Degree Of Cardiac Hypertrophy Research Articles

Loss of ADAM15 in female mice does not worsen pressure overload cardiomyopathy, independent of ovarian hormones.

Cardiac hypertrophy is a common feature in several cardiomyopathies. We previously reported that loss of ADAM15 (disintegrin and metalloproteinase 15) worsened cardiac hypertrophy and dilated cardiomyopathy following cardiac pressure overload. Here, we investigated the impact of ADAM15 loss in female mice following cardiac pressure overload induced by transverse aortic constriction (TAC). Female Adam15-/-mice developed the same degree of cardiac hypertrophy, dilation and dysfunction as the parallel female wildtype (WT) mice at 6 weeks post-TAC. To determine if this is due to the protective effects of estrogen which could mask the negative impact of Adam15 loss, WT and Adam15-/- mice underwent ovariectomy (OVx) 2 weeks prior to TAC. Cardiac structure and function analyses were performed at 6 weeks post-TAC. OVx similarly impacted females of both genotypes post-TAC. Calcineurin (Cn) activity was increased post-OVx-TAC, and more in Adam15-/- mice, however this increase was not reflected in the total-to-phospho NFAT levels. Integrin α7 expression, which was upstream of Cn activation in male Adam15-/--TAC mice, remained unchanged in female mice. However, activation of the Mitogen Activated Protein Kinases (ERK, JNK, P38) were greater in Adam15-/--OVx-TAC compared to WT-OVx-TAC mice. In addition, ADAM15 protein levels were significantly increased post-TAC in male but not in female WT mice. Myocardial fibrosis was comparable in non-OVx WT-TAC and Adam15-/--TAC mice. OVx increased the perivascular fibrosis more in Adam15-/- compared to WT mice post-TAC. Our data demonstrate that loss of ovarian hormones did not fully replicate the male phenotype in the female Adam15-/- mice post-TAC. Since ADAM15 levels were increased in males but not in females post-TAC, it is plausible that ADAM15 does not play a prominent role in post-TAC events in female mice. Our findings highlight the significance of factors other than sex hormones in mediating cardiomyopathies in females, which require a more thorough understanding.

PKD knockdown mitigates Ang II-induced cardiac hypertrophy and ferroptosis via the JNK/P53 signaling pathway

BackgroundCardiac hypertrophy is studied in relation to energy metabolism, autophagy, and ferroptosis, which are associated with cardiovascular adverse events and chronic heart failure. Protein kinase D (PKD) has been shown to play a degenerative role in cardiac hypertrophy. However, the role of ferroptosis in PKD-involved cardiac hypertrophy remains unclear. MethodsA cardiac hypertrophy model was induced by a subcutaneous injection of angiotensin II (Ang II) for 4 weeks. Adeno-associated virus serotype 9 (AAV9)-PKD or AAV9-Negative control were injected through the caudal vein 2 weeks prior to the injection of Ang II. The degree of cardiac hypertrophy was assessed using echocardiography and by observing cardiomyocyte morphology. Levels of ferroptosis and protein expression in the Jun N-terminal kinase (JNK)/P53 signaling pathway were measured both in vivo and in vitro. ResultsThe results indicated that PKD knockdown reduces Ang II-induced cardiac hypertrophy, enhances cardiac function and inhibits ferroptosis. The involvement of the JNK/P53 pathway in this process was further confirmed by in vivo and in vitro experiments. ConclusionIn conclusion, our findings suggest that PKD knockdown mitigates Ang II-induced cardiac hypertrophy and ferroptosis via the JNK/P53 signaling pathway.

Notch1 Is Involved in Physiologic Cardiac Hypertrophy of Mice via the p38 Signaling Pathway after Voluntary Running.

Appropriate exercise such as voluntary wheel-running can induce physiological cardiac hypertrophy. Notch1 plays an important role in cardiac hypertrophy; however, the experimental results are inconsistent. In this experiment, we aimed to explore the role of Notch1 in physiological cardiac hypertrophy. Twenty-nine adult male mice were randomly divided into a Notch1 heterozygous deficient control (Notch1+/- CON) group, a Notch1 heterozygous deficient running (Notch1+/- RUN) group, a wild type control (WT CON) group, and a wild type running (WT RUN) group. Mice in the Notch1+/- RUN and WT RUN groups had access to voluntary wheel-running for two weeks. Next, the cardiac function of all of the mice was examined by echocardiography. The H&E staining, Masson trichrome staining, and a Western blot assay were carried out to analyze cardiac hypertrophy, cardiac fibrosis, and the expression of proteins relating to cardiac hypertrophy. After two-weeks of running, the Notch1 receptor expression was decreased in the hearts of the WT RUN group. The degree of cardiac hypertrophy in the Notch1+/- RUN mice was lower than that of their littermate control. Compared to the Notch1+/- CON group, Notch1 heterozygous deficiency could lead to a decrease in Beclin-1 expression and the ratio of LC3II/LC3I in the Notch1+/- RUN group. The results suggest that Notch1 heterozygous deficiency could partly dampen the induction of autophagy. Moreover, Notch1 deficiency may lead to the inactivation of p38 and the reduction of β-catenin expression in the Notch1+/- RUN group. In conclusion, Notch1 plays a critical role in physiologic cardiac hypertrophy through the p38 signaling pathway. Our results will help to understand the underlying mechanism of Notch1 on physiological cardiac hypertrophy.

Association of diet with left ventricular wall thickness, troponin I and IGF-1 in cats with subclinical hypertrophic cardiomyopathy.

BackgroundCats with subclinical hypertrophic cardiomyopathy (sHCM) have elevated serum insulin and serum amyloid A concentrations correlating with the degree of cardiac hypertrophy. Diet might affect these and other cardiac variables.ObjectiveEvaluate the effect of a complete, balanced diet with restricted starch and supplemented with eicosapentaenoic acid + docosahexaenoic acid (EPA + DHA) on echocardiographic variables and cardiac biomarkers in cats with sHCM.AnimalsForty‐four client‐owned cats with sHCM.MethodsA prospective, randomized, double‐blind, multicenter study enrolled cats with end‐diastole interventricular septum thickness (IVSd) or left ventricular wall thickness (LVWd) ≥6 mm, or both. Nonsedated, fasted cats were examined at baseline and after 6 and 12 months of Test (restricted starch and EPA + DHA supplements) (n = 23) or Control (unrestricted starch without EPA + DHA supplementation) (n = 21) diet. Assessments included auscultation, body weight, body condition score, echocardiography and blood analysis. Linear and generalized mixed models analyzed diet, time and diet * time interactions (5% significance level).ResultsNo differences between diet groups were significant for any variable at any timepoint. There were significant decreases in the Test but not Control group in maximum IVSd (P = .03), maximum LVWd (P = .02) and insulin‐like growth factor‐1 levels (P = .04) after 12 months, and in ultrasensitive cardiac troponin I (cTnI) (P = .001) after 6 months; effect sizes (95% confidence interval) were 0.53 (0.09; 0.99), 0.63 (0.18; 1.09), 0.61 (0.16; 1.07), and 0.37 (−0.06; 0.8), respectively.Conclusions and Clinical ImportanceCats with sHCM fed Test diet had significant decreases in echocardiographic variables of sHCM and in cTnI and IGF‐1.

