies. Baseline LV injection fraction [LVEF (%)] and LV chamber size did not differ among the five groups (p>0.5). By day 60, LVEF was highest in group 1 and lowest in group 2, significantly higher in group 5 than that in groups 3 and 4, and significantly higher in group 4 than that in group 3 (p<0.001). Cellular and protein levels of VEGF, CXCR4, and SDF-1α were significantly increased progressively from groups 1 to 5 (all p<0.05). Small vessel number and protein expressions of CD31 and eNOS were highest in groups 1 and 5, lowest in group 2, and significantly higher in group 4 than those in group 3 (p<0.001). Protein (MMP-9, TNF-1α and NF-κB) and cellular (CD14+, CD40+) levels of inflammatory biomarkers, protein expressions of oxidative stress (oxidized protein, NOX-1, NOX-2), apoptosis (Bax, caspase-3, PARP), infarct size, and LV dimensions showed a pattern opposite to that of LVEF among all groups (all p<0.001). ConclusionsCombined SW-BMDMSC therapy is superior to either therapy alone for improving LVEF, reducing infarct size, and inhibiting LV remodeling.

Invited Commentary

Invited Commentary

EP News: Allied Professionals

In this report by Ruwald et al (Circulation 2014; PMID 25301831), 752 Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) patients who were randomized to cardiac resynchronization therapy–defibrillator (CRT-D) and who also had echocardiograms at baseline and 12 months were studied for an average of 22 months after the second echocardiogram to assess outcome (ventricular arrhythmias [VAs], heart failure [HF], death, and inappropriate implantable cardioverter-defibrillator [ICD] therapy). Patients were grouped on the basis of their left ventricular ejection fraction (LVEF) on the 12-month echocardiogram: ≤35%, 36%–50% (“subnormalization”), and >50% (“normalization”). The authors found that 7.3% of patients normalized their LVEF and 79% obtained an LVEF of 36%–50%. Those with normalization and subnormalization had reduced risk of VAs, HF, and death as compared with those with LVEF ≤35%. Only 3 patients with normal LVEF had VAs, and none were shocked by the ICD. Factors associated with normalization include female sex, left bundle branch block, non–ischemic cardiomyopathy, baseline LVEF >30%, and baseline small left atrial and left ventricular chamber sizes. Of the 42 patients who had all these 6 variables and LVEF normalization, none had VAs. There was continued risk of inappropriate ICD therapy even in those with normal EF. The authors conclude that in patients treated with CRT-D who normalize their LVEF, the outcome is very good with a low risk of VAs and downgrade from CRT-D to CRT-pacemaker could be considered at generator replacement, especially in those with all 6 favorable characteristics at baseline and no VAs before implantation or during follow-up.