Left Ventricular Contractile Function Research Articles

Stress Echocardiography in Regurgitant Valve Disease

Because of its wide availability, low cost, versatility, and clinical use, stress echocardiography has become increasingly recognized as a valuable tool in the assessment of patients with regurgitant valvular heart disease. Exercise testing is favored compared with pharmacological stress testing for risk stratification in asymptomatic patients and can identify what might otherwise be considered as a moderate valve disease. It has been shown to provide insights into exertional symptoms disproportionate to resting hemodynamics in these patients and to facilitate individual risk stratification. Aggravation of valvular regurgitation severity, exercise-induced pulmonary hypertension (PHT), impaired left ventricular (LV) contractile reserve, inducible ischemia, dynamic LV dyssynchrony, and altered exercise capacity, together with the development of symptoms during exercise echocardiography, provide the clinician with straightforward prognostic information, therefore enabling a more accurate definition of the optimal timing of intervention in patients with valvular regurgitation.1,2 In contrast, dobutamine stress echocardiography has little value in cases of valvular regurgitation. Dobutamine infusion is almost systematically associated with a decrease in the severity of regurgitation; however, it might be of interest in the detection of LV contractile reserve and inducible ischemia. The most common form of exercise used in conjunction with echocardiography is immediate postexercise imaging on a treadmill or upright bicycle ergometer. However, semisupine exercise testing on an appropriate tilted table allows continuous echocardiographic monitoring, which represents an advantageous tool for quantifying changes in valvular regurgitation severity, LV function, and pulmonary pressure (Table). This exercise stress echocardiography modality (ie, per-exercise echocardiography) is the most used in Europe, and we strongly suggest this approach in the setting of valvular heart disease to detect evanescent changes. A symptom-limited graded exercise test is recommended, and ≥80% of the age-predicted upper heart rate should be reached in the absence of symptoms. The test is adapted to the clinical conditions …

Abstract 035: Mechanism of Chronic CaMKII Inhibition-Caused Regression of Heart Failure: Beneficial Effects on Neurohormonal Activation, Left Ventricular and Cardiomyocyte Contractile Function, [Ca 2 +]i Regulation and Beta-Adrenergic Modulation

Background: Recent evidence indicates that Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) is upregulated in heart failure (HF), contributing to electric, structural and functional remodeling. CaMKII has been proposed to be a therapeutic target for HF. However, the role and mechanism of chronic CaMKII inhibition (I) in HF is unclear. We assessed the hypothesis that CaMKII I improves cardiomyocyte function, [Ca 2+ ] i regulation, and β-adrenergic reserve, thus limiting HF progression. Methods: We compared left ventricular (LV) and myocyte functional responses and plasma levels of norepinephrine (NE) over a period of 16 weeks (W) in 6 control (C) and 14 rats with HF induced by isoproterenol (ISO) (170 mg/kg sq for 2 days). After ISO for 12 weeks, HF animals were assigned to receive 4 W treatment with: placebo (saline) (n=6), KN-93 (70 µg/kg/day sq via mini pump) (n=6), or KN-92 (70 µg/kg/day sq via pump) (n=2), respectively. Results: Compared with C, ISO-treated rats had HF onset at 4 W after ISO and progressed to severe HF at 16 W with increased plasma NE (1398 vs 342 pg/ml), decreased ejection fraction (EF, 37% vs 62%) and LV contractility (E ES , 0.8 vs 1.3 mmHg/μl). LV time constant of relaxation (τ) (17.8 vs 10.6 ms) increased, accompanied with significant reductions in cell contraction (dL/dt max , 78 vs 151 μm/s), relaxation (dR/dt max , 59 vs 114 μm/s) and [Ca 2+ ] i transient ([Ca 2+ ] iT ) (0.18 vs 0.28). HF myocyte response to β-AR stimulation (ISO, 10 -8 M) was attenuated with significantly less increases in dL/dt max (34% vs 79%) and [Ca 2+ ] iT (19% vs 36%). The LV and myocyte dysfunction persisted in KN-92-treated HF group. In contrast, treatment with KN-93 significantly increased E ES (1.2 mmHg/μl) and EF (60%), decreased τ (12.1 ms) and corrected the elevation of plasma NE (319 pg/ml). Importantly, basal myocyte contraction (dL/dt max ,147 μm/s), relaxation (dR/dt max ,107 μm/s), and [Ca 2+ ] iT (0.25) improved. ISO-induced increase in dL/dt max (71%) and [Ca 2+ ] iT (32%) were augmented and close to normal control levels. Conclusion: Chronic CaMKII I prevents HF-induced sympathetic nervous system activation and improves LV and cardiomyocyte basal and β-AR stimulated contraction and relaxation, thus playing a salutary role at later stages of HF.

