Role of renin-angiotensin system antagonists in the prevention of bevacizumab- and sunitinib-mediated cardiac dysfunction.

Although anticancer systemic therapy agents clearly lead to improved survival in patients with cancer, these can come at the cost of serious complications including cardiotoxicity. Two types of targeted systemic therapies currently in use for colorectal cancer (CRC) and renal cell cancer (RCC), respectively, include the vascular endothelial growth factor inhibitor bevacizumab (BVZ) and the tyrosine kinase inhibitor sunitinib (SNT). Despite the beneficial effects of BVZ and SNT in improving clinical outcomes in the settings of CRC and RCC, there is an increased risk of cardiac dysfunction. The aim of the present study was to determine whether prophylactic administration of renin-angiotensin system (RAS) inhibitors would attenuate the cardiotoxic side effects of BVZ or SNT in a chronic in vivo murine model. A total of 194 wild-type C57Bl/6 male mice received: 1) 0.9% saline, 2) BVZ (10 mg·kg-1·wk-1), or 3) SNT (40 mg·kg-1·day-1) for 4 wk. Within each arm, mice received daily prophylactic treatment with hydralazine (0.05 mg/ml), aliskiren (50 mg/kg), perindopril (4 mg/kg), or valsartan (2 mg/kg). Although hydralazine effectively lowered blood pressure in BVZ- or SNT-treated mice, it did not prevent left ventricular systolic dysfunction. Prophylactic administration of aliskiren, perindopril, or valsartan prevented adverse cardiovascular remodeling in mice treated with either BVZ or SNT. The addition of RAS antagonists also downregulated expression of phosphorylated p38 and Bcl-2-like 19-kDa interacting protein 3 in SNT-treated mice. In our chronic in vivo murine model, RAS antagonists partially attenuated the development of BVZ- or SNT-mediated cardiac dysfunction. Future clinical studies are warranted to investigate the cardioprotective effects of prophylactic treatment with RAS inhibitors in the settings of CRC and RCC. NEW & NOTEWORTHY In the evolving field of cardio-oncology, bevacizumab and sunitinib improve clinical outcomes in the settings of metastatic colorectal cancer and renal cell cancer, respectively. These anticancer drugs, however, are associated with an increased risk of cardiotoxicity. The prophylactic administration of renin-angiotensin system antagonists is partially cardioprotective against bevacizumab- and sunitinib-mediated cardiac dysfunction.

Puerarin protects against heart failure induced by pressure overload through mitigation of ferroptosis.

Heart failure (HF) is the end stage of cardiovascular disease and is characterized by the loss of myocytes caused by cell death. Puerarin has been found to improve HF clinically, and animal study findings have confirmed its anti-cell-death properties. However, the underlying mechanisms remain unclear, especially with respect to the impact on ferroptosis, a newly defined mechanism of iron-dependent non-apoptotic cell death in HF. Here, ferroptosis-like cell death was observed in erastin- or isoprenaline (ISO)-treated H9c2 myocytes in vitro and in rats with aortic banding inducing HF, characterized by reduced cell viability with increased lipid peroxidation and labile iron pool. Interestingly, the increased iron overload and lipid peroxidation observed in either rats with HF or H9c2 cells incubated with ISO were significantly blocked by puerarin administration. These results provide compelling evidence that puerarin plays a role in inhibiting myocyte loss during HF, partly through ferroptosis mitigation, suggesting a new mechanism of puerarin as a potential therapy for HF.

Does Levetiracetam Administration Prevent Cardiac Damage in Adulthood Rats Following Neonatal Hypoxia/Ischemia-Induced Brain Injury?

