Impaired Contractile Reserve Research Articles

Hypertensive Patients Have Impaired Left Ventricular Contractile Reserve Despite Normal Ejection Fraction

Hypertension (HT) may lead to LV systolic impairment through chronic pressure overload. LV hypertrophy and systolic dysfunction occur late. An impaired contractile reserve (CR) may be an early manifestation of LV dysfunction in hypertensive patients. We examined CR and its correlates in hypertensive patients and compared that with normotensive controls. Methods: 129 prospectively recruited patients (68 men, aged 58.6 ± 9.5 years) underwent dobutamine echocardiography. Patients with diabetes, coronary disease, or significant valvular disease were excluded. 72 patients (56%) had treated HT. LV global longitudinal strain (GLS) was measured at rest and at low dose dobutamine. Absolute CR was calculated as the difference in GLS between low dose and resting values. Relative CR is the ratio of absolute CR to resting GLS. Results: There was no difference in LV ejection fraction between hypertensive patients and controls (64.5 ± 6.1% vs 64.5 ± 6.6% at rest, 72.1 ± 6.6% vs 71.2 ± 6.9% at low dose dobutamine; both p = NS). LVGLS in hypertensive patients was significantly impaired at rest (-16.8 ± 2.2% vs -19.5 ± 1.5%; both p < 0.001) and at low dose dobutamine (-17.9 ± 2.7% vs -22.7 ± 2.6%; both p < 0.001). More importantly, both the absolute and relative CR were significantly lower in hypertensive patients (-1.12% vs -3.17%; 7.24% vs 16.4% respectively, both p < 0.001). CR was not correlated with LV mass, prevailing blood pressure, septal e’ velocities, E/e’ ratio. Conclusions: Compared with controls, hypertensive patients not only had impaired LV GLS at rest, but also an impaired ability to augment contractility with inotropic stimulation, i.e. CR. This impaired CR is independent of LV mass, diastolic function or filling pressures.

Exercise speckle-tracking strain imaging demonstrates impaired right ventricular contractile reserve in hypertrophic cardiomyopathy

AimsTo analyse right ventricular (RV) systolic function in patients with hypertrophic cardiomyopathy (HCM) at rest and during exercise, and its possible correlation with left ventricular(LV) morphology and function. Methods and resultsStandard echo, exercise stress echo, and RV 2D speckle-tracking strain (2DSE) were performed in 45 patients with HCM and in 45 age- and sex-comparable healthy controls. RV global longitudinal strain (GLS) was calculated by averaging local strains along the entire right ventricle. LV mass index and IVS wall thickness were significantly increased in HCM, while LV ejection fraction, RV diameters, RV tissue Doppler systolic peak and the RV end-systolic pressure-area relationship at rest were comparable between the two groups. Conversely, all transmitral Doppler indexes were significantly impaired in HCM. In addition, RV GLS and regional peak myocardial RV strains were significantly reduced in patients with HCM (all P<0.001). During physical effort, LV ejection fraction was comparable between the two groups. Conversely, LV E/Em ratio was significantly increased in HCM. Increase in TAPSE and RV tissue Doppler Sm peak velocity during effort were similar between the two groups. Conversely, increases of RV end-systolic pressure-area, regional and global RV strain were significantly lower in HCM patients (RV lateral strain: 10.3±3.5% of increase in HCM vs 20.5±4.5% in controls; p<0.0001). Multivariable analysis detected independent associations of RV lateral strain at peak stress with LV IVS thickness, maximal workload during exercise, and LV E/Em ratio during effort (all p<0.0001). An RV lateral 2DSE cut-off point of −14% differentiated controls and HCM with an 86%sensitivity and a 92% specificity. ConclusionsRV contractile reserve for HCM is impaired and this suggests that the lower resting values of RV in HCM may represent early subclinical myocardial damage, closely associated with exercise capacity.