Soluble guanylyl cyclase mediates concomitant coronary vasodilator and positive inotropic actions of the HNO donor Angeli's salt in the intact rat heart

Background The NO redox sibling nitroxyl (HNO) elicits soluble guanylyl cyclase (sGC)-dependent vasodilatation. HNO has high reactivity with thiols (unlike NO), which is attributed with HNO-enhanced left ventricular (LV) function. The present study tested the hypothesis that the concomitant vasodilatation and inotropic actions induced by the HNO donor, Angeli’s salt (sodium trioxodinitrate), are sGC-dependent and sGC-independent, respectively. Materials and methods Haemodynamic responses to bolus doses of Angeli’ ss alt (10pmol - 10μmol), alone and in the presence of selective scavengers of HNO (L-cysteine, 4mM) or NO (hydroxocobalamin HXC, 50µM) or selective inhibitors of sGC (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one ODQ, 10μM), calcitonin gene-related peptide (CGRP) receptors (CGRP8-37 ,0 .1 μM) or voltage-dependent potassium channels (4-aminopyridine 4-AP, 1mM) were determined in isolated adult male rat hearts. Results Angeli’s salt elicited concomitant, potent dose-dependent increases in coronary flow and LV systolic and diastolic function. Both L-cysteine and ODQ caused a rightward shift in the dose-response curve of each of these effects, implicating HNO and sGC in both the vasodilator and inotropic actions of Angeli’s salt. In contrast, neither HXC, CGRP8-37 nor 4-AP affected Angeli’s salt actions. Conclusion These data suggest that each of the vasodilator, inotropic and lusitropic actions of Angeli’s salt are mediated by L-cysteine-sensitive, HNO/sGC-dependent mechanisms. Our findings represent the first evidence that sGC specifically contributes a significant component of the inotropic and lusitropic actions of an HNO donor in the intact heart. Thus, HNO acutely enhances LV contractile function and LV relaxation, whilst concomitantly unloading the heart, potentially favourable properties for the failing heart.

Abstract 312: STIM1 And The Development Of Pressure-overload Induced Cardiac Hypertrophy In Rodents

STromal Interaction Molecule 1 (STIM1), a membrane protein of the sarcoplasmic reticulum, has recently been proposed as a positive regulator of cardiomyocyte growth by promoting Ca2+ entry through the plasma membrane and the activation of Ca2+-mediated signaling pathways. We studied the role of STIM1 in a pressure-overload induced cardiac hypertrophy model in mice. We observed that STIM1 cardiac expression is increased during left ventricular hypertrophy (LVH) induced by Transverse Aortic Constriction (TAC). We then used recombinant Associated Adenovirus 9 (AAV9) to perform cardiac-targeted gene silencing in vivo. C57Bl/6 mice were injected with saline (noAAV) or with AAV9 expressing shRNA against STIM1 (shSTIM1) at the dose of 1e+11 viral genome which resulted in 70% decrease of STIM1 cardiac expression compared to control mice. Three weeks later, TAC was performed and mice were studied three other weeks later. We found that TAC-shSTIM1 treated mice did not develop LVH compared to noAAV despite the same increase in aortic pressure. Echocardiographic and hemodynamic measurements (see table) showed that TAC-shSTIM1-treated mice had LV dilation and a decreased left ventricular contractile function in line with the absence of compensatory LVH in these mice. Immunohistochemistry demonstrated that LVH prevention was observed at the cellular level with cardiac myocytes cross-section area comparable to sham littermates however with a trend towards more interstitial fibrosis. This study reveals the essential role of STIM1 in the development of compensatory LVH in mice.