Cardiovascular abnormalities are widespread when a newborn is exposed to a hypoxic-ischemic injury in the neonatal period. Although the neuroprotective effects of levetiracetam (LEV) have been reported after hypoxia, the cardioprotective effects of LEV have not been documented. Therefore, we aimed to investigate whether levetiracetam (LEV) has a protective effect on cardiac-contractility and ultrastructure of heart muscle in rats exposed to hypoxia-ischemia (HI) during the neonatal period. A total of 49 seven-day-old rat pups were separated into four groups. For HI induction, a combination of right common carotid artery ligation with 8% oxygen in seven-day-old rat pups for 2 h was performed for saline, LEV100, and LEV200 groups. Just after hypoxia, LEV100 and LEV200 groups were administered with 100 mg/kg and 200 mg/kg of LEV, respectively. The arteries of rats in the control group were only detected; no ligation or hypoxia was performed. At the end of the 16th week after HI, cardiac mechanograms were recorded, and samples of tissue were explored by electronmicroscopy.While ventricular contractility in the control group was similar to LEV100, there were significant decreases in both saline and LEV200 groups (p < 0.05). Although ventricular contractile duration of the control and saline groups was found to be similar, durations in the LEV100 and LEV200 groups were significantly higher (p < 0.05). After HI, mitochondrial damage and ultrastructural deteriorative alterations in ventricles and atriums of the LEV-administered groups were significantly less severe than the saline group. The present study showed that neonatal HI caused long-term cardiac dysfunction and ultrastructural deteriorations in cardiac muscles. LEV administration just after HI might possess some protective effects against myocardial damage and contractility.

All-Trans Retinoic Acid supplementation prevents cardiac fibrosis and cytokines induced by Methylglyoxal.

Methylglyoxal (MG), a metabolic intermediate of glycolysis is a precursor for endogeneous production of advanced glycation end-products. The increased production of MG have negative influence over the structure and function of different biomolecules and thus plays an important role in the pathogenesis of diabetic cardiac complications. Retinoic acid (RA), an active metabolite of vitamin A, has a major role in preventing cardiac remodeling and ventricular fibrosis. Hence, the objective of the present study was to determine whether rats administered with all-trans retinoic acid (RA) could attenuate MG induced pathological effects. Wistar rats were divided into 4 groups. Group 1 rats were kept as control; Group 2 rats were administrated with MG (75 mg/kg/day) for 8 weeks. Group 3 rats were given RA (Orally, 1.0 mg/kg/day) along with MG; Group 4 rats received RA alone. Cardiac antioxidant status, induction of fibrosis, AGE receptor (RAGE) and cytokines expression was evaluated in the heart tissues. Administration of MG led to depletion of antioxidant enzymes, induction of fibrosis (p < 0.001), up-regulated expression of RAGE (3.5 fold), TGF-ß (4.4 fold), SMAD2 (3.7 fold), SMAD3 (6.0 fold), IL-6 (4.3 fold) and TNF-α (5.5 fold) in the heart tissues compared to control rats. Moreover, the exogenous administration of MG caused significant (p < 0.001) increase in the circulating CML levels. Whereas, RA treatment prevented the induction of fibrosis and restored the levels of cytokines and RAGE expression. Methylglyoxal-induced fibrosis can lead to pathological effects in the heart tissues. RA attenuates the effects of MG in the heart, suggesting that it can be of added value to usual diabetic therapy.

Efficacy of losartan as add-on therapy to prevent aortic growth and ventricular dysfunction in patients with Marfan syndrome: a randomized, double-blind clinical trial.

BACKGROUND: Marfan syndrome (MFS) is a multisystemic hereditary connective tissue disease. Aortic root aneurysms and dissections are the most common and life-threatening cardiovascular disorders affecting these patients. Other cardiac manifestations include mitral valve prolapse, ventricular dysfunction and arrhythmias. Medical treatment of cardiovascular features is ultimately aimed at slowing down aortic root growth rate and preventing dissection. Losartan has been proposed as a new therapeutic tool for this purpose. To which extent losartan affects cardiac function has not been studied previously. METHODS: We designed a prospective, double-blind, randomized placebo-controlled trial to evaluate the effect of losartan added to beta-blocker therapy on aortic growth and ventricular function in patients with MFS. Secondary outcomes were aortic dissection, prophylactic aortic surgery and death. RESULTS: Twenty-two patients were enrolled in the trial. There was a mild and similar increase in the aortic root during the 3 years of follow-up in both groups (median 1 mm, IQR [-1-1.5] and 1 mm, IQR [-0.25-1] in the losartan and placebo group, respectively, p = 1). Diastolic and systolic ventricular function was normal at baseline in both groups and remained stable during the study. One patient in the placebo group presented a subclavian artery dissection during follow-up. CONCLUSION: Losartan on top of beta-blocker therapy has no additional effect on aortic growth or on cardiac function in patients with MFS. Our results are underpowered but are in line with the result from other groups. In order to have a better insight on whether a group of patients could benefit more from losartan therapy, the outcome of an on-going meta-analysis should be awaited.