BRD4 blockage alleviates pathological cardiac hypertrophy through the suppression of fibrosis and inflammation via reducing ROS generation

Hypertension is an essential regulator of cardiac injury and remodeling. However, the pathogenesis that contributes to cardiac hypertrophy remains to be fully explored. BRD4, as a bromodomain and extra-terminal (BET) family member, plays an important role in critical biological processes. In the study, our results showed that BRD4 expression was up-regulated in human and mouse hypertrophied hearts, and importantly these effects were modulated by reactive oxygen species (ROS) generation. In angiotensin II (Ang II)-treated cardiomyocytes, BRD4 decrease markedly blunted the prohypertrophic effect, which was further promoted by the combinational treatment of ROS scavenger (N-acetyl-cysteine, NAC). In addition, NAC pre-treatment markedly elevated the anti-fibrotic role of BRD4 suppression in Ang II-incubated cardiomyocytes by repressing transforming growth factor β1 (TGF-β1)/SMADs signaling pathway. NAC combined with BRD4 reduction further alleviated inflammation and oxidative stress in Ang II-exposed cardiomyocytes, which was partly through inhibiting nuclear factor-κB (NF-κB) signaling and improving nuclear erythroid factor 2-related factor 2 (Nrf-2)/heme oxygenase-1 (HO-1) pathway, respectively. Furthermore, the in vivo results confirmed the protective effects of BRD4 suppression on mice against aortic banding (AB)-induced cardiac hypertrophy, as evidenced by the reduced cross sectional area and fibrotic area using H&E and Masson trichrome staining. What’s more, the degree of cardiac hypertrophy (ANP and BNP), the expression of pro-fibrotic genes (TGF-β1, Collagen I, Collagen III and CTGF), the levels of inflammation and oxidative stress were all significantly attenuated by the blockage of BRD4 in AB-operated mice. Taken together, repressing BRD4 expression was found to confer a protective effect against experimental cardiac hypertrophy in mice, demonstrating its potential as an effective therapeutic target for pathological cardiac hypertrophy.

Association between plasma microRNA-29a and left ventricular hypertrophy in patients with hypertension

Objective: Previous studies have shown that plasma microRNA-29a (miRNA-29a) is associated with myocardial fibrosis and the degree of cardiac hypertrophy in patients with hypertrophic cardiomyopathy. However, the relationship between plasma miRNA-29a and hypertensive left ventricular hypertrophy (LVH) has not yet been reported. So the purpose of this study is to investigate the relationship between the plasma miRNA-29a and hypertensive LVH. Method: Enrolled 168 hypertensive patients and classified the patients into 2 groups: those with LVH (LVH group, n=41) and those without LVH (NLVH group, n=127). All patients underwent echocardiography examination. Left ventricular mass index (LVMI) was calculated by interventricular septal thickness (IVSd), left ventricular posterior wall thickness(LVPWTd), left ventricular end diastolic dimension (LVEDD) and left ventricular mass index (LVMI) were obtained. Plasma levels of miRNA-29a were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between plasma miRNA-29a levels and LVH was analyzed. Results: Plasma miRNA-29a was significantly higher in LVH group than in NLVH group (0.52±0.10 vs. 0.37±0.07, t=9.788, P<0.01) . Pearson correlation analysis evidenced a positive correlation between plasma miRNA-29a levels and IVSd(R=0.459, P<0.01), LVPWTd (R=0.398, P<0.01), and LVMI (R=0.745, P<0.01). After adjustment for gender, age, systolic blood pressure, diastolic blood pressure, body mass index, hypertension duration, antihypertensive drugs, multiple regression analysis showed that there were still positive correlations between plasma miRNA-29a level and IVSd (β=0.535, P<0.01), LVPWTd (β=0.085, P<0.01), and LVMI (β=0.806, P<0.01). Conclusion: Plasma miRNA-29a level is positively associated with LVH in hypertensive patients, and future studies are warranted to explore if miRNA-29a could be used as a potential biomarker for LVH assessment in hypertensive patients.

O45-5 - DPP-4 Inhibition Ameliorates the Progression of Heart Failure after Transverse Aortic Constriction through Inhibition of Synthesis of Collagen Type III

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors are oral hypoglycemic agents. Role of DPP-4 on cardiac fibrosis after transverse aortic constriction (TAC) is not well known. Methods and Results: Wild-type mice and DPP-4 knockout (DPP-4KO) mice were subjected to TAC. Wild-type mice were then treated with vehicle (Control) or DPP-4 inhibitor (DPP-4i). DPP-4 activities in serum and myocardium were significantly increased at 2 weeks after TAC in Control group, but they were significantly decreased in DPP-4i group. The degree of cardiac hypertrophy was not different between three groups throughout the study. Fractional shortening was significantly higher in DPP-4i group and DPP-4KO group compared to Control group (Control, 36.4 ± 1.6%, DPP-4i, 40.4 ± 1.5%, DPP-4KO, 42.4 ± 0.3%, P < .05) at 4 weeks after TAC. The degree of myocardial fibrosis was significantly lower in DPP-4i group, DPP-4KO group compared to Control group (Control, 5.0 ± 0.7%, DPP-4i, 2.4 ± 0.3%, DPP-4KO, 2.3 ± 0.3%, P < .05) at 4 weeks after TAC by Masson trichrome staining. In transmission electron microscopy findings, there were no significant differences in structure of collagen fibrils between Control group and DPP-4KO group. The degree of collagen type III was decreased in DPP-4KO group compared with Control group (Control, 1.1 ± 0.2%, DPP-4KO, 0.4 ± 0.1%, P < .05) at 2 weeks after TAC by picrosirius red staining. Conclusion: DPP-4 inhibition ameliorates the progression of heart failure after TAC through inhibition of collagen type III.

Neonatal Diesel Exhaust Particulate Exposure Does Not Predispose Mice to Adult Cardiac Hypertrophy or Heart Failure.

Background: We have previously reported that in utero and early life exposure to diesel exhaust particulates predisposes mice to adult heart failure, and that in utero exposure alone is sufficient to confer this predisposition. This follow up study addresses whether neonatal exposure alone can also confer this predisposition. Methods: Newborn male C57BL/6 mice were exposed to diesel exhaust (DE) particulates immediately after birth until weaning at 21 days of age, whereupon they were transferred to filtered air (FA) conditions. At the age of 12 weeks, transverse aortic constriction (TAC) was performed followed by weekly echocardiography for three weeks. After the last echocardiogram, mice were euthanized for organ harvest, gravimetry and histology. Results: Neonatal exposure to DE particulates did not increase susceptibility to cardiac hypertrophy or heart failure after TAC when compared to FA exposed controls (ventricular weight/body weight ratio 7.505 vs. 7.517 mg/g, p = Not Significant (NS)). The left ventricular ejection fraction after TAC was similar between groups at one week, two weeks, and three weeks after procedure. Histological analysis showed no difference in the degree of cardiac hypertrophy or fibrosis. Conclusions: Neonatal exposure to DE particulates does not predispose mice to TAC-induced cardiac hypertrophy and heart failure in adulthood, in contrast to previously published results showing susceptibility due to in utero exposure.

Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy.

BackgroundIn cardiac hypertrophy and failure, there is a widespread alteration in mRNA splicing, but the role of splice variants in cardiac hypertrophy has not yet been fully elucidated. In this study, we used an exon array to identify novel splice variants associated with cardiac hypertrophy.Methods and ResultsWe performed genome‐wide exon array analysis and developed a splicing profile in murine hearts with hypertrophy induced by transverse aortic constriction for 8 weeks. Following global analysis of splice variants using the Mouse Exon 1.0 ST Array, we identified 46 spliced genes and narrowed our focus to 1 gene, mitochondrial tumor suppressor 1 (Mtus1), whose splice variants were registered in the NCBI RefSeq database. Notably, one of the splice variants Mtus1A was specifically upregulated, although the total expression of the Mtus1 gene remained unchanged. We showed that Mtus1A was localized in the mitochondria, and its expression level increased with the degree of cardiac hypertrophy. In cultured cardiomyocytes, Mtus1A overexpression reduced phenylephrine‐induced reactive oxygen species production and consequent ERK phosphorylation, resulting in a decrease in both cell size and protein synthesis. In vivo, cardiac‐specific Mtus1A transgenic mice showed left ventricle wall thinning and a reduced hypertrophic response to pressure overload and phenylephrine treatment.ConclusionsWe found that Mtus1 is specifically spliced in hypertrophic hearts and that the Mtus1A variant has an inhibitory effect on cardiac hypertrophy. Mtus1A is, therefore, a possible diagnostic and therapeutic target for cardiac hypertrophy and failure.

Risk factors for pulmonary hypertension in maintenance hemodialysis patients: a cross-sectional study.

Pulmonary hypertension (PH) in maintenance hemodialysis (MHD) patients has attracted increasing attention. This cross-sectional survey aimed to explore PH prevalence and identify potential risk factors in MHD patients. A total of 136 MHD patients were assessed at the Fifth Affiliated Hospital of Sun Yat-sen University (China) between October 2012 and November 2014. Relevant parameters included primary disease, dialysis duration, height, weight, and interdialytic weight gain. Doppler echocardiography was performed post-hemodialysis to evaluate cardiac structure and function; fistula diameters and blood flow rates were measured by vascular ultrasound. Before and 4 weeks after echocardiography, biochemical parameters were measured. Patients were divided into PH and nPH groups, and their primary diseases were analyzed. T test and Chi-square test were used as appropriate; Pearson’s correlation and logistic regression analysis were employed to assess possible PH risk factors. PH prevalence was 38.23 % in MHD patients and 73.68 % in those with concurrent diabetes, i.e., higher than in chronic glomerulonephritis (35 %) and hypertension (33.33 %) groups. Interestingly, PH was positively correlated with left atrium, right atrium, and ventricle dimensions, and the degree of cardiac hypertrophy. In addition, diabetes and interdialytic weight gain were positively correlated with PH, while hemoglobin levels showed a negative correlation. Finally, multiple logistic regression analysis revealed interdialytic weight gain and hemoglobin as major risk factors for PH in MHD patients. PH prevalence was 38.23 % in MHD patients, a ratio increased in individuals with concurrent diabetes. Other major risk factors for PH in MHD patients include declined hemoglobin levels and increased interdialytic weight gain.

Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats.

Hypertension is an important mediator of cardiac damage and remodelling. Hydrogen sulfide (H2S) is an endogenously produced gasotransmitter with cardioprotective properties. However, it is not yet in clinical use. We, therefore, investigated the protective effects of sodium thiosulfate (STS), a clinically applicable H2 S donor substance, in angiotensin II (Ang II)-induced hypertensive cardiac disease in rats. Male Sprague Dawley rats were infused with Ang II (435 ng kg min(-1)) or saline (control) for 3 weeks via s.c. placed osmotic minipumps. During these 3 weeks, rats received i.p. injections of either STS, NaHS or vehicle (0.9% NaCl). Compared with controls, Ang II infusion caused an increase in systolic and diastolic BP with associated cardiac damage as evidenced by cardiac hypertrophy, an increase in atrial natriuretic peptide (ANP) mRNA, cardiac fibrosis and increased oxidative stress. Treatment with NaHS and STS prevented the development of hypertension and the increase in ANP mRNA levels. Furthermore, the degree of cardiac hypertrophy, the extent of histological fibrosis in combination with the expression of profibrotic genes and the levels of oxidative stress were all significantly decreased. Ang II-induced hypertensive cardiac disease can be attenuated by treatment with STS and NaHS. Although BP regulation is the most plausible mechanism of cardiac protection, the antifibrotic and antioxidant properties of released sulfide may also contribute to their effects. Our data show that H2 S might be a valuable addition to the already existing antihypertensive and cardioprotective therapies.

Tomoregulin-1 prevents cardiac hypertrophy after pressure overload in mice by inhibiting TAK1-JNK pathways.