Acute changes in electromechanical parameters during different pacing configurations using a quadripolar left ventricular lead

Quadripolar left ventricular (LV) leads allow for several pacing configurations in candidates for cardiac resynchronization therapy (CRT). Whether different pacing configurations may affect LV dyssynchrony and systolic function is not completely known. We aimed to evaluate the acute effects of different pacing vectors on LV electromechanical parameters in patients implanted with a quadripolar LV lead. In this two-centre study, within 1 month of implantation 21 CRT patients (65 ± 8 years, 76 % men, 38 % ischemic) receiving a quadripolar LV lead (Quartet 1458Q, St Jude Medical) underwent LV capture threshold assessment, intracardiac electrogram optimization, and two-dimensional echocardiography during four pacing configurations: D1-P4, P4-RV coil, D1-RV coil, and P4-M2. LV dyssynchrony and contractile function were expressed by septal-to-lateral delay and global longitudinal strain (GLS). LV capture threshold varied between the configurations (P < 0.001), showing higher values in the configurations P4-RV coil and P4-M2. Septal-to-lateral delay decreased in the configurations D1-P4 and D1-RV coil (P = 0.003 and P = 0.033 vs. spontaneous rhythm, respectively). GLS improved significantly vs. spontaneous rhythm only in the configuration D1-P4 (from -8.6 ± 3.5 to -11.0 ± 3.2 %, P = 0.001). Accordingly, an increase in stroke volume and a decrease in mitral regurgitation were observed in the configuration D1-P4 (P ≤ 0.001 vs. spontaneous rhythm). In CRT patients receiving a quadripolar LV lead, significant variations in electromechanical parameters were observed by changing pacing vector. Individually targeting the optimal pacing site may enhance the acute haemodynamic response to CRT.

Ventricular-Arterial Coupling, Remodeling, and Prognosis in Chronic Heart Failure

The objective of this study was to compare the physiological determinants of ejection fraction (EF)-ventricular size, contractile function, and ventricular-arterial (VA) interaction-and their associations with clinical outcomes in chronic heart failure (HF). EF is a potent predictor of HF outcomes, but represents a complex summary measure that integrates several components including left ventricular size, contractile function, and VA coupling. The relative importance of each of these parameters in determining prognosis is unknown. In 466 participants with chronic systolic HF, we derived quantitative echocardiographic measures of EF: cardiac size (end-diastolic volume [EDV]); contractile function (the end-systolic pressure volume relationship slope [Eessb] and intercept [V0]); and VA coupling (arterial elastance [Ea]/Eessb). We determined the association between these parameters and the following adverse outcomes: 1) the combined endpoint of death, cardiac transplantation, or ventricular assist device (VAD) placement; and 2) cardiac hospitalization. Over a median follow-up of 3.4 years, there were 76 deaths, 52 transplantations, 14 VAD placements, and 684 cardiac hospitalizations. EF was independently associated with death, transplantation, and VAD placement (adjusted hazard ratio [HR]: 3.0; 95% confidence interval [CI]: 1.8 to 5.0 comparing third and first tertiles), as were EDV (HR: 2.6; 95% CI: 1.5 to 4.2); V0 (HR: 3.6; 95% CI: 2.1 to 6.1); and Ea/Eessb (HR: 2.1; 95% CI: 1.3 to 3.3). EDV, V0, and Ea/Eessb were also associated with risk of cardiac hospitalization. Eessb was not significantly associated with any adverse outcomes in adjusted analyses. Left ventricular size, V0, and VA coupling are associated with prognosis in systolic HF, but end-systolic elastance (Eessb) is not. Assessment of VA coupling via Ea/Eessb is an additional noninvasively derived metric that can be used to gauge prognosis in human HF.

Comparison of left atrial function in healthy individuals versus patients with non-ST-segment elevation myocardial infarction using two-dimensional speckle tracking echocardiography : cardiovascular topics

Left atrial (LA) function has been associated with adverse outcomes in patients after acute myocardial infarction. The purpose of the current study was to evaluate LA function in patients with non-ST-segment elevation myocardial infarction (NSTEMI) by two-dimensional speckle tracking echocardiography (2D STE). Fifty-one patients with NSTEMI and 40 age-matched normal control individuals were enrolled in this study. Conventional echocardiographic parameters and global longitudinal strain rate (GLSR) were measured at left ventricular (LV) and LA segments. Compared with healthy subjects, patients with NSTEMI had significantly increased LA volumes but significantly decreased LA emptying fraction and GLSR. LA-GLSR had significant correlations with the 2D Doppler echocardiographic parameters of LA function. In particular, global LA peak negative strain rate during early ventricular diastole (LA-GLSRe) was significantly correlated with both LA 2D Doppler echocardiographic parameters and LV contractile function. This could be suggested as a better indicator to evaluate LA function as a preferred parameter of STE.