Intensified Chemotherapy With Dexrazoxane Cardioprotection in Newly Diagnosed Nonmetastatic Osteosarcoma: A Report From the Children's Oncology Group.

BACKGROUND: Although chemotherapy has improved outcome of osteosarcoma, 30-40% of patients succumb to this disease. Survivors experience substantial morbidity and mortality from anthracycline-induced cardiotoxicity. We hypothesized that the cardioprotectant dexrazoxane would (i) support escalation of the cumulative doxorubicin dose (600 mg/m(2)) and (ii) not interfere with the cytotoxicity of chemotherapy measured by necrosis grading in comparison to historical control data. PROCEDURE: Children and adolescents with nonmetastatic osteosarcoma were treated with MAP (methotrexate, doxorubicin, cisplatin) or MAPI (MAP/ifosfamide). Dexrazoxane was administered with all doxorubicin doses. Cardioprotection was assessed by measuring left ventricular fractional shortening. Interference with chemotherapy-induced cytotoxicity was determined by measuring tumor necrosis after induction chemotherapy. Feasibility of intensifying therapy with either high cumulative-dose doxorubicin or high-dose ifosfamide/etoposide was evaluated for "standard responders" (SR, <98% tumor necrosis at definitive surgery). RESULTS: Dexrazoxane did not compromise response to induction chemotherapy. With doxorubicin (450-600 mg/m(2)) and dexrazoxane, grade 1 or 2 left ventricular dysfunction occurred in five patients; 4/5 had transient effects. Left ventricular fractional shortening z-scores (FSZ) showed minimal reductions (0.0170 ± 0.009/week) over 78 weeks. Two patients (<1%) had secondary leukemia, one as a first event, a similar rate to what has been observed in prior trials. Intensification with high-dose ifosfamide/etoposide was also feasible. CONCLUSIONS: Dexrazoxane cardioprotection was safely administered. It did not impair tumor response or increase the risk of secondary malignancy. Dexrazoxane allowed for therapeutic intensification increasing the cumulative doxorubicin dose in SR to induction chemotherapy. These findings support the use of dexrazoxane in children and adolescents with osteosarcoma.

Fatty Acid Oxidation and Its Relation with Insulin Resistance and Associated Disorders.

Alterations in muscle fatty acid metabolism have been implicated in mediating the severity of insulin resistance. In the insulin resistant heart fatty acids are favored as an energy source over glucose, which is thus associated with increased fatty acid oxidation, and an overall decrease in glycolysis and glucose oxidation. In addition, excessive uptake and beta-oxidation of fatty acids in obesity and diabetes can compromise cardiac function. In animal studies, mice fed a high fat diet (HFD) show cardiac insulin resistance in which the accumulation of intra-myocardial diacylglycerol has been implicated, likely involving parallel signaling pathways. A HFD also results in accumulation of fatty acid oxidation byproducts in muscle, further contributing to insulin resistance. Carnitine acetyltransferase (CrAT) has an essential role in the cardiomyocyte because of its need for large amounts of carnitine. In the cardiomyocyte, carnitine switches energy substrate preference in the heart from fatty acid oxidation to glucose oxidation. This carnitine-induced switch in fatty acid oxidation to glucose oxidation is due to the presence of cytosolic CrAT and reverse CrAT activity. Accordingly, inhibition of fatty acid oxidation, or stimulation of CrAT, may be a novel approach to treatment of insulin resistance.

Assessment of Impact of Weight Loss on Left and Right Ventricular Functions and Value of Tissue Doppler Echocardiography in Obese Patients.

