Dietary supplementation with vitamin E ameliorates cardiac failure in type I diabetic cardiomyopathy by suppressing myocardial generation of 8-iso-prostaglandin F2alpha and oxidized glutathione

BackgroundDiabetic cardiomyopathy has been documented as an underlying cause of heart failure in diabetic patients. Although oxidative stress has been implicated in diabetic cardiomyopathy, much of the current evidence lacks specificity. Furthermore, studies investigating antioxidant protection with vitamin E in this unique cardiac phenomenon have yet to be performed. In the present study, we sought to determine whether vitamin E supplementation can confer cardioprotective effects against diabetic cardiomyopathy in relation to specific and quantitative markers of myocardial oxidative stress.Methods and ResultsDiabetes was induced in rats by a single injection of streptozotocin. Animals were fed either a basal diet or a diet enriched with 2000 IU of vitamin E per kilogram beginning immediately after induction of diabetes and continued for 8 weeks. Rats were examined for diabetic cardiomyopathy by left ventricular (LV) hemodynamic analysis. Myocardial oxidative stress was assessed by measuring the formation of 8-iso-prostaglandin F_2α and oxidized glutathione. In the unsupplemented streptozotocin-diabetic rats, LV systolic pressure, rate of pressure increase (+dP/dt), and rate of pressure decay (−dP/dt) were depressed, whereas LV end-diastolic pressure was increased, indicating reduced LV contractility and slowing of LV relaxation. These hemodynamic alterations were accompanied by increased myocardial formation of 8-iso-prostaglandin F_2α and oxidized glutathione. Vitamin E supplementation improved LV function and significantly attenuated myocardial 8-iso-prostaglandin F_2α and oxidized glutathione accumulation in streptozotocin-diabetic rats.ConclusionsThese findings demonstrate the usefulness of vitamin E supplementation during the early phases of type I diabetes for the prophylaxis of cardiomyopathy and subsequent heart failure.     

Alterations in the diabetic myocardial proteome coupled with increased myocardial oxidative stress underlies diabetic cardiomyopathy

Diabetic cardiomyopathy has been documented as an underlying etiology of heart failure (HF) among diabetics. Although oxidative stress has been proposed to contribute to diabetic cardiomyopathy, much of the evidence lacks specificity. Furthermore, whether alterations occur at the cardiac proteome level in diabetic cardiac complications with attendant oxidative stress remains unknown. Therefore, we sought to identify cardiac protein changes in relation to myocardial oxidative stress that are specific to diabetic cardiomyopathy. Diabetes was induced in rats by a single injection of streptozotocin (STZ). STZ-treated rats were examined for diabetic cardiomyopathy at 8 weeks post-STZ by left ventricular (LV) hemodynamic analysis. LV systolic pressure (LVSP), rate of pressure rise (+ dP/dt), and rate of pressure decay (− dP/dt) were depressed while LV end-diastolic pressure (LVEDP) was increased. Myocardial oxidative stress was increased in STZ-diabetic rats, as indexed by significant increases in myocardial formation of 8-iso PGF_2α and oxidized glutathione (GSSG). In-depth mining of the diabetic myocardial proteome by proteomic analysis utilizing two-dimensional difference gel electrophoresis and mass spectrometry (DIGE/MS) techniques revealed that a high proportion (12 of 24) of the altered proteins that could be identified by mass spectrometry were localized to the mitochondria. Down-regulation of antioxidant and anti-apoptotic proteins was also observed in STZ-diabetic hearts. These results characterize a specific ‘type I diabetic’ pattern of cardiac proteome changes indicative of diabetic cardiomyopathy presenting with higher oxidative stress, supporting the idea that analysis of isoprostane biosynthesis and protein expression profiles may be useful diagnostically to assess the efficacy of antioxidant therapies as prophylactic treatments against type I diabetes mellitus complications involving the heart.     

Waon therapy attenuates cardiac hypertrophy and promotes myocardial capillary growth in hypertensive rats: a comparative study with fluvastatin

Cardiac hypertrophy and fibrosis in heart failure with preserved ejection fraction are associated with a pro-inflammatory state and reduced NO bioavailability. Effects on myocardial structural and molecular alterations were compared between Waon therapy (WT; repeated dry sauna therapy) and statin in hypertensive rats. Seven-week-old Dahl salt-sensitive rats were assigned to 4 groups: low-salt (LS) diet, high-salt (HS) diet, HS diet with oral fluvastatin (FL; 10 mg/kg/day for 4 weeks) starting from the age of 9 weeks, and HS diet with WT treatment in a far-infrared dry sauna (39 °C for 15 min followed by 34 °C for 20 min once daily for 4 weeks). HS rats developed left ventricular (LV) hypertrophy with preserved LV systolic function. WT reduced LV wall thickness and myocyte cross-sectional area along with decreased levels of myocardial ANP and BNP mRNA expression compared with HS rats. Reduction in LV fibrosis and increase in capillary density in WT animals were accompanied by reductions in myocardial levels of TGF-β1, MMP2, p22^phox and gp91^phox mRNA expression, and increases in myocardial levels of VEGF and HSP90 mRNA and phosphorylated eNOS protein. These effects were comparable between WT and FL animals. WT improves structural and molecular alterations in salt-induced hypertensive rats similarly to fluvastatin.     