Treatment of Acute and Recurrent Idiopathic Pericarditis

Case Presentation: A 56-year-old previously healthy man presented with 2 days of pleuritic left anterior chest pain, lessened by sitting forward. His examination was pertinent for low-grade fever (37.6°C), blood pressure 122/76 mm Hg without paradox, no jugular venous distension, clear lungs, and a 3-component pericardial friction rub. The ECG showed diffuse concave-upward ST-segment elevation and PR-segment depression in the inferior leads. The serum C-reactive protein level was 64 mg/L, and the cardiac troponin T was not elevated. Echocardiography showed normal left ventricular contractile function without wall motion abnormalities and no pericardial effusion. He was diagnosed with acute pericarditis, and the symptoms responded promptly to oral ibuprofen, continued for 2 weeks. Six weeks later, he redeveloped pleuritic chest pain and clinical and ECG findings identical to the initial presentation. His primary care physician asks for advice about appropriate therapy. Pericarditis accounts for 5% of emergency department visits for chest pain in the absence of myocardial infarction.1 In ≈80% of cases in developed countries, the cause of pericarditis is either postviral or “idiopathic,” in that it cannot be attributed to a specific condition.2,3 Because these 2 etiologies are clinically equivalent, the term idiopathic pericarditis will refer to both in this Clinician Update. Even when managed effectively, many patients with acute pericarditis present with 1 or more repeated episodes, termed recurrent pericarditis .4 Treatment of idiopathic pericarditis has long been empirical, because until recently, there have been few therapeutic trials addressing this condition. The European Society of Cardiology published the only treatment guideline for pericarditis almost a decade ago, and many of the recommendations were based on opinion because of the lack of available study evidence.4 Most patients with idiopathic pericarditis experience self-limited symptoms that improve spontaneously within days to weeks. More rapid relief can be …

Are measures of left ventricular systolic performance during low dose dobutamine stress echocardiograms repeatable over time?

To establish the test-retest reliability and the normal dose-response relationship of echocardiographic measures of Left Ventricular (LV) contractile function to low dose dobutamine stress in healthy individuals. Thirty healthy volunteers (23 males, 7 females) with an average age of 38 ± 13 years underwent dobutamine stress echocardiography (DSE) (at successive doses of 0, 5, 10, and 20 mcg/kg/min) on two occasions, separated by 14 days. Ejection fraction (EF) was determined from 2D echocardiographic measures of left ventricular (LV) end diastolic and end systolic volumes. Longitudinal strain (S) and strain rate (SR) were measured using 2D speckle tracking analysis from three consecutive cardiac cycles. The Intraclass Correlation Coefficient (ICC) and the Coefficient of Variation (CV) were calculated to assess reliability and variability of the study population's EF, S, and SR responses to increasing doses of dobutamine. Left ventricular S and EF gradually increased with low doses of dobutamine but reached a plateau between 10 and 20 mcg/kg/min. Strain rate, however, gradually increases with each increasing dose of dobutamine. These responses were replicated on Day 2 with a high degree of reliability as determined from the ICC and low variability as determined from the CV, which fell within acceptable limits (<10 %). Left ventricular EF, S and SR can be measured during DSE with a high degree of test-retest reliability, and may be of clinical value when serial follow up of DSE measures of LV performance is indicated over time.