OBJECTIVE: In our study, we aimed to evaluate the effect of weight loss on left and right ventricular functions in obese patients. METHODS: Thirty patients with a BMI greater than 30 kg/m(2) and without any exclusion criteria were included in the study. Left ventricular systolic and diastolic functions were assessed with conventional and tissue Doppler echocardiography (TDE). At the end of 3 months, echocardiographic examination was repeated in patients with weight loss for cardiac function evaluation and it was compared to the baseline echocardiographic parameters. RESULTS: At the end of 3 months of weight loss period, conventional Doppler echocardiography revealed an improvement in diastolic functions with an increase in mitral E-wave, a decrease in mitral A-wave and an increase in E/A ratio. Deceleration time and isovolumetric relaxation time were ascertained shortened and Tei index decreased. TDE showed an increase in left ventricular lateral wall systolic wave (Sm) and E-wave velocity (Em). Mitral septal annular isovolumetric acceleration time (IVA), Sm and Em, were found to be increased, whereas Tei index was ascertained reduced. Right ventricular tissue Doppler examination following weight loss revealed an increase in RV- IVA, RV-Sm, and RV-Em, and a decrease in Tei index. CONCLUSION: We disclosed that left ventricular structural changes and diastolic dysfunction occur in obese patients, and by weight loss, these abnormalities may be reversible which we demonstrated both by conventional and TDE. In addition, obesity might impair RV function as well, and we observed an enhancement in right ventricular functions by weight loss.

Two-Dimensional Speckle Tracking Echocardiography in Heart Transplant Patients: Two-Year Follow-Up of Right and Left Ventricular Function.

BACKGROUND: Evolution of left and right ventricular (LV and RV) function after heart transplantation (HT) has not been well described. Our objective was to evaluate the evolution of echocardiographic parameters of both ventricles along the first 2 years after HT. METHODS: We followed 31 HT recipients with serial echocardiograms for up to 2 years. Echocardiograms with AR ≥2R were excluded. We analyzed LV global longitudinal strain (LV GLS) by speckle tracking in 12 segments in four- and two-chamber views and RV global longitudinal strain (RV GLS) in four-chamber view. Control group included 25 healthy volunteers. RESULTS: Even though LVEF was preserved, LV GLS was reduced early post-HT (-17.7 ± 3.0 in HT vs. -20.7 ± 2.8 in controls, P = 0.02), improving progressively until its complete normalization 2 years after HT (-20.0 ± 3.7 vs. -20.7 ± 2.8, P = 0.60). TAPSE was impaired in the early post-HT period and increased progressively (11.9 ± 2.9 mm at baseline vs. 19.0 ± 3.6 mm at 2 years, P < 0.001). RV GLS rose during follow-up as well (-17.4 ± 3.5 at baseline vs. -22.6 ± 3.3 at 2 years, P = 0.001), reaching normal values 1 year after HT. CONCLUSION: In this series of HT recipients with uneventful postoperative course, LV and RV GLS values were significantly reduced early after HT and improved progressively until their complete normalization two and 1 year after HT, respectively. This is the first study to show a full recovery of LV and RV deformation parameters and offers "normal" strain values that, if confirmed in larger studies, could be useful for monitoring the evolution of HT recipients.

His bundle pacing: Initial experience and lessons learned.

Direct His bundle pacing provides the most physiologic means of artificial pacing of the ventricles with a preserved His-Purkinje system and may play a role in patients with a diseased intrinsic conduction system. We describe our initial motivations and experience with permanent direct His bundle pacing and important lessons learned since that time.

Exercise training promotes cardioprotection through oxygen-sparing action in high fat-fed mice.