ABSTRACTCardiac hypertrophy is associated with many forms of heart disease, and identifying important modifier genes involved in the pathogenesis of cardiac hypertrophy could lead to the development of new therapeutic strategies. Tomoregulin-1 is a growth factor that is primarily involved in embryonic development and adult central nervous system (CNS) function, and it is expressed abnormally in a variety of CNS pathologies. Tomoregulin-1 is also expressed in the myocardium. However, the effects of tomoregulin-1 on the heart, particularly on cardiac hypertrophy, remains unknown. The aim of the study is to examine whether and by what mechanism tomoregulin-1 regulates the development of cardiac hypertrophy induced by pressure overload. In this study, we found that tomoregulin-1 was significantly upregulated in two cardiac hypertrophy models: cTnTR92Q transgenic mice and thoracic aorta constriction (TAC)-induced cardiac hypertrophy mice. The transgenic overexpression of tomoregulin-1 increased the survival rate, improved the cardiac geometry and functional parameters of echocardiography, and decreased the degree of cardiac hypertrophy of the TAC mice, whereas knockdown of tomoregulin-1 expression resulted in an opposite phenotype and exacerbated phenotypes of cardiac hypertrophy induced by TAC. A possible mechanism by which tomoregulin-1 regulates the development of cardiac hypertrophy in TAC-induced cardiac hypertrophy is through inhibiting TGFβ non-canonical (TAK1-JNK) pathways in the myocardium. Tomoregulin-1 plays a protective role in the modulation of adverse cardiac remodeling from pressure overload in mice. Tomoregulin-1 could be a therapeutic target to control the development of cardiac hypertrophy.

MITOCHONDRIAL DYSFUNCTION AND OXIDATIVE STRESS IN URAEMIC CARDIOMYOPATHY

Patients with chronic kidney disease (CKD) have greater morbidity and mortality from cardiac causes with a defined uraemic cardiomyopathy (UCM). There is growing evidence that oxidative stress and mitochondrial dysfunction...

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

Arrhythmic risk and echocardiographic correlation of increased QTc interval in patients with hypertrophic cardiomyopathy

Background: Due to the underlying muscle disease, patients with hypertrophic cardiomyopathy (HCM) have a high risk for life-threatening arrhythmias and may have an increased QT interval. However, the independent contribution of the long QT interval to the arrhythmic risk in this population is not well known. Purpose: The purpose of this study was to investigate the role of increased long QT corrected (QTc) interval in the development of malignant arrhythmias in a population of patients with hypertrophic cardiomyopathy (HCM), and also the relationship between QTc and clinical and echocardiographic variables in these patients. Methods: We studied 312 patients with HCM (118 females, age at diagnosis 47±19, maximal left ventricular wall thickness (MLVWT) 19±6mm]. A clinical, an electrocardiographic and an echocardiographic evaluation were carried out in each of them. Results: In this group of patients, 31% (n=96) had prolonged QT interval in the electrocardiogram, defined as QTc value >460ms, being the mean value of the QTc in this population of 447ms±32ms. Of these patients, 244 (78%) underwent to 24-hours electrocardiogram monitoring, presenting 23% of them (n=56) at least one episode of non-sustained ventricular tachycardia (NSVT) on Holter. However, no significant differences in QTc interval between both groups were shown (446±34ms in patients with documented NSVT vs 445±30ms in idividuals with no evidence of NSVT on Holter; p = 0.6). There were no statistically significant differences between the presence/development of atrial fibrillation or syncope and prolongated QTc interval. Finally, there was a weak but significant direct linear relationship between QTc and maximal left ventricular wall thickness (MLVWT) (r2=0.07 p<0.0001). Conclusions: QT prolongation was present in 31% of the patients with HCM studied. This study corroborates the findings of previous publications that the QTc interval is related with the degree of cardiac hypertrophy, and adds that there is no significant relationship with the presence of NSVT on 24h Holter, atrial fibrillation or syncope.

Cardiac and skeletal muscle expression of mutant β‐myosin heavy chains, degree of functional impairment and phenotypic heterogeneity in hypertrophic cardiomyopathy

Several mutations in distinct genes, all coding for sarcomeric proteins, have been reported in unrelated kindreds with familial hypertrophic cardiomyopathy (FHC). We have identified nine individuals from three families harboring two distinct mutations in one copy of the β-myosin heavy chain (β-MHC) gene. In this study, the expression of the mutant β-myosin protein isoform, isolated from slow-twitch fibers of skeletal muscle, was demonstrated by Northern and Western blot analysis; this myosin showed a decreased in vitro motility activity and produced a lower actin-activated ATPase activity. Isometric tension, measured in single slow-twitch fibers isolated from the affected individuals, also showed a significant decrease. The degree of impairment of β-myosin function, as well as the loss in isometric tension development, were strictly dependent on the amount of the isoform transcribed from the mutated allele. Interestingly, a strong correlation was also demonstrated between mutant β-myosin content and clinical features of FHC. On the other hand, we were unable to detect any correlation between mutant β-myosin expression and degree of cardiac hypertrophy, thereby strengthening the hypothesis that hypertrophy, one of the hallmarks of FHC, might not necessarily be related to the clinical evolution of this disease. These findings lend support to the notion that additional factors rather than the mutated gene may play a pathogenetic role in cardiac wall thickening, whereas the prognosis appears to be strongly related to the amount of mutant protein.

In vivo alterations in cardiac metabolism and function in the spontaneously hypertensive rat heart

The aim of this work was to use hyperpolarized carbon-13 ((13)C) magnetic resonance (MR) spectroscopy and cine MR imaging (MRI) to assess in vivo cardiac metabolism and function in the 15-week-old spontaneously hypertensive rat (SHR) heart. At this time point, the SHR displays hypertension and concentric hypertrophy. One of the cellular adaptations to hypertrophy is a reduction in β-oxidation, and it has previously been shown that in response to hypertrophy the SHR heart switches to a glycolytic/glucose-oxidative phenotype. Cine-MRI (magnetic resonance imaging) was used to assess cardiac function and degree of cardiac hypertrophy. Wistar rats were used as controls. SHRs displayed functional changes in stroke volume, heart rate, and late peak-diastolic filling alongside significant hypertrophy (a 56% increase in left ventricular mass). Using hyperpolarized [1-(13)C] and [2-(13)C]pyruvate, an 85% increase in (13)C label flux through pyruvate dehydrogenase (PDH) was seen in the SHR heart and (13)C label incorporation into citrate, acetylcarnitine, and glutamate pools was elevated in proportion to the increase in PDH flux. These findings were confirmed using biochemical analysis of PDH activity and protein expression of PDH regulatory enzymes. Functional and structural alterations in the SHR heart are consistent with the hypertrophied phenotype. Our in vivo work indicates a preference for glucose metabolism in the SHR heart, a move away from predominantly fatty acid oxidative metabolism. Interestingly, (13)C label flux into lactate was unchanged, indicating no switch to an anaerobic glycolytic phenotype, but rather an increased reliance on glucose oxidation in the SHR heart.

Metformin attenuates pressure overload-induced cardiac hypertrophy via AMPK activation

To identify the role of metformin in cardiac hypertrophy and investigate the possible mechanism underlying this effect. Wild type and AMPKα2 knockout (AMPKα2⁻/⁻) littermates were subjected to left ventricular pressure overload caused by transverse aortic constriction. After administration of metformin (200 mg·kg⁻¹·d⁻¹) for 6 weeks, the degree of cardiac hypertrophy was evaluated using echocardiography and anatomic and histological methods. The antihypertrophic mechanism of metformin was analyzed using Western blotting. Metformin significantly attenuated cardiac hypertrophy induced by pressure overload in wild type mice, but the antihypertrophic actions of metformin were ablated in AMPKα2⁻/⁻ mice. Furthermore, metformin suppressed the phosphorylation of Akt/protein kinase B (AKT) and mammalian target of rapamycin (mTOR) in response to pressure overload in wild type mice, but not in AMPKα2⁻/⁻ mice. Long-term administration of metformin may attenuate cardiac hypertrophy induced by pressure overload in nondiabetic mice, and this attenuation is highly dependent on AMPK activation. These findings may provide a potential therapy for patients at risk of developing pathological cardiac hypertrophy.

Adaptations in the balance between coronary blood flow and myocardial metabolism in endurance athletes

Due to the limited anaerobic capability of the myocardium, the heart is highly dependent on a continuous supply of oxygen to meet its metabolic requirements. If this need for oxygen is not met, cardiac function declines within seconds. Since resting left ventricular oxygen extraction is high (∼75%), increases in metabolic demand are met largely by increases in coronary flow. The mechanisms underlying metabolic coronary vasodilatation are not fully understood; however, recent studies have identified β-adrenoceptor ‘feedforward’ dilatation, H2O2 and ATP as potential contributors (Duncker & Bache, 2008). There are numerous conditions that affect the myocardial oxygen supply–demand balance. One such condition is endurance exercise training which has been the focus of much research, albeit with little consensus. Earlier studies in endurance athletes found either reduced or no change in baseline coronary flow while adenosine-mediated vasodilatation was either increased or unchanged compared to untrained individuals (Kalliokoski et al. 2002; Kjaer et al. 2005). Confounding factors that could contribute to these disparate findings are differences in the degree of cardiac hypertrophy and/or myocardial workload. In addition, Mizuno et al. (2005) recently documented that the expression of adenosine A2A receptors is increased in endurance-trained athletes. However, whether differences in myocardial mass, metabolism or coronary A2A receptor density could account for differences in baseline flow and/or coronary flow reserve in endurance athletes has not been delineated. In this issue of The Journal of Physiology, Heinonen et al. (2008) examined the relationship of left ventricular coronary flow at rest and during adenosine-induced vasodilatation to cardiac mass, estimates of myocardial work and adenosine A2A receptor expression in untrained and endurance-trained athletes. They found that total coronary flow under baseline conditions is elevated in athletes while flow reserve to adenosine is unchanged. The increase in baseline coronary flow is clearly related to the ∼70% increase in cardiac mass in the endurance athletes as normalization revealed a significant reduction in myocardial perfusion per gram of tissue mass. When this normalized flow is further related to an index of cardiac workload (reduced ∼45% in endurance athletes), myocardial perfusion per gram of tissue was ∼40% higher in athletes. Interestingly, this relative ‘overperfusion’ is actually constrained by an increase in coronary vascular resistance. Therefore, endurance training elicits alterations in the myocardial oxygen supply–demand balance that produce a left ventricle that is more phenotypically consistent with the more efficient right ventricle (Hart et al. 2001), i.e. lower myocardial workload and flow per gram with a relative ‘overperfusion’ as evidenced by a decrease in baseline oxygen extraction or increased oxygen extraction reserve (Hannukainen et al. 2007). Heinonen et al. (2008) found no differences in coronary flow reserve to adenosine between untrained and trained athletes. Estimates of cardiac A2A receptor density were also unchanged and were not directly coupled with changes in myocardial perfusion. The authors suggest that the degree of adenosine-induced vasodilatation declined as the level of fitness increased; however, this trend is probably related to the decrease in myocardial perfusion per gram of tissue as absolute changes in flow from baseline were similar between groups. These findings demonstrate that the vasodilatory capacity of the coronary circulation is unaltered in highly trained endurance athletes and argues against the presence of maladaptive hypertrophic cardiomyopathy. In conclusion, the present study by Heinonen et al. (2008) demonstrates important adaptations in the balance between coronary blood flow and myocardial metabolism in endurance athletes. The findings underscore the complex interaction between myocardial perfusion, mass and workload and highlight a key phenotypic switch in cardiac energy balance that occurs in highly trained endurance athletes.

Is cardiac hypertrophy a required compensatory mechanism in pressure-overloaded heart?

Is cardiac hypertrophy a required compensatory mechanism in pressure-overloaded heart?