Oral Pretreatment With Liposomal Glutathione Attenuates Reperfusion Injury in Rabbit Isolated Hearts

Reactive oxygen species are a key mediator of myocardial reperfusion injury. Endogenous cellular defenses against reactive oxygen species often become overwhelmed after ischemia and reperfusion. Therefore, exogenous supplementation of various antioxidant compounds has been hypothesized to protect against reperfusion. Reduced glutathione (GSH) is an important endogenous antioxidant that affords protection against oxidative damage. Oral administration of GSH is limited due to poor gastrointestinal absorption. A liposomal preparation of glutathione (lipGSH) capable of oral administration was investigated for its ability to attenuate tissue injury and increase myocardial glutathione levels in an isolated heart model of reperfusion injury. Male, New Zealand white rabbits were assigned randomly among 4 groups as follows: control and daily oral administration of lipGSH for 3, 7, or 14 days. At completion of the dosing regimen, hearts were harvested and perfused in a retrograde manner with the use of a Langendorff apparatus. The hearts were subjected to 30 minutes of global ischemia followed by 60 minutes of reperfusion. Hearts from lipGSH-treated rabbits exhibited better recovery of left ventricular contractile function during reperfusion and had attenuated oxidative damage. Furthermore, hearts from lipGSH-treated animals had increased myocardial tissue levels of GSH demonstrating effective absorption of lipGSH.

Acute Effects of Withdrawal of Cardiac Resynchronization Therapy on Left and Right Ventricular Function, Dyssynchrony, and Contractile Function in Patients With New York Heart Association Functional Class I/II Heart Failure: MADIT-CRT

BackgroundCardiac resynchronization therapy (CRT) improves left ventricular (LV) function, size, mitral regurgitation, and clinical outcomes. Whether these improvements are due to the short-term effects of improvement in synchrony or contractile performance, or to long-term improvement in ventricular structure and function remains insufficiently elucidated. Methods and ResultsWe used echocardiographic data from 63 patients enrolled in the MADIT-CRT trial who, after 1 year of CRT therapy, underwent echocardiographic evaluation with CRT turned both on and off within minutes. LV volumes, LV ejection fraction, left atrial (LA) volumes, and right ventricular function were assessed at baseline and in the on and off modes within a 5-minute time-frame at 12 months. Speckle-tracking strain analysis was used to assess LV dyssynchrony and contractile function. Interruption of long-term CRT resulted in acute deterioration of LV and RV function and acute increase in LV and LA volumes, although not to baseline. Acute withdrawal was also associated with increased dyssynchrony (SD time to peak transverse strain 178 ± 68 ms vs 195 ± 62 ms; P = .16; and SD time to peak longitudinal strain 108 ± 46 ms vs 125 ± 55 ms; P = .046). However, there was no deterioration in contractile function (global longitudinal strain), which had improved with CRT (−9.8 ± 4.3% vs −10.0 ± 3.7%; P = .93). ConclusionsDespite substantial LV reverse remodeling with CRT, interruption of long-term CRT after 12 months resulted in an acute worsening of LV size and function, LA volumes, and right ventricular function, with concomitant worsening of ventricular synchrony despite minimal change to the observed improvement in LV strain measures of contractile function. These findings suggest that the beneficial reverse remodeling associated with CRT may be mostly dependent on active pacing, although intrinsic improvements in contractile function may persist beyond termination of pacing.

Myocardial contractile dysfunction associated with increased 3-month and 1-year mortality in hospitalized patients with heart failure and preserved ejection fraction

There is a clinical need for a contractility index that reflects myocardial contractile dysfunction even when ejection fraction (EF) is preserved. We used novel relative load-independent global and regional contractility indices to compare left ventricular (LV) contractile function in three groups: heart failure (HF) with preserved ejection fraction (HFPEF), HF with reduced ejection fraction (HFREF) and normal subjects. Also, we determined the associations of these parameters with 3-month and 1-year mortality in HFPEF patients. 199 HFPEF patients [median age (IQR): 75 (67-80) years] and 327 HFREF patients [69 (59-76) years] were recruited following hospitalization for HF; 22 normal control subjects [65 (54-71) years] were recruited for comparison. All patients underwent standard two-dimensional Doppler and tissue Doppler echocardiography to characterize LV dimension, structure, global and regional contractile function. The median (IQR) global LV contractility index, dσ*/dtmax was 4.30s(-1) (3.51-4.57s(-1)) in normal subjects but reduced in HFPEF [2.57 (2.08-3.64)] and HFREF patients [1.77 (1.34-2.30)]. Similarly, median (IQR) regional LV contractility index was 99% (88-104%) in normal subjects and reduced in HFPEF [81% (66-96%)] and HFREF [56% (41-71%)] patients. Multi-variable logistic regression analysis on HFPEF identified sc-mFS <76% as the most consistent predictor of both 3-month (OR=7.15, p<0.05) and 1-year (OR=2.57, p<0.05) mortality after adjusting for medical conditions and other echocardiographic measurements. Patients with HFPEF exhibited decreased LV global and regional contractility. This population-based study demonstrated that depressed regional contractility index was associated with higher 3-month and 1-year mortality in HFPEF patients.