Although exercise training has been demonstrated to have beneficial cardiovascular effects in diabetes, the effect of exercise training on hearts from obese/diabetic models is unclear. In the present study, mice were fed a high-fat diet, which led to obesity, reduced aerobic capacity, development of mild diastolic dysfunction, and impaired glucose tolerance. Following 8 wk on high-fat diet, mice were assigned to 5 weekly high-intensity interval training (HIT) sessions (10 × 4 min at 85-90% of maximum oxygen uptake) or remained sedentary for the next 10 constitutive weeks. HIT increased maximum oxygen uptake by 13%, reduced body weight by 16%, and improved systemic glucose homeostasis. Exercise training was found to normalize diastolic function, attenuate diet-induced changes in myocardial substrate utilization, and dampen cardiac reactive oxygen species content and fibrosis. These changes were accompanied by normalization of obesity-related impairment of mechanical efficiency due to a decrease in work-independent myocardial oxygen consumption. Finally, we found HIT to reduce infarct size by 47% in ex vivo hearts subjected to ischemia-reperfusion. This study therefore demonstrated for the first time that exercise training mediates cardioprotection following ischemia in diet-induced obese mice and that this was associated with oxygen-sparing effects. These findings highlight the importance of optimal myocardial energetics during ischemic stress.

Impaired right and left ventricular function in asymptomatic children with repaired tetralogy of Fallot by two-dimensional speckle tracking echocardiography study.

BACKGROUND: Early detection of right ventricular (RV) and left ventricular (LV) dysfunction in patients with repaired tetralogy of Fallot (TOF) is essential because dysfunction is correlated with a poor clinical outcome. The aim of this study was to assess RV and LV function in asymptomatic children with repaired TOF by two-dimensional ultrasound speckle tracking echocardiography (STE). METHODS: Fifty-six asymptomatic children with a preserved biventricular ejection fraction (EF) after repair of TOF and 35 healthy control subjects were studied. RV and LV strain and strain rate were measured by STE. RVEF and pulmonary regurgitation (PR) were assessed using cardiac magnetic resonance imaging. RESULTS: Compared with the control subjects, RV regional longitudinal strain and strain rate and global longitudinal strain (GLS) and strain rate (GLSR) were impaired in children with repaired TOF. Likewise, LV circumferential and radial strain and strain rate were reduced in patients with TOF. In contrast, longitudinal strain and strain rate did not differ between the groups. RV and LV GLSR were correlated with postoperative follow-up period (r1 = -0.44; r2 = -0.48). RV GLS and GLSR were associated with RVEF (r1 = 0.64; r2 = 0.60) and PR (r1 = -0.48; r2 = -0.49). LV circumferential strain rate was related to PR (r = -0.45). CONCLUSIONS: STE can identify abnormalities that may represent early impairment of RV and LV systolic function in postoperative TOF patients with a preserved EF. PR is associated with decreased biventricular performance in repaired patients. STE-derived strain and strain rate may be useful indices for detecting the early deterioration of biventricular performance in patients with TOF.

Dichloroacetate selectively improves cardiac function and metabolism in female and male rainbow trout.

Cardiac tissue from female rainbow trout demonstrates a sex-specific preference for exogenous glucose and glycolysis, impaired Ca(2+) handling, and a greater tolerance for hypoxia and reoxygenation than cardiac tissue from male rainbow trout. We tested the hypothesis that dichloroacetate (DCA), an activator of pyruvate dehydrogenase, enhances cardiac energy metabolism and Ca(2+) handling in female preparations and provide cardioprotection for hypoxic male tissue. Ventricle strips from sexually immature fish with very low (male) and nondetectable (female) plasma sex steroids were electrically paced in oxygenated or hypoxic Ringer solution with or without 1 mM DCA. In the presence of 5 mM glucose, aerobic tissue from male trout could be paced at a higher frequency (1.79 vs. 1.36 Hz) with lower resting tension and less contractile dysfunction than female tissue. At 0.5 Hz, DCA selectively reduced resting tension below baseline values and lactate efflux by 75% in aerobic female ventricle strips. DCA improved the functional recovery of developed twitch force, reduced lactate efflux by 50%, and doubled citrate in male preparations after hypoxia-reoxygenation. Independent of female sex steroids, reduced myocardial pyruvate dehydrogenase activity and impaired carbohydrate oxidation might explain the higher lactate efflux, compromised function of the sarcoplasmic reticulum, and reduced mechanical performance of aerobic female tissue. Elevated oxidative metabolism and reduced glycolysis might also underlie the beneficial effects of DCA on the mechanical recovery of male cardiac tissue after hypoxia-reoxygenation. These results support the use of rainbow trout as an experimental model of sex differences of cardiovascular energetics and function, with the potential for modifying metabolic phenotypes and cardioprotection independent of sex steroids.