Decreased myocardial free fatty acid uptake in patients with idiopathic dilated cardiomyopathy: evidence of relationship with insulin resistance and left ventricular dysfunction

BackgroundResults on myocardial substrate metabolism in the failing heart have been contradictory. Insulin resistance, a common comorbidity in heart failure patients, and medical therapy may modify myocardial metabolism in complex fashions. Therefore, we characterized myocardial oxidative and free fatty acid (FFA) metabolism in patients with idiopathic dilated cardiomyopathy (IDCM) and investigated the contributions of insulin resistance and β-blocker therapy.Methods and ResultsNineteen patients with IDCM (age 58 ± 8 years, ejection fraction 33 ± 8.8%) and 15 healthy controls underwent examination of myocardial blood perfusion, oxidative and FFA metabolism using positron emission tomography and [¹⁵O]H₂O, [¹¹C]acetate and [¹¹C]palmitate, respectively. Echocardiography was used to assess myocardial function, work, and efficiency of forward work. Insulin resistance was calculated using the homeostasis model assessment index (HOMA index) and the degree of β-blockade was estimated with a β-adrenoceptor occupancy test. IDCM patients were characterized by decreased cardiac efficiency (35 ± 2 versus 57 ± 12 mm Hg·L·g⁻¹, P < .0001) and reduced myocardial FFA uptake (5.5 ± 2.0 versus 6.4 ± 1.2 μmol·100 g⁻¹·min⁻¹, P < .05), but the FFA β-oxidation rate constant was not changed. In the patients, myocardial FFA uptake was inversely associated with left ventricular (LV) ejection fraction (r = −0.63, P < .01), indicating that further depression of LV function induces an opposite switch to greater FFA uptake. The FFA β-oxidation rate constant correlated positively with the HOMA index (r = 0.53, P < .05). In patients on β-1 selective β-blockers, β-1 adrenoceptor occupancy correlated inversely with LV work, oxidative metabolism, and FFA uptake; similar relationships were not found in patients on nonselective β-blocker.ConclusionsMyocardial FFA metabolism is reduced in patients with IDCM. However, when LV function is further depressed and insulin resistance manifested, myocardial FFA uptake and oxidation are, in turn, upregulated. These findings may partly explain the discrepancies between previous studies about cardiac metabolism in heart failure.     

Hypercholesterolemia exacerbates ventricular remodeling in the rat model of myocardial infarction

BackgroundDetrimental left ventricular (LV) remodeling is exacerbated in hypercholesterolemic patients with myocardial infarction; however, this could result from either larger infarcts or more extensive remodeling itself in this population. Therefore, we sought to investigate whether high cholesterol feeding exacerbates LV remodeling and heart failure in rats with myocardial infarction independently from its influence on infarct size.Methods and ResultsMyocardial infarction was induced by permanent ligation of left coronary artery in rats fed normal and high-cholesterol diet and the animals were followed for 8 weeks. Hypercholesterolemic rats were matched with normocholesterolemic animals for infarct size 24 hours after infarction and exhibited more pronounced LV dilation at 8 weeks after infarction (LV systolic/diastolic diameter 8.1 ± 0.2/10.2 ± 0.3 versus 6.7 ± 0.2/8.9 ± 0.2, respectively, measured by echocardiography, P < .05 each). Pressure-volume curves obtained in isolated Langendorff-perfused hearts revealed higher diastolic LV volumes (1677 ± 102 versus 1385 ± 46 μL/kg body weight, P < .05) and hemodynamic examination demonstrated higher LV end-diastolic pressure (21.8 ± 0.7 versus 18.7 ± 1.0 mm Hg, P < .05) in hypercholesterolemic rats compared with normocholesterolemic animals.ConclusionIn a rat model of myocardial infarction, LV remodeling and heart failure are more pronounced in rats fed high-cholesterol diet in comparison to animals fed normal chow. This effect is independent from effect of hypercholesterolemia on infarct size.     