Effect of Acute Hyperglycemia on Left Ventricular Contractile Function in Diabetic Patients with and without Heart Failure: Two Randomized Cross-Over Studies

BackgroundIt is unknown whether changes in circulating glucose levels due to short-term insulin discontinuation affect left ventricular contractile function in type 2 diabetic patients with (T2D-HF) and without (T2D-nonHF) heart failure.Materials and MethodsIn two randomized cross-over-designed trials, 18 insulin-treated type 2 diabetic patients with (Ejection Fraction (EF) 36±6%, n = 10) (trial 2) and without systolic heart failure (EF 60±3%, n = 8) (trial 1) were subjected to hyper- and normoglycemia for 9–12 hours on two different occasions. Advanced echocardiography, bicycle exercise tests and 6-minute hall walk distance were applied.ResultsPlasma glucose levels differed between study arms (6.5±0.8 mM vs 14.1±2.6 mM (T2D-HF), 5.8±0.4 mM vs 9.9±2.1 mM (T2D-nonHF), p<0.001). Hyperglycemia was associated with an increase in several parameters: maximal global systolic tissue velocity (Vmax) (p<0.001), maximal mitral annulus velocity (S'max) (p<0.001), strain rate (p = 0.02) and strain (p = 0.05). Indices of increased myocardial systolic contractile function were significant in both T2D-HF (Vmax: 14%, p = 0.02; S'max: 10%, p = 0.04), T2D-nonHF (Vmax: 12%, p<0.01; S'max: 9%, p<0.001) and in post exercise S'max (7%, p = 0.049) during hyperglycemia as opposed to normoglycemia. LVEF did not differ between normo- and hyperglycemia (p = 0.17), and neither did peak exercise capacity nor catecholamine levels. Type 2 diabetic heart failure patients' 6-minute hall walk distance improved by 7% (p = 0.02) during hyperglycemia as compared with normoglycemia.ConclusionsShort-term hyperglycemia by insulin discontinuation is associated with an increase in myocardial systolic contractile function in type 2 diabetic patients with and without heart failure and with a slightly prolonged walking distance in type 2 diabetic heart failure patients. (Clinicaltrials.gov identifier NCT00653510)

Early Cardiac Retention of Administered Stem Cells Determines Clinical Efficacy of Cell Therapy in Patients With Dilated Cardiomyopathy

The diagnosis of nonischemic dilated cardiomypathy (DCM) comprises a primary myocardial disease of various causes, which is characterized by left ventricular (LV) dilation and impaired myocardial contractility. Although a broad range of pharmacological and device therapies are available, morbidity and mortality remain high in patients with advanced DCM. Thus, there is an urgent need for novel therapies aiming at functional regeneration of myocardial contractility in DCM. Although regenerative therapies using administration of a variety of different cell types have emerged as a promising approach to improve heart function in patients with ischemic disease,1 only a few pilot studies have investigated intracoronary application of autologous bone marrow–derived cells (BMC) in patients with DCM. Seth et al2 performed intracoronary infusion of BMC in 24 patients with DCM and reported a modest 5% increase in LV ejection fraction in parallel with an increased ratio of capillaries to myocytes as evidenced by endomyocardial biopsies at 6 months. In the TOPCARE-DCM pilot study including 33 patients, the improvement in global and regional LV contractile function was rather heterogeneous but was also paralleled by improved microvascular function as assessed by measuring coronary flow reserve at 3 months after intracoronary infusion of BMC.3 Article, see p 165 In this issue of Circulation Research , Vrtovec et al4 now considerably extend these previous observations. The authors randomized 110 patients with DCM to either intracoronary …

Activation of Liver X receptors in the heart leads to accumulation of intracellular lipids and attenuation of ischemia–reperfusion injury

Liver X receptor (LXR)-α and -β play a major role in lipid and glucose homeostasis. Their expression and function in the heart is not well characterized. Our aim was to describe the expression of LXRs in the murine heart, and to determine effects of cardiac LXR activation on target gene expression, lipid homeostasis and ischemia. Both LXRα and -β were expressed in heart tissues, HL-1 cells and isolated cardiomyocytes as determined by qRT-PCR. Elevated cardiac expression of LXR target genes and LXRβ was observed 24h after in vivo permanent coronary artery ligation. The synthetic LXR agonist GW3965 induced mRNA expression of the LXR target genes in HL-1 cells and isolated cardiomyocytes. This was associated with a buildup of intracellular triglycerides and expanding lipid droplets as quantified by confocal microscopy. Mice injected with GW3965 had cardiac LXR activation as judged by increased target gene expression and lipid droplet accumulation. GW3965 in vivo and in vitro increased expression of genes inducing triglyceride synthesis, and altered expression of lipid droplet-binding protein genes. GW3965 protected HL-1 cells against hypoxia-reoxygenation induced apoptosis. LXR activation by GW3965 in vivo prior to heart isolation and perfusion with induced global ischemia and reperfusion improved left ventricular contractile function and decreased infarct size. In conclusion, LXRs are expressed in the murine heart in the basal state, and are activated by myocardial infarction. Activation of LXR by the synthetic agonist GW3965 is associated with intracardiac accumulation of lipid droplets and protection against myocardial ischemia-reperfusion injury.

EP News: Basic and Translational

SERCA2a is the pump responsible for reuptake of cytosolic calcium during diastole. It plays a central role in the molecular mechanism of cardiac alternans. Heart failure (HF) is associated with deficient SERCA2a and increased susceptibility to cardiac alternans. Cutler et al (Circulation 2012;Epub, PMID 23019291) performed a study to test the hypothesis that restoring deficient SERCA2a by gene transfer will significantly reduce arrhythmogenic cardiac alternans in the failing heart. They studied 3 groups of guinea pigs: (1) control, (2) HF, and (3) HF+AAV9.SERCA2a gene transfer. In vivo gene transfer of AAV9.SERCA2a in the failing heart improved left ventricular contractile function, suppressed cardiac alternans, and decreased incidence of inducible ventricular arrhythmias. The authors conclude that SERCA2a gene transfer in the failing heart not only improves contractile function but directly restores electrical stability through the amelioration of key arrhythmogenic substrate (i.e., cardiac alternans) and triggers (i.e., SR Ca2+ leak).

Targeted Sarcoplasmic Reticulum Ca 2+ ATPase 2a Gene Delivery to Restore Electrical Stability in the Failing Heart

Background— Recently, we reported that sarcoplasmic reticulum Ca 2+ ATPase 2a (SERCA2a), the pump responsible for reuptake of cytosolic calcium during diastole, plays a central role in the molecular mechanism of cardiac alternans. Heart failure (HF) is associated with impaired myocardial calcium handling, deficient SERCA2a, and increased susceptibility to cardiac alternans. Therefore, we hypothesized that restoring deficient SERCA2a by gene transfer will significantly reduce arrhythmogenic cardiac alternans in the failing heart. Methods and Results— Adult guinea pigs were divided into 3 groups: control, HF, and HF+AAV9.SERCA2a gene transfer. HF resulted in a decrease in left ventricular fractional shortening compared with controls ( P &lt;0.001). As expected, isolated HF myocytes demonstrated slower sarcoplasmic reticulum calcium uptake, decreased Ca 2+ release, and increased diastolic Ca 2+ ( P &lt;0.05) compared with controls. Moreover, SERCA2a, cardiac ryanodine receptor 2, and sodium-calcium exchanger protein expression was decreased in HF compared with control ( P &lt;0.05). As predicted, HF increased susceptibility to cardiac alternans, as evidenced by decreased heart rate thresholds for both V m alternans and Ca alternans compared with controls ( P &lt;0.01). Interestingly, in vivo gene transfer of AAV9.SERCA2a in the failing heart improved left ventricular contractile function ( P &lt;0.01), suppressed cardiac alternans ( P &lt;0.01), and reduced ryanodine receptor 2 P o secondary to reduction of ryanodine receptor 2–P S2814 ( P &lt;0.01). This ultimately resulted in a decreased incidence of inducible ventricular arrhythmias ( P= 0.05). Conclusions— These data show that SERCA2a gene transfer in the failing heart not only improves contractile function but also directly restores electric stability through the amelioration of key arrhythmogenic substrate (ie, cardiac alternans) and triggers (ie, sarcoplasmic reticulum Ca 2+ leak).

Effects of late REopening of Coronary total Occlusion on micRovascular perfusion and myocarDial function: the RECORD study

The effects of the reopening of a coronary total occlusion (CoTO) on microvascular perfusion in subacute or chronic coronary syndromes are actually unclear. We aimed at evaluating the microvascular perfusion pattern by myocardial contrast echocardiography (MCE), in addition to contractile function, before and after CoTO reopening. Twenty four patients with subacute and chronic coronary syndromes and CoTO datable >7 days underwent evaluation of microvascular perfusion and left ventricular (LV) function by MCE (Acuson Sequoia, with Sonovue, Bracco) before the reopening of the CoTO and at 9 ± 3 months of follow-up. Microvascular perfusion was semi-quantitatively assessed by the contrast score index (CSI), whereas the endocardial length of the perfusion defect [contrast defect length (CDL)], measured in three apical views and averaged, was expressed as a percentage of the total LV endocardial border. The wall motion score index (WMSI), LV volumes, and ejection fraction were also calculated. At baseline, a mild impairment of LV contractile function was observed, which corresponded to a similar impairment of the coronary microvascular perfusion in the overall study population. At follow-up, a significant reduction of CDL% [8.23 (0-19.63) vs. 0 (0-3.68), P = 0.005], improvement of the CSI (1.41 ± 0.29 vs. 1.12 ± 0.17, P = 0.001) and the WMSI (1.73 ± 0.41 vs. 1.33 ± 0.34, P = 0.0004), and increase in the ejection fraction (47.48% ± 8.66 vs. 55.60% ± 8.29, P = 0.0001) were found. Reopening of a CoTO in patients with clinical indications to myocardial revascularization is associated with the improvement of coronary microvascular perfusion and the recovery of contractile function.

MAGNETIC RESONANCE IMAGING WITH SUPERPARAMAGNETIC IRON OXIDE FAILS TO TRACK THE LONG-TERM FATE OF MESENCHYMAL STEM CELLS AFTER TRANSPLANTATION IN THE HEART

ObjectivesCurrently, magnetic resonance imaging (MRI) are adopted to evaluate the outcomes of cardiac cell therapy such as on left ventricular (LV) contractile function and LV remodelling. While the ability of...

Abstract 310: Inhibition of Class I Histone Deacetylase Activity Improves Left Ventricular Contractile Function and Cardiac Strain in Coronary Artery Occlusion-Induced Myocardial Infarction

Protection from coronary heart disease-induced damage of the myocardium during myocardial infarction (MI) injury has been a target of investigation for the development of innovative cardioprotective therapies. Histone deacetylases (HDACs) are a class of enzymes that affect the transcriptional regulation of genes during pathological conditions. We observed that class I/IIb HDAC activity was nearly 5 times greater in the 7-day post-MI LV when compared to the sham ventricles. In vitro inhibition studies indicated that the majority of increased activity was due to class I HDACs. Therefore we hypothesized that suppression of class I HDACs would prevent the pathophysiological changes occurring during MI, thus improving LV pump function in post-MI myocardium. CD-1 mice were administered with the a class I HDAC inhibitor pimelic diphenylamide (PD106) or vehicle immediately after induction of MI and the treatment continued every other day for 7 days post MI. LV end-diastolic volumes, expressed as change from pre-MI values, was significantly lower in the PD106 treated mice compared to vehicle treated mice. Further, the post-MI reduction in LV ejection faction was significantly attenuated in the PD106-treated mice compared to the MI alone group. Similarly, echo cardiac strain analysis showed improved LV strain and better coherence in contractile function among infarct and border zones in PD106 MI group compared to MI only. These unique findings demonstrate that class I HDAC inhibitors may provide a novel therapeutic means to attenuate adverse post-MI LV remodeling.