Tissue Doppler imaging during exercise stress echocardiography demonstrates a mechanism for impaired exercise performance in children with hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is associated with decreased exercise tolerance in children, presumably due to diastolic dysfunction. Modern imaging techniques to assess myocardial function during active exercise have not been applied to this population. We hypothesized that impaired contractile reserve, as assessed by tissue Doppler imaging (TDI) and strain, contributes to reduced exercise capacity in affected individuals. Children (<18years) with HCM and healthy age- and sex-matched controls were prospectively enrolled. Resting echocardiograms and staged upright cycle ergometry with simultaneous echocardiograms were performed. During exercise, left ventricular outflow tract (LVOT) gradients and color Doppler maps of apical four-chamber and parasternal short-axis views were obtained. Post processing of images was performed to obtain TDI velocities, and measurements of strain were attempted. Exercise parameters and staged TDI values were compared. The study population consisted of 58 subjects (22 with HCM and 36 controls). Patients with HCM had significantly higher peak LVOT gradients compared to controls at baseline and at each exercise stage. TDI revealed that diastolic function, as assessed by E' velocities at septal and lateral mitral annuli, normalized with exercise in HCM patients. Further, systolic function (S' velocity) of HCM patients at rest was normal but failed to augment normally at peak exercise. Children with HCM have decreased TDI velocities at rest. With exercise, they may increase their E' velocities but fail to augment S' velocities, demonstrating decreased contractile reserve. In the patient with suspected HCM but equivocal findings, exercise TDI assessment may complement the diagnostic evaluation.

Abstract 15830: ‘Out of Target’ Radiation Therapy Leads to Impaired Cardiac Contractile Reserve in the Mouse

Introduction: Radiation therapy (XRT) used for the treatment of cancer, can expose the heart to the radiation beam causing cardiac injury. However, fatigue and exercise intolerance are common symptoms in patients treated with XRT for different types of cancer, in which the XRT field does not involve the heart. Hypothesis: We hypothesize that impaired cardiac reserve may occur even when the XRT field is distant from the heart (‘out of target effect’). Methods: C57BL/6J female mice underwent two different radiation treatments (20 Gray, single dose) using a Small Animal Radiation Research Platform: a) the isocenter was pointed to the right lung sparing the heart (‘out of target’) and b) the heart was chosen as isocenter, as positive control. An additional group of mice were sham-irradiated, as negative control. Transthoracic echocardiography was used to assess the left ventricular ejection fraction (LVEF) at baseline and the contractile reserve expressed as percentage change in the LVEF measured at rest (LVEFr) and 3 minutes after intraperitoneal administration of the β-adrenergic agonist, isoproterenol (LVEFi)[(LVEFi-LVEFr)/LVEFr]*100]. Results: Three days after radiation treatment irradiated and sham mice showed normal LVEF at rest. However, the ‘out of target’ irradiation group showed a significant impairment in cardiac contractile reserve compared with sham, and similar to the ‘on target’ group (Figure). Conclusions: ‘Out of target’ radiation therapy leads to impaired cardiac contractile reserve in the mouse.

Selective TNF-α targeting with infliximab attenuates impaired oxygen metabolism and contractile function induced by an acute exposure to air particulate matter.

Inflammation plays a central role in the onset and progression of cardiovascular diseases associated with the exposure to air pollution particulate matter (PM). The aim of this work was to analyze the cardioprotective effect of selective TNF-α targeting with a blocking anti-TNF-α antibody (infliximab) in an in vivo mice model of acute exposure to residual oil fly ash (ROFA). Female Swiss mice received an intraperitoneal injection of infliximab (10 mg/kg body wt) or saline solution, and were intranasally instilled with a ROFA suspension (1 mg/kg body wt). Control animals were instilled with saline solution and handled in parallel. After 3 h, heart O2 consumption was assessed by high-resolution respirometry in left ventricle tissue cubes and isolated mitochondria, and ventricular contractile reserve and lusitropic reserve were evaluated according to the Langendorff technique. ROFA instillation induced a significant decrease in tissue O2 consumption and active mitochondrial respiration by 32 and 31%, respectively, compared with the control group. While ventricular contractile state and isovolumic relaxation were not altered in ROFA-exposed mice, impaired contractile reserve and lusitropic reserve were observed in this group. Infliximab pretreatment significantly attenuated the decrease in heart O2 consumption and prevented the decrease in ventricular contractile and lusitropic reserve in ROFA-exposed mice. Moreover, infliximab-pretreated ROFA-exposed mice showed conserved left ventricular developed pressure and cardiac O2 consumption in response to a β-adrenergic stimulus with isoproterenol. These results provides direct evidence linking systemic inflammation and altered cardiac function following an acute exposure to PM and contribute to the understanding of PM-associated cardiovascular morbidity and mortality.

The right ventricle in scleroderma (2013 Grover Conference Series).

Pulmonary arterial hypertension (PAH) results from severe remodeling of the distal lung vessels leading irremediably to death through right ventricular (RV) failure. PAH (Group 1 of the World Health Organization classification of pulmonary hypertension) can be idiopathic (IPAH) or associated with other disorders, such as connective tissue diseases. Prominent among the latter is systemic sclerosis (SSc), a heterogeneous disorder characterized by endothelium dysfunction, dysregulation of fibroblasts resulting in excessive collagen production, and immune abnormalities. For as-yet-unknown reasons, SSc-associated PAH (SSc-PAH) carries a significantly worse prognosis compared with any other form of PAH in Group 1, including IPAH. We have previously shown that patients with SSc-PAH have a median survival of only 3 years, compared with 8 years for IPAH, despite modern PAH therapy. Because death is principally due to RV failure, we speculated that RV adaptation to PAH differed between the two entities due to disparate pulmonary artery loading, perhaps from vessel stiffening, or intrinsic RV myocardial disease that might limit function and adaptation to high afterload. In SSc, RV function may also be impaired by inflammatory processes, excess fibrosis of the myocardium, or altered angiogenesis, which may all contribute to impaired contractile reserve exacerbating cardiopulmonary impedance mismatch. This is now suggested by recent findings from our group that demonstrate that, although pulmonary vascular load may be similar between patients with IPAH and those with SSc-PAH, the latter display reduced myocardial contractility as assessed by pressure-volume loop measurements. This review focuses on fundamental hemodynamic, structural, and functional differences in RV from patients with SSc-PAH compared with IPAH, which may account for survival discrepancies between the two populations. Possible underlying basic mechanisms are discussed.

Assessment of cardiovascular physiology using magnetic resonance myocardial stress testing reveals impaired contractile reserve in patients with cirrhotic cardiomyopathy

Background Liver cirrhosis has been shown to affect cardiac performance. However cardiac dysfunction may only be revealed under stress conditions. The value of non-invasive stress tests in diagnosing cirrhotic cardiomyopathy is unclear since their ability to detect abnormalities has been inconsistent using different imaging modalities. We sought to investigate the response to pharmacological stimulation with dobutamine in patients with cirrhosis using cardiovascular magnetic resonance. Methods Thirty-six patients and eight controls were studied. Conventional volumetric and myocardial deformation parameter analysis using feature tracking at rest and during low to intermediate dose dobutamine stress were performed. Results Whilst volumetry based parameters were similar between patients and controls at rest, patients had a smaller increase in cardiac output during stress (2.2 l/min vs. 3.8 l/min), p=0.015). Chronotropic response was not different in the two groups (24 bpm vs 25 bpm, p=0.44). Ejection fraction increase was impaired in patients during 10 μg/Kg/min dobutamine as compared to controls (6.9% vs. 16.5%, p=0.007), but not with 20 μg/Kg/min (12.1% vs. 17.6%, p=0.12). This was paralleled by an impaired improvement in circumferential strain with low dose (median percentual increase of 14.4% vs. 30.9%, p=0.03), but not with intermediate dose dobutamine (median percentual increase of 29.4% vs. 33.9%, p=0.54). There was an impaired longitudinal strain increase in patients as compared to controls during low (median percentual increase of 6.6% vs 28.6%, p<0.001) and intermediate dose dobutamine (median percentual increase of 2.6%vs, 12.6% p=0.016). Radial strain response to dobutamine was similar in patients and controls (median percentual increase of 7.7% (-2.4-15.2) vs 13.6% (5.7-26), p=0.11 with10 μg/Kg/min of dobutamine and 4.3% (0.6-8.1) vs 3.1% (-0.2-9.3), p=0.82 with 20 μg/Kg/min of dobutamine). Conclusions Cirrhotic cardiomyopathy is characterized by an impaired cardiac pharmacological response that can be detected with magnetic resonance myocardial stress testing. Deformation analysis parameters may be more sensitive in identifying abnormalities in inotropic response to stress than conventional methods. Funding NA.

Assessment of cardiovascular physiology using dobutamine stress cardiovascular magnetic resonance reveals impaired contractile reserve in patients with cirrhotic cardiomyopathy.

BackgroundLiver cirrhosis has been shown to affect cardiac performance. However cardiac dysfunction may only be revealed under stress conditions. The value of non-invasive stress tests in diagnosing cirrhotic cardiomyopathy is unclear. We sought to investigate the response to pharmacological stimulation with dobutamine in patients with cirrhosis using cardiovascular magnetic resonance.MethodsThirty-six patients and eight controls were scanned using a 1.5 T scanner (Siemens Symphony TIM; Siemens, Erlangen, Germany). Conventional volumetric and feature tracking analysis using dedicated software (CMR42; Circle Cardiovascular Imaging Inc, Calgary, Canada and Diogenes MRI; Tomtec; Germany, respectively) were performed at rest and during low to intermediate dose dobutamine stress.ResultsWhilst volumetry based parameters were similar between patients and controls at rest, patients had a smaller increase in cardiac output during stress (p = 0.015). Ejection fraction increase was impaired in patients during 10 μg/kg/min dobutamine as compared to controls (6.9 % vs. 16.5 %, p = 0.007), but not with 20 μg/kg/min (12.1 % vs. 17.6 %, p = 0.12). This was paralleled by an impaired improvement in circumferential strain with low dose (median increase of 14.4 % vs. 30.9 %, p = 0.03), but not with intermediate dose dobutamine (median increase of 29.4 % vs. 33.9 %, p = 0.54). There was an impaired longitudinal strain increase in patients as compared to controls during low (median increase of 6.6 % vs 28.6 %, p < 0.001) and intermediate dose dobutamine (median increase of 2.6%vs, 12.6 % p = 0.016). Radial strain response to dobutamine was similar in patients and controls (p > 0.05).ConclusionCirrhotic cardiomyopathy is characterized by an impaired cardiac pharmacological response that can be detected with magnetic resonance myocardial stress testing. Deformation analysis parameters may be more sensitive in identifying abnormalities in inotropic response to stress than conventional methods.

Abstract 12622: Western Diet for One Month Impairs Myocardial Energetics and Both Systolic and Diastolic Pump Function in the Mouse Heart

Background and Significance: Metabolic heart disease(MHD) is common in patients with obesity, type 2 diabetes and/or metabolic syndrome. We found cardiac mitochondrial dysfunction in mice with obesity-related MHD due to consumption of a high fat high sucrose (HFHS) diet. The effects of diet-induced obesity on cardiac energetics and pump function in the intact organ are largely unknown. Hypothesis: We tested the hypothesis that cardiac mitochondrial dysfunction due to HFHS diet for one month impairs energetic and contractile reserve in the intact heart. Methods and Results: Mice were fed a HFHS or control diet (CD) for 1 month. In isolated cardiac mitochondria from HFHS-fed mice (vs. CD) the maximal rate of ATP synthesis was decreased for complex I (down by 42%; p&lt;0.05) and II (down by 37%; p&lt;0.05) substrates. We measured myocardial energetics in isolated perfused hearts using 31P NMR spectroscopy at baseline (450 bpm, 2 mM Ca++) and high workload (600 bpm, 4 mM Ca++) in HFHS (n=7) and CD (n=8) hearts. In HFHS-fed hearts, myocardial ATP concentration was the same at baseline (10.5±0.4 vs 10.4±0.5 mM) and high workload (7.4±0.9 vs. 7.5±0.5 mM) as that of CD hearts. However, in HFHS-fed hearts the concentration of phosphocreatine, which reflects energy reserve, was decreased at baseline (13±0.7 vs. 17.5±0.8 mM; p&lt;0.01) and decreased further at high workload (down to 7.3±0.7; p&lt;0.01 vs. baseline and p&lt;0.01 vs. CD at 10.5±0.4 mM) - indicating a mismatch between ATP production and utilization. In HFHS hearts, the diastolic pressure-volume relationship was shifted upward and leftward at baseline, indicative of diastolic dysfunction. In HFHS hearts, baseline systolic function was preserved (rate pressure product 41,600±2,200 vs. 41,000±2,000 mmHg/min), but was decreased at high workload (54,800±7,200 vs. 85,300±4,300 mmHg/min; p&lt;0.01 vs. CD), reflecting an impaired contractile reserve. Conclusion: Consumption of a HFHS diet for one month causes cardiac mitochondrial dysfunction with reduced ATP synthesis leading to impaired energetic reserve in the intact heart. Diastolic dysfunction at rest and the impaired ability to increase systolic function with increased work demands may result from impaired energetics in MHD.

Expression of uncoupling protein-2 remains increased within hibernating myocardium despite successful coronary artery bypass grafting at 4 wk post-revascularization

BackgroundWe have previously shown that mitochondrial uncoupling protein-2 (UCP-2) is increased in a swine model of hibernating myocardium (HM). Although UCP-2 reduces oxidant stress, it can promote inefficiency of the electron transport chain. In this study, we tested whether UCP-2 remains increased in revascularized HM (RHM) after coronary artery bypass grafting (CABG). MethodsSeven swine underwent thoracotomy with placement of a constrictor on the left anterior descending artery (LAD). Twelve weeks later, a left internal mammary artery graft was placed on the distal LAD. Four weeks post-CABG, computed tomography angiography documented patent grafts and function. At the terminal study, blood flow to the LAD and remote territories were assessed during high dose dobutamine and mitochondria isolated from both regions for analysis. Comparisons were made to a group of swine with HM who underwent constrictor placement without bypass grafting (n = 4). ResultsDuring dobutamine infusion, RHM demonstrated lower blood flows (2.44 ± 0.23 versus 3.43 ± 0.30 mL/min/g; P < 0.05) and reduced wall thickening (33 ± 9% versus 52 ± 13%; P < 0.05) compared with remote regions. RHM had lower respiratory control indices (3.7 ± 0.3 versus 4.3 ± 0.4; P < 0.05) with persistently increased UCP-2 content. ConclusionsDespite patent grafts, RHM demonstrates a submaximal response to dobutamine infusion and increased mitochondrial UCP-2 expression. These data support the notion that recovery of the mitochondria in RHM is delayed early post-CABG and may contribute to impaired oxygen consumption and contractile reserve during catecholamine challenges.

Interleukin-1β induces a reversible cardiomyopathy in the mouse

Inflammatory mediators play a key role in the development and progression of heart failure. Interleukin-1β (IL-1β) is a prototypical inflammatory cytokine that suppresses myocyte contractility following acute administration. Healthy mice were randomly assigned to daily intraperitoneal injections of recombinant murine IL-1β (3 μg/kg in 0.2 ml) or matching volumes of NaCl 0.9 % solution (vehicle) for 15 days. Echocardiography was performed at baseline and 4 h (acute), followed by repeat measurements immediately prior to IL-1β or saline injections on days 5, 10, and 15 (chronic). Final echocardiography was performed on day 20 (5 days after last treatment). A subgroup of animals underwent isoproterenol challenge to evaluate contractile reserve at baseline, 4 h (acute), 15 days (chronic) and 20 days (recovery). IL-1β reduced left ventricular fractional shortening (LVFS) at 4 h versus vehicle (-24 vs. 0 %, respectively, P < 0.05). This reduction was maintained throughout chronic dosing at day 15. IL-1β-treated mice also showed impaired contractile reserve with a right shift of the dose-response curve to isoproterenol (P < 0.05) at 4 h and 15 days. By day 20, 5 days after stopping IL-1β, LVFS and contractile reserve had returned to baseline. IL-1β induces a reversible contractile dysfunction associated with impaired response to β-receptor stimulation.

Increased 99mTc-Sestamibi Washout Reflects Impaired Myocardial Contractile and Relaxation Reserve During Dobutamine Stress Due to Mitochondrial Dysfunction in Dilated Cardiomyopathy Patients

This study investigated whether the technitium-99m sestamibi (MIBI) washout rate (WR) would predict mitochondrial damage and myocardial dysfunction in patients with dilated cardiomyopathy (DCM). Myocardial mitochondrial damage reduces adenosine triphosphate production, resulting in myocardial dysfunction. Increased myocardial (99m)Tc-MIBI washout is reportedly caused by mitochondrial dysfunction. Twenty DCM patients (New York Heart Association functional class I-III) underwent myocardial (99m)Tc-MIBI scintigraphy and cardiac catheterization. Myocardial MIBI uptake was quantified as an early and delayed heart-to-mediastinum ratio, and WR was calculated. Maximum first derivative of left ventricular (LV) pressure (LV dP/dtmax) (an index of myocardial contractility) and LV pressure half-time (T1/2) (an index of myocardial relaxation) were calculated by the left ventricular pressure curve at baseline and during dobutamine infusion (15 μg/kg/min at maximum). Endomyocardial biopsy specimens were obtained for quantitative mRNA analysis and electron microscopy. The patients were divided into two groups as follows: 1) group A of 10 patients showing a WR ≤ 24.3% (median value) and 2) group B of 10 patients showing a WR >24.3%. WR was significantly correlated with the percentage changes in LV dP/dtmax (%LV dP/dtmax) (r: -0.59; p = 0.01) and T1/2 (r: -0.57; p = 0.03) from baseline to peak dobutamine stress. The %LV dP/dtmax was significantly greater in group B than in group A. The abundance of mRNAs for mitochondrial electron transport-related enzymes was more significantly reduced in group B than in group A. Electron microscopy revealed significant correlations between WR and the severity of mitochondrial damage (r: 0.88; p = 0.048) and glycogen accumulation (r: 0.90; p = 0.044). Increased (99m)Tc-MIBI washout may predict mitochondrial dysfunction and the impairment of myocardial contractile and relaxation reserves during dobutamine stress in DCM patients.

Impaired cardiac mitochondrial function and contractile reserve following an acute exposure to environmental particulate matter

BackgroundIt has been suggested that mitochondrial function plays a central role in cardiovascular diseases associated with particulate matter inhalation. The aim of this study was to evaluate this hypothesis, with focus on cardiac O2 and energetic metabolism, and its impact over cardiac contractility. MethodsSwiss mice were intranasally instilled with either residual oil fly ash (ROFA) (1.0mg/kg body weight) or saline solution. After 1, 3 or 5h of exposure, O2 consumption was evaluated in heart tissue samples. Mitochondrial respiration, respiratory chain complexes activity, membrane potential and ATP content and production rate were assessed in isolated mitochondria. Cardiac contractile reserve was evaluated according to the Langendorff technique. ResultsThree hours after ROFA exposure, tissue O2 consumption was significantly decreased by 35% (from 1180±70 to 760±60ng-at O/ming tissue), as well as mitochondrial rest (state 4) and active (state 3) respiration, by 30 and 24%, respectively (control state 4: 88±5ng-at O/minmg protein; state 3: 240±20ng-at O/minmg protein). These findings were associated with decreased complex II activity, mitochondrial depolarization and deficient ATP production. Even though basal contractility was not modified (control: 75±5mm Hg), isolated perfused hearts failed to properly respond to isoproterenol in ROFA-exposed mice. Tissue O2 consumption rates positively correlated with cardiac contractile state in controls (r2=0.8271), but not in treated mice (r2=0.1396). General SignificanceThe present results show an impaired mitochondrial function associated with deficient cardiac contractility, which could represent an early cardiovascular alteration after the exposure to environmental particulate matter.

Dynamic Dyssynchrony and Impaired Contractile Reserve of the Left Ventricle in Beta-Thalassaemia Major: An Exercise Echocardiographic Study

BackgroundPerformance of the left ventricle during exercise stress in thalassaemia patients is uncertain. We aimed to explore the phenomenon of dynamic dyssynchrony and assess contractile reserve in patients with beta-thalassaemia major and determine their relationships with myocardial iron load.Methods and ResultsThirty-two thalassaemia patients (16 males), aged 26.8±6.9 years, without heart failure and 17 healthy controls were studied. Their left ventricular (LV) volumes, ejection fraction, systolic dyssynchrony index (SDI), and myocardial acceleration during isovolumic LV contraction (IVA) were determined at rest and during submaximal bicycle exercise testing using 3-dimensional and tissue Doppler echocardiography. Myocardial iron load as assessed by T2* cardiac magnetic resonance in patients were further related to indices of LV dyssynchrony and contractile reserve. At rest, patients had significantly greater LV SDI (p<0.001) but similar IVA (p = 0.22) compared with controls. With exercise stress, the prevalence of mechanical dyssynchrony (SDI>4.6%, control+2SD) increased from baseline 25% to 84% in patients. Δ SDIexercise-baseline correlated with exercise-baseline differences in LV ejection fraction (p<0.001) and stroke volume (p = 0.006). Compared with controls, patients had significantly less exercise-induced increase in LV ejection fraction, cardiac index, and IVA (interaction, all p<0.05) and had impaired contractile reserve as reflected by the gentler IVA-heart rate slope (p = 0.018). Cardiac T2* in patients correlated with baseline LV SDI (r = −0.44, p = 0.011) and IVA-heart rate slope (r = 0.36, p = 0.044).ConclusionsResting LV dyssynchrony is associated with myocardial iron load. Exercise stress further unveils LV dynamic dyssynchrony and impaired contractile reserve in patients with beta-thalassaemia major.

A mouse model of radiation-induced cardiomyopathy

A mouse model of radiation-induced cardiomyopathy

Transforming Growth Factor β1 Oppositely Regulates the Hypertrophic and Contractile Response to β-Adrenergic Stimulation in the Heart

BackgroundNeuroendocrine activation and local mediators such as transforming growth factor-β1 (TGF-β1) contribute to the pathobiology of cardiac hypertrophy and failure, but the underlying mechanisms are incompletely understood. We aimed to characterize the functional network involving TGF-β1, the renin-angiotensin system, and the β-adrenergic system in the heart.MethodsTransgenic mice overexpressing TGF-β1 (TGF-β1-Tg) were treated with a β-blocker, an AT1-receptor antagonist, or a TGF-β-antagonist (sTGFβR-Fc), were morphologically characterized. Contractile function was assessed by dobutamine stress echocardiography in vivo and isolated myocytes in vitro. Functional alterations were related to regulators of cardiac energy metabolism.ResultsCompared to wild-type controls, TGF-β1-Tg mice displayed an increased heart-to-body-weight ratio involving both fibrosis and myocyte hypertrophy. TGF-β1 overexpression increased the hypertrophic responsiveness to β-adrenergic stimulation. In contrast, the inotropic response to β-adrenergic stimulation was diminished in TGF-β1-Tg mice, albeit unchanged basal contractility. Treatment with sTGF-βR-Fc completely prevented the cardiac phenotype in transgenic mice. Chronic β-blocker treatment also prevented hypertrophy and ANF induction by isoprenaline, and restored the inotropic response to β-adrenergic stimulation without affecting TGF-β1 levels, whereas AT1-receptor blockade had no effect. The impaired contractile reserve in TGF-β1-Tg mice was accompanied by an upregulation of mitochondrial uncoupling proteins (UCPs) which was reversed by β-adrenoceptor blockade. UCP-inhibition restored the contractile response to β-adrenoceptor stimulation in vitro and in vivo. Finally, cardiac TGF-β1 and UCP expression were elevated in heart failure in humans, and UCP – but not TGF-β1 – was downregulated by β-blocker treatment.ConclusionsOur data support the concept that TGF-β1 acts downstream of angiotensin II in cardiomyocytes, and furthermore, highlight the critical role of the β-adrenergic system in TGF-β1-induced cardiac phenotype. Our data indicate for the first time, that TGF-β1 directly influences mitochondrial energy metabolism by regulating UCP3 expression. β-blockers may act beneficially by normalizing regulatory mechanisms of cellular hypertrophy and energy metabolism.

Relation of 99mTc-sestamibi washout with myocardial properties in patients with hypertrophic cardiomyopathy

BackgroundWe sought to determine the relationship between 99mTc-sestamibi washout and myocardial properties in hypertrophic cardiomyopathy (HCM) patients. Methods and ResultsTwenty-four HCM patients underwent biventricular cardiac catheterization, with a micromanometer-tipped catheter, both at rest and during atrial pacing, echocardiography and myocardial 99mTc-sestamibi scintigraphy at rest. The 99mTc-sestamibi washout rate (WR) was calculated using initial and delayed planar images. The HCM patients were divided into two groups as follows: Group A consisted of 13 patients showing 99mTc-sestamibi WR < 22.5%; group B of 11 patients showing 99mTc-sestamibi WR ≥ 22.5%. Significant correlations were observed between 99mTc-sestamibi WR and percentage changes in pressure half-time (T1/2), as well as those in the maximum first derivative LV pressure (LV dP/dtmax) (r = .43, P = .033; r = −.63, P = .001). The percentage changes in LV dP/dtmax and those in T1/2 were significantly more reduced in group B than in group A (P < .05). The biphasic force-frequency relation was more frequently observed in group B than in group A (82% vs. 18%). ConclusionIncreased 99mTc-sestamibi washout is associated with an impaired contractile reserve and prolonged relaxation, suggesting that myocardial 99mTc-sestamibi scintigraphy may be useful in noninvasively detecting the early impairment of myocardial function in HCM patients.

Histone deacetylase inhibition (HDACi) attenuates catecholamine‐induced impairments in contractile reserve

Chronic catecholamine excess is a well‐characterized model of cardiac hypertrophy and dysfunction. We recently demonstrated adult, non‐senescent rats have impaired contractile reserve, and increased hypertrophic gene expression and caspase activity following chronic isoproterenol (ISO) administration. HDACi is reported to decrease stress‐induced cardiac hypertrophy, hypertrophic gene expression, and cell apoptosis. We evaluated the efficacy of Scriptaid, a hydroxamate pan‐HDACi, to inhibit impairments in contractile reserve following chronic ISO. Rats were administered Scriptaid (10 mg/kg, i.p.) or vehicle (100% DMSO) daily, followed 1 hr later by ISO (0.1 mg/kg, s.c.) or its vehicle for 3 wks. Chronic ISO impaired contractile reserve (Δ+dP/dtmax) to milrinone (20 – 200 μl/kg/min) by &gt;50%, increased left ventricular (LV) collagen1a (13 fold) and ANF (5 fold) mRNA expression and caspase‐3 activity (24%), while inducing LV hypertrophy (33±10%). Scriptaid completely prevented decreases in contractile reserve and attenuated ISO‐induced LV hypertrophy by 37%. Scriptaid treatment reduced ISO‐induced increases in collagen1a and ANF mRNA expression (−53% and −33%, respectively) while normalizing caspase‐3 activity. These results suggest HDACi modulates epigenetic and apoptotic pathways thus improving cardiac performance in a model of catecholamine‐induced cardiac contractile dysfunction.

Impaired cardiac functional reserve in type 2 diabetic db/db mice is associated with metabolic, but not structural, remodeling

To identify the nature of myocardial alterations associated with diabetes, cardiac function, structural remodeling, and gene expression in hearts of type 2 diabetic db/db mice were studied.Db/db mice showed typical characteristics of type 2 diabetes and preserved cardiac function up to 18 wks of age under non‐challenging conditions. However, β‐adrenergic stimulation with dobutamine revealed impaired contractile and relaxation reserve capacity. Tissue analyses showed no signs of structural remodeling. Neither β1‐adrenoceptor (β1AR) expression nor phosphorylation state of contractile protein targets of β1AR – protein kinase A (PKA) signaling were altered. In contrast, the substantially increased expression of uncoupling protein‐3 (UCP3) and angiopoietin‐like‐4 (Angptl4), along with decreased phosphorylation of AMP‐activated protein‐kinase (AMPK) in the heart of diabetic animals, are indicative of altered mitochondrial efficiency, decline in plasma triacylglycerol consumption and changes in intermediary substrate metabolism, respectively, which together may compromise ATP synthesis, required for maintenance of cardiac function at increased work load.We conclude that impaired cardiac functional reserve capacity during maximal β‐adrenergic stimulation, is an early sign of cardiac dysfunction in db/db mice which is primarily associated with unfavorable changes in cardiac metabolism.

002 Compensation for impaired myocardial phosphotransfer in guanidinoacetate-N-methyltransferase knockout mice

Guanidinoacetate-N-methyltransferase (GAMT) is a key enzyme in creatine biosynthesis, such that GAMT knockout mice lack phosphocreatine (PCr) as a substrate for energy transfer via the creatine kinase (CK) reaction. Despite...