Cardiospheres reverse adverse remodeling in chronic rat myocardial infarction: roles of soluble endoglin and Tgf-β signaling

The mechanism of flow propagation during diastole in the left ventricle (LV) has been well described. Little is known about the associated waves propagating along the heart walls. These waves may have a mechanism similar to pulse wave propagation in arteries. The major goal of the study was to evaluate the effect of myocardial stiffness and preload on this wave transmission. Longitudinal late diastolic deformation and wave speed (Vp) of myocardial stretch in the anterior LV wall were measured using sonomicrometry in 16 pigs. Animals with normal and altered myocardial stiffness (acute myocardial infarction) were studied with and without preload alterations. Elastic modulus estimated from Vp (E _VP; Moens–Korteweg equation) was compared to incremental elastic modulus obtained from exponential end-diastolic stress–strain relation (E _SS). Myocardial distensibility and α- and β-coefficients of stress–strain relations were calculated. Vp was higher at reperfusion compared to baseline (2.6 ± 1.3 vs. 1.3 ± 0.4 m/s; p = 0.005) and best correlated with E _SS (r ² = 0.80, p < 0.0001), β-coefficient (r ² = 0.78, p < 0.0001), distensibility (r ² = 0.47, p = 0.005), and wall thickness/diameter ratio (r ² = 0.42, p = 0.009). Elastic moduli (E _VP and E _SS) were strongly correlated (r ² = 0.83, p < 0.0001). Increasing preload increased Vp and E _VP and decreased distensibility. At multivariate analysis, E _SS, wall thickness, and end-diastolic and systolic LV pressures were independent predictors of Vp (r ² model = 0.83, p < 0.0001). In conclusion, the main determinants of wave propagation of longitudinal myocardial stretch were myocardial stiffness and LV geometry and pressure. This local wave speed could potentially be measured noninvasively by echocardiography.     

Effects of simultaneous and optimized sequential cardiac resynchronization therapy on myocardial oxidative metabolism and efficiency

Introduction: Cardiac resynchronization therapy (CRT) can improve left ventricular (LV) hemodynamics and function. Recent data suggest the energy cost of such improvement is favorable. The effects of sequential CRT on myocardial oxidative metabolism (MVO₂) and efficiency have not been previously assessed. Methods and Results: Eight patients with NYHA class III heart failure were studied 196 ± 180 days after CRT implant. Dynamic [¹¹C]acetate positron emission tomography (PET) and echocardiography were performed after 1 hour of: 1) AAI pacing, 2) simultaneous CRT, and 3) sequential CRT. MVO₂ was calculated using the monoexponential clearance rate of [¹¹C]acetate (k_mono). Myocardial efficiency was expressed in terms of the work metabolic index (WMI). P values represent overall significance from repeated measures analysis. Global LV and right ventricular (RV) MVO₂ were not significantly different between pacing modes, but the septal/lateral MVO₂ ratio differed significantly with the change in pacing mode (AAI pacing = 0.696 ± 0.094 min^?1, simultaneous CRT = 0.975 ± 0.143 min^?1, and sequential CRT = 0.938 ± 0.189 min^?1; overall P = 0.001). Stroke volume index (SVI) (AAI pacing = 26.7 ± 10.4 mL/m², simultaneous CRT = 30.6 ± 11.2 mL/m², sequential CRT = 33.5 ± 12.2 mL/m²; overall P < 0.001) and WMI (AAI pacing = 3.29 ± 1.34 mmHg*mL/m²*10⁶, simultaneous CRT = 4.29 ± 1.72 mmHg*mL/m²*10⁶, sequential CRT = 4.79 ± 1.92 mmHg*mL/m²*10⁶; overall P = 0.002) also differed between pacing modes. Compared with simultaneous CRT, additional changes in septal/lateral MVO₂, SVI, and WMI with sequential CRT were not statistically significant on post hoc analysis. Conclusion: In this small selected population, CRT increases LV SVI without increasing MVO₂, resulting in improved myocardial efficiency. Additional improvements in LV work, oxidative metabolism, and efficiency from simultaneous to sequential CRT were not significant.     

High signal intensity on T2-weighted cardiac magnetic resonance imaging correlates with the ventricular tachyarrhythmia in hypertrophic cardiomyopathy

Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) can predict ventricular arrhythmia and poor prognosis in hypertrophic cardiomyopathy (HCM) patients. Although myocardial T2-high signal has been reported to appear within LGE in those patients, its clinical significance remains unclear. We investigated the relationship between the T2-high signal and nonsustained ventricular tachycardia (NSVT) in HCM patients. Eighty-one HCM patients who underwent Holter ECG and CMR including T2-weighted and LGE imaging were retrospectively recruited. They were divided into NSVT-positive and NSVT-negative groups. We compared the clinical and CMR characteristics between both of the groups, and assessed predictors of NSVT with multivariate analysis. Myocardial T2-high signal was observed in 15/81 (18.5 %) patients. Each T2-high signal was localized within LGE. Significantly in the NSVT-positive group, the prevalence of atrial fibrillation [5/17 (29.4 %) vs. 2/64 (3.1 %), p = 0.0006] and T2-high signal [9/17 (52.9 %) vs. 6/64 (9.4 %), p < 0.0001] and the left ventricular (LV) end-systolic volume index (32.2 ± 15.9 ml/m² vs. 23.3 ± 14.9 ml/m², p = 0.034) and the number of segments with LGE (5.8 ± 3.3 vs. 2.7 ± 2.7, p < 0.0001) was increased, and the LV ejection fraction (54.8 ± 10.9 % vs. 65.1 ± 10.6 %, p = 0.0007) was decreased, compared to the NSVT-negative group. On multivariate analysis, the presence of atrial fibrillation (OR 29.49, p = 0.0025) and DM (OR 7.36, p = 0.0455) and T2-high signal (OR 14.96, p = 0.0014) and reduced LV ejection fraction (OR 0.93, p = 0.0222) were significantly associated with NSVT. The presence of myocardial T2-high signal is a significant independent predictor of NSVT in HCM patients.     

Activation of natriuretic peptide receptor-C attenuates the enhanced oxidative stress in vascular smooth muscle cells from spontaneously hypertensive rats: implication of Gialpha protein

We have recently shown that vascular smooth muscle cells (VSMC) from spontaneously hypertensive rats (SHR) exhibit enhanced expression of Giα proteins, which was attributed to the enhanced oxidative stress. Since C-ANP_4-23 that specifically interacts with natriuretic peptide C (NPR-C) receptor has been shown to decrease the expression of Giα protein in VSMC, the present study was undertaken to examine if C-ANP_4-23 can also decrease the enhanced expression of Giα protein in VSMC from SHR and whether it is attributed to its ability to attenuate the enhanced oxidative stress. Aortic VSMC from 12-week-old SHR and their age-matched Wistar-Kyoto (WKY) rats were used for the present studies. VSMC from SHR exhibited enhanced expression of Giα-2 and Giα-3 proteins, different subunits of NADPH oxidase such as Nox⁴ and p^47phox proteins but not of p^22phox, enhanced production of superoxide anion as well as NADPH oxidase activity as compared to age-matched WKY rats. Treatment of VSMC from SHR with C-ANP_4-23 decreased towards control levels the enhanced expression of Giα proteins, enhanced superoxide anion production and enhanced NADPH oxidase activity as well as the enhanced expression of Nox⁴ and p^47phox. However, C-ANP_4-23-induced attenuation of the enhanced level of O₂⁻ and NADPH oxidase activity occurs at 4 h before the decrease in the enhanced expression of p^47phox that occurs at 16 h of C-ANP_4-23 treatment. The decreased expression of NADPH oxidase in SHR was also associated with further decrease in O₂⁻ and NADPH oxidase activity. Furthermore, treatment of VSMC from SHR with pertussis toxin (PT) decreased the enhanced levels of superoxide anion as well as NADPH oxidase activity; however, the enhanced levels of different subunits of NADPH oxidase were not attenuated by PT treatment. These results suggest that C-ANP_4-23 decreases the enhanced oxidative stress in SHR by attenuating the enhanced expression of Giα proteins and also the enhanced levels of NADPH oxidase.     

Reduction of development of left ventricular hypertrophy in salt-loaded Dahl salt-sensitive rats by angiotensin II receptor inhibition

To determine the effect of the angiotensin II AT₁ receptor antagonist losartan (DuP753) on echocardiographic left ventricular (LV) anatomy in Dahl rats on high sodium diet, 27 Dahl salt-sensitive (Dahl-S, 13 on drug and 14 receiving tap water) and 27 Dahl salt-resistant rats (Dahl-R, 13 on drug and 14 receiving tap water) were studied by M-mode echocardiography during 8 weeks of 8% NaCl diet. At the endpoint (after 8 weeks or the last echocardiogram for animals who died earlier), Dahl-S receiving losartan had lower LV mass (1.6 ± 0.4 g/kg^0.59) than Dahl-S receiving tap water (2.2 ± 0.7 g/kg^0.59; P < .005), although blood pressure was only partially reduced (167 ± 29 v 195 ± 52; P = .05). This difference was mainly due to lower LV wall thickness (P < .02), with a less consistent decrease in LV chamber size in Dahl-S receiving losartan. Blood pressure was normal in Dahl-R (tap water group = 116 ± 11 mm Hg; losartan group = 115 ± 13 mm Hg) and losartan had no effect on LV mass (1.6 ± 0.4 g/kg^0.59 in both groups). In the majority of rats, echocardiographic measurements were compared between the end of second or third week and the last available study: LV mass increased in salt-loaded Dahl-S receiving tap water (1.6 ± 0.6 to 2.1 ± 0.7 g/kg^0.59, P < .04) and was stable in Dahl-S receiving losartan (1.5 ± 0.1 to 1.5 ± 0.3 g/kg^0.59), paralleling changes in LV chamber dimension. Thus, a high salt diet leads to hypertension and eccentric LV hypertrophy in Dahl-S but not in Dahl-R. Inhibition of angiotensin II AT₁ receptors reduces the development of LV hypertrophy in Dahl-S rats despite lack of efficient control of blood pressure.     

In vivo effects of myocardial creatine depletion on left ventricular function, morphology, and energy metabolism--consequences in acute myocardial infarction

BackgroundThe failing heart is characterized by disturbed myocardial energy metabolism and creatine (Cr) depletion. The aims of this study were to in vivo evaluate the effects of Cr depletion on: a) left ventricular (LV) function and morphology during rest and stress, b) LV energy metabolism, c) catecholamine in LV and plasma content, and d) incidence of malignant ventricular arrhythmias (MVA) during acute myocardial infarction (MI).Methods and ResultsMale rats weighing approximately 200 g were used. Two groups were studied: the rats treated with Cr analogue beta-guanidinopropionic acid (BGP) (n = 25) and controls (n = 23). BGP (1 M) was administered by subcutaneously implanted osmotic minipumps over 4 weeks. The rats (BGP n = 9, control n = 12) were than examined with transthoracic echocardiography at basal and at stress conditions induced by transesophageal pacing. In vivo ³¹P magnetic resonance spectroscopy (MRS) was used for evaluation of myocardial energy status (BGP n = 7, control n = 12). ³¹P MRS, echocardiography and high-performance liquid chromatography analysis of myocardial Cr, total adenine nucleotides and catecholamines in myocardium and plasma were performed on noninfarcted hearts. Myocardial infarction was induced in a subgroup of animals (BGP n = 15, control n = 15) by ligation of the left coronary artery resulting in a large (∼50%) anterolateral MI and acute HF. A computerized electrocardiogram tracing was obtained continuously before induction of MI and up to 60 minutes postinfarction. Qualitative and quantitative variables of ventricular arrhythmias were analyzed using arrhythmia score. Body weight (BW) was lower (P < .01), whereas LV/BW was higher (P < .01) in the BGP group. Total myocardial Cr pool was decreased for at least 50% (P < .01) compared with the controls. There was no difference in total nucleotide pool. Phosphocreatine/adenosine-3-phosphate ratio was lower in the BGP group (P < .01). LV systolic function was disturbed during rest and stress (P < .05). Similarly, LV dimensions were increased in the BGP group (P < .05). Induction of acute MI resulted in markedly increased incidence of MVA and higher mortality in the BGP group (P < .01).ConclusionsMyocardial Cr depletion results in functional and structural LV alterations associated with lower myocardial energy reserve. Intact myocardial Cr metabolism is important for normal LV function during basal and stress conditions. Acute MI in the setting of myocardial Cr depletion leads to excessive mortality from ventricular arrhythmias and progressive heart failure.     

Cardiocirculatory and myocardial energetic effects of prostaglandin E1 in severe left ventricular failure due to chronic coronary heart disease

The cardiocirculatory actions of brief (69 ± 5 minutes) infusions of prostaglandin E₁ were evaluated in nine chronic coronary heart disease patients with severe left ventricular (LV) failure caused by previous myocardial infarction. Prostaglandin E₁ infusion did not alter heart rate (HR) and produced modest declines in mean systemic blood pressure (BP) (85 ± 6 to 76 ± 5 mm Hg, p < 0.025) and LV filling pressure (19 ± 3 to 15 ± 2 mm Hg, p < 0.01). Simultaneously, prostaglandin E₁ augmented LV pump function raising cardiac index from 1.9 ± 0.2 to 2.5 ± 0.2 L/min/m² (p < 0.005), elevating stroke index from 28 ± 2.4 to 35 ± 2.9 ml/beat/m² (p < 0.01), and increasing stroke work index from 26 ± 4.3 to 30 ± 4.4 gm·m/m² (p < 0.02). Additionally, total systemic vascular resistance decreased from 1862 ± 192 to 1282 ± 100 dynes-sec-cm^?5 (p < 0.02) and double product LV aerobic index of HR · systolic BP diminished from 9492 ± 666 to 8278 ± 493 (p < 0.02). Concomitantly, in the forearm, vascular resistance fell, blood flow rose, and venous tone remained unchanged. These results indicate that prostaglandin E₁ is a potent systemic arteriolar dilator with markedly beneficial effects on cardiac function in chronic coronary patients having severe ischemic LV failure refractory to conventional therapy.     

Serial alterations of beta-adrenergic signaling in dilated cardiomyopathic hamsters: possible role of myocardial oxidative stress.

BACKGROUND: The relationship between enhanced myocardial oxidative stress and impaired beta-adrenergic signaling remains to be characterized during the development of dilated cardiomyopathy. METHODS AND RESULTS: Alterations in myocardial oxidative stress and beta-adrenergic signaling, as well as left ventricular (LV) functional and structural changes, were evaluated during the development of cardiomyopathy in TO-2 hamsters; F1B hamsters served as controls. LV dysfunction was first apparent at 8 weeks of age and deteriorated thereafter in the TO-2 hamsters. At 32 weeks, the animals exhibited heart failure with an increased plasma norepinephrine concentration. Cardiac myolysis, as demonstrated by elevated plasma concentration of cardiac troponin T, peaked at 8 weeks. The glutathione redox ratio revealed increased oxidative stress in the LV myocardium in TO-2 hamsters even at 4 weeks and became manifest after 8 weeks. The hearts of TO-2 hamsters had significantly reduced superoxide dismutase activity from 8 weeks onward compared with control hamsters. However, glutathione peroxidase activity was unchanged at any time point. The LV functional response to isoproterenol was markedly reduced at 8 weeks, without any apparent changes in the amount of beta-adrenergic signaling molecules, and it deteriorated thereafter. Adenylyl cyclase activity was significantly decreased, despite increased amounts of both G(s) alpha mRNA and protein, in the LV myocardium at 18 weeks. CONCLUSIONS: Myocardial oxidative stress is actually enhanced in the initial development of LV dysfunction. Both activation of myocardial oxidative stress and impairment of beta-adrenergic signaling become prominent at the stage of severe LV dysfunction. Myocardial oxidative stress may be involved in the development of beta-adrenergic desensitization.     

“Supranormal” Cardiac Function in Athletes Related to Better Arterial and Endothelial Function

Objective: Athlete's heart is associated with left ventricular (LV) hypertrophy (LVH), and “supranormal” cardiac function, suggesting that this is a physiological process. Hypertrophy alone cannot explain increase in cardiac function, therefore, other mechanisms, such as better ventriculo‐arterial coupling might be involved. Methods: We studied 60 male (21 ± 3 years) subjects: 27 endurance athletes, and a control group of 33 age‐matched sedentary subjects. We assessed global systolic and diastolic LV function, short‐ and long‐axis myocardial velocities, arterial structure and function and ventriculo‐arterial coupling, endothelial function by flow‐mediated dilatation, and amino‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and biological markers of myocardial fibrosis and of oxidative stress. Results: Athletes had “supranormal” LV longitudinal function (12.4 ± 1.0 vs 10.1 ± 1.4 cm/s for longitudinal systolic velocity, and 17.4 ± 2.6 vs 15.1 ± 2.4 cm/s for longitudinal early diastolic velocity, both P < 0.01), whereas ejection fraction and short‐axis function were similar to controls. Meanwhile, they had better endothelial function (16.7 ± 7.0 vs 13.3 ± 5.3%, P < 0.05) and lower arterial stiffness (pulse wave velocity 7.1 ± 0.6 vs 8.8 ± 1.1 m/s, P = 0.0001), related to lower oxidative stress (0.259 ± 0.71 vs 0.428 ± 0.88 nmol/mL, P = 0.0001), with improved ventriculo‐arterial coupling (37.1 ± 21.5 vs 15.5 ± 13.4 mmHg.m/s³× 10³, P = 0.0001). NT‐proBNP and markers of myocardial fibrosis were not different from controls. LV longitudinal function was directly related to ventriculo‐arterial coupling, and inversely related to arterial stiffness and to oxidative stress. Conclusions: “Supranormal” cardiac function in athletes is due to better endothelial and arterial function, related to lower oxidative stress, with optimized ventriculo‐arterial coupling; athlete's heart is purely a physiological phenomenon, associated with “supranormal” cardiac function, and there are no markers of myocardial fibrosis. (Echocardiography 2010;27:659‐667)     

Enhanced phosphoinositide 3-kinase(p110α) activity prevents diabetes-induced cardiomyopathy and superoxide generation in a mouse model of diabetes

Aims/hypothesis

Diabetic cardiomyopathy is characterised by diastolic dysfunction, oxidative stress, fibrosis, apoptosis and pathological cardiomyocyte hypertrophy. Phosphoinositide 3-kinase (PI3K)(p110α) is a cardioprotective kinase, but its role in the diabetic heart is unknown. The aim of this study was to assess whether PI3K(p110α) plays a critical role in the induction of diabetic cardiomyopathy, and whether increasing PI3K(p110α) activity in the heart can prevent the development of cardiac dysfunction in a setting of diabetes.

Methods

Type 1 diabetes was induced with streptozotocin in adult male cardiac-specific transgenic mice with increased PI3K(p110α) activity (constitutively active PI3K [p110α], caPI3K] or decreased PI3K(p110α) activity (dominant-negative PI3K [p110α], dnPI3K) and non-transgenic (Ntg) mice for 12 weeks. Cardiac function, histological and molecular analyses were performed.

Results

Diabetic Ntg mice displayed diastolic dysfunction and increased cardiomyocyte size, expression of atrial and B-type natriuretic peptides (Anp, Bnp), fibrosis and apoptosis, as well as increased superoxide generation and increased protein kinase C β2 (PKCβ2), p22 ^phox and apoptosis signal-regulating kinase 1 (Ask1) expression. Diabetic dnPI3K mice displayed an exaggerated cardiomyopathy phenotype compared with diabetic Ntg mice. In contrast, diabetic caPI3K mice were protected against diastolic dysfunction, pathological cardiomyocyte hypertrophy, fibrosis and apoptosis. Protection in diabetic caPI3K mice was associated with attenuation of left ventricular superoxide generation, attenuated Anp, Bnp, PKCβ2, Ask1 and p22 ^phox expression, and elevated AKT. Further, in cardiomyocyte-like cells, increased PI3K(p110α) activity suppressed high glucose-induced superoxide generation and enhanced mitochondrial function.

Conclusions/interpretation

These results demonstrate that reduced PI3K activity accelerates the development of diabetic cardiomyopathy, and that enhanced PI3K(p110α) activity can prevent adverse cardiac remodelling and dysfunction in a setting of diabetes.     

3-Dimensional Strain Analysis of Hypertrophic Cardiomyopathy: Insights From the NHLBI International HCM Registry

BackgroundAbnormal global longitudinal strain (GLS) has been independently associated with adverse cardiac outcomes in both obstructive and nonobstructive hypertrophic cardiomyopathy.ObjectivesThe goal of this study was to understand predictors of abnormal GLS from baseline data from the National Heart, Lung, and Blood Institute (NHLBI) Hypertrophic Cardiomyopathy Registry (HCMR).MethodsThe study evaluated comprehensive 3-dimensional left ventricular myocardial strain from cine cardiac magnetic resonance in 2,311 patients from HCMR using in-house validated feature-tracking software. These data were correlated with other imaging markers, serum biomarkers, and demographic variables.ResultsAbnormal median GLS (> –11.0%) was associated with higher left ventricular (LV) mass index (93.8 ± 29.2 g/m² vs 75.1 ± 19.7 g/m²; P < 0.0001) and maximal wall thickness (21.7 ± 5.2 mm vs 19.3 ± 4.1 mm; P < 0.0001), lower left (62% ± 9% vs 66% ± 7%; P < 0.0001) and right (68% ± 11% vs 69% ± 10%; P < 0.01) ventricular ejection fractions, lower left atrial emptying functions (P < 0.0001 for all), and higher presence and myocardial extent of late gadolinium enhancement (6 SD and visual quantification; P < 0.0001 for both). Elastic net regression showed that adjusted predictors of GLS included female sex, Black race, history of syncope, presence of systolic anterior motion of the mitral valve, reverse curvature and apical morphologies, LV ejection fraction, LV mass index, and both presence/extent of late gadolinium enhancement and baseline N-terminal pro–B-type natriuretic peptide and troponin levels.ConclusionsAbnormal strain in hypertrophic cardiomyopathy is associated with other imaging and serum biomarkers of increased risk. Further follow-up of the HCMR cohort is needed to understand the independent relationship between LV strain and adverse cardiac outcomes in hypertrophic cardiomyopathy.     

Effect of coronary vasodilation on ventricular fibrillation threshold: Role of exogenous vasodilators and perfusion conditions

Even without myocardial ischemia, coronary blood flow (CBF) constitutes a major determinant of ventricular fibrillation threshold (VFT). To clarify whether abnormal distribution of normal or increased CBF plays any additional role, 14 open-chest chloralose-anesthetized dogs with fixednormalized heart rate, cardiac output, and systemic arterial pressure and separate servocontrolled left main coronary artery perfusion were studied as follows: VFT was determined first with coronary perfusion pressure (CPP) set at systemic level (80 mm Hg). Then CBF index was fixed at control levels (134.0 ± 9.5 ml/min · 100 gm^?1 LV) and coronary vasodilation was induced by intracoronary infusion of adenosine until CPP decreased to 49.0 ± 2.0 mm Hg. Myocardial O₂ consumption, LV pressure, LV $\text{dp}\text{dt}$, and surface ECG remained unchanged. However, VFT decreased in all trials by about 45% (p < 0.001). When CPP was reset to 80 mm Hg while maintaining vasodilation, CBF index increased by 90% to 255.4 ± 15.4 ml/min · 100 gm^?1 LV and VFT by 26% (p < 0.005) from control. Yet these VFT increases in response to intraluminal pharmacologic vasodilation were about 19% (p < 0.002) lower than expected for similar CBF index increases occurring physiologically. We conclude that intraluminal coronary vasodilation not matched by appropriate CBF increase results in substantial decrease of VFT. Moreover, at comparable increase of CBF, spontaneous physiologic vasodilation is more effective than intraluminal pharmacologic coronary vasodilation in increasing VFT.     

Effect of left ventricular size on mitral E point to ventricular septal separation in assessment of cardiac performance

Increased mitral valve E point to ventricular septal separation (EPSS) is widely used as an echocardiographic index of depressed left ventricular (LV) ejection traction (EF), yet LV size has not been examined as an independent variable potentially affecting EPSS. Accordingly, we studied the relationship between EPSS and functionally normal or depressed LV with or without increased enddiastolic dimensions (EDD). Twenty normal controls had EPSS 3.2 ± 2.2 mm (mean ± SD), EDD 47 ± 5 mm, $\text{EPSS}\text{EDD}$ (“normalized” EPSS) 0.07 ± 0.04, and fractional shortening (FS%) 38 ± 6%. Nine patients with pure chronic mitral regurgitation had dilated LV (EDD = 65 ± 7 mm) with normal LV function (FS% 41 ± 5%; angiographic EF 62 ± 9%); eight patients had dilated cardiomyopathy (EDD 69 ± 8 mm) with decreased LV function (FS% 16 ± 7%; angiographic EF 32 ± 8%); and eight patients with amyloid cardiomyopathy had nondilated LV (EDD 42 ± 5 mm) with decreased LV function (FS% 19 ± 6; angiographic EF 35 ± 7%). Mitral E point to ventricular septal separation and $\text{EPSS}\text{EDD}$ accurately separated individuals with normal and abnormal LV function irrespective of LV size (χ² = 36.7; p < 0.00001). Increased internal dimensions per se did not affect EPSS unless depressed LV function coexisted. EPSS is therefore a valid predictor of depressed ejection phase indices independent of LV size.     

Heart rate reduction with ivabradine prevents thyroid hormone-induced cardiac remodeling in rat

Ivabradine slows the heart rate (HR) by selectively inhibiting the I(f) current in the sinus node without a negative inotropic effect. We aimed to investigate the effects of ivabradine on thyroid hormone-induced left ventricular (LV) remodeling and ion channel activity in rats. Thirty Sprague–Dawley rats were randomly selected into the groups of control, injection of l-thyroxine (T₄, 100 μg/kg/day), and injection of l-thyroxine with ivabradine (T₄-Iva, T₄ + 10 mg/kg/day). Circumferential (S _circ), radial (S _rad), and longitudinal (S _long) strains were assessed by speckle tracking echocardiography (STE). Myocardial width and fibrosis were assessed from histological LV cross sections, and electrophysiological analysis was done by patch clamp method. In comparison with the control group, the T₄ group showed significantly increased HR and LV end-systolic diameter (LVESD), reduced S _circ (?16.04 ± 3.95 vs. ?7.84 ± 2.98 %, p < 0.001), S _rad (20.94 ± 3.81 vs. 40.57 ± 6.70 %, p < 0.001), and S _long (?15.26 ± 5.15 vs. ?23.83 ± 5.19 %, p < 0.001), despite the 59.5 % increase of average I _Ca,L density at 0 mV (13.4 ± 1.2 pA/pF) compared to control group (8.4 ± 0.8 pA/pF). Treatment with ivabradine significantly reduced HR and LVESD, improved SR_circ, S _long and SR_long in the T₄ group, and the average I _Ca,L density at 0 mV in T₄-Iva groups (9.9 ± 1.6 pA/pF) was restored to the control level. Morphologically, the T₄ group showed significantly increased cardiomyocyte width (25.3 ± 1.89 vs. 18.90 ± 1.14 μm in control, p < 0.001) and fibrosis, which were not significantly changed by ivabradine. In conclusion, selective HR reduction by ivabradine attenuates thyroid hormone-induced reduction of myocardial deformation and altered intracellular Ca²⁺ handling without modification of the myocyte hypertrophy with fibrosis in rats.     

氟伐他汀对糖尿病大鼠早期心肌病变的作用

目的探讨氟伐他汀对糖尿病大鼠早期心肌病变的作用。方法研究对象为链脲佐菌素诱导的SD大鼠糖尿病模型,氟伐他汀(2mg·kg-1·d-1)治疗组、糖尿病对照组和正常组各10只,实验第6周末进行血糖(BG)、总胆固醇(TC)、三酰甘油(TG)、高密度脂蛋白胆固醇(HDL-C)、脂蛋白(a)[Lp(a)]测定及大鼠左心室前壁心肌标本的光镜HE染色和透射电镜检查。结果 治疗组与糖尿病组比较,TC、TG及Lp(a)降低,HDL-C升高(P<0.05),血糖差异无显著性(P>0.05),光镜和电镜下病理改变明显减轻。结论 氟伐他汀对糖尿病大鼠心肌细胞及微血管内皮有保护作用,提示可能对糖尿病性心肌病的治疗有重要意义。