Renal sympathetic denervation modulates ventricular electrophysiology and has a protective effect on ischaemia-induced ventricular arrhythmia.

Recently, a beneficial effect of renal sympathetic denervation (RSD) has been seen in patients with ventricular electrical storm. However, the effect of RSD on ventricular electrophysiology remains unclear. Thirty-three mongrel dogs were included in the present study. Renal sympathetic denervation was performed by radiofrequency ablation of the adventitial surface of the renal artery. In group 1 (n = 8), programmed stimulation was performed before and after RSD to determine the ventricular effective refractory period (ERP) and action potential duration (APD) restitution properties. The same parameters were measured in five other animals that underwent sham RSD to serve as controls. In group 2 (n = 10), acute myocardial ischaemia (AMI) was induced by ligating the proximal left anterior descending coronary artery after the performance of RSD, and the incidence of ventricular arrhythmia (VA) was calculated during 1 h of recording. In another 10 dogs (group 3), AMI was induced and VA was measured with sham RSD. In group 1, RSD significantly prolonged ventricular ERP and APD, reduced the maximal slope (Smax) of the restitution curve and suppressed APD alternans at each site. Renal sympathetic denervation also significantly decreased the spatial dispersion of ERP, APD and Smax. In the five control animals, no significant electrophysiological change was detected after sham RSD. The occurrence of spontaneous VA during 1 h of AMI in group 2 was significantly lower than that in group 3. These data suggest that RSD stabilizes ventricular electrophysiological properties in normal hearts and reduces the occurrence of VA in hearts experiencing AMI.

Reduction of unnecessary right ventricular pacing by managed ventricular pacing and search AV+ algorithms in pacemaker patients: 12-month follow-up results of a randomized study.

AIMS: The present study was to assess the reduction of right ventricular pacing (RVP) by pacemaker algorithms of Managed Ventricular Pacing (MVP) and Search AV+ (SAV+) interval over a period of 12 months. METHODS AND RESULTS: A total of 385 patients indicated for a dual-chamber pacemaker (DC-PM) were enrolled in the prospective, randomized COMPARE study at 29 centres in China between June 2009 and April 2011. Patients implanted with DC-PMs were randomized in a 1 : 1 ratio to the MVP group or the SAV+ group. The percentage of VP (%VP) was obtained from the device diagnostic data at 1-, 6-, and 12-month follow-ups and was expressed as the median %VP over all beats in patients with sinus node dysfunction (SND) and atrioventricular block (AVB) excluding persistent third-degree AVB. Of 385 enrolled patients, 253 had SND and 72 had AVB. The %VP in the MVP group was significantly lower than that in the SAV+ group at 1-, 6-, and 12-month follow-ups, respectively. At 12-month follow-up, the median %VP in SND patients was 0.20% in the MVP group and 1.4% in the SAV+ group (P < 0.0001) and the median %VP in AVB patients was 11.8% in the MVP group and 98.1% in the SAV+ group (P < 0.001). There was no statistical difference in %VP from 1- to 12-month follow-up. A trend in the correlation between %VP and AT/AF burden was observed. CONCLUSION: Over 12-month follow-up, the %VP was lower for MVP than SAV+ in patients with either SND or AVB. The sustainable %VP reduction has potential implications in reducing the development of heart failure and/or atrial arrhythmia morbidity.

Myocardial substrate metabolism in obesity.

Obesity is linked to a wide variety of cardiac changes, from subclinical diastolic dysfunction to end-stage systolic heart failure. Obesity causes changes in cardiac metabolism, which make ATP production and utilization less efficient, producing functional consequences that are linked to the increased rate of heart failure in this population. As a result of the increases in circulating fatty acids and insulin resistance that accompanies excess fat storage, several of the proteins and genes that are responsible for fatty acid uptake and metabolism are upregulated, and the metabolic machinery responsible for glucose utilization and oxidation are inhibited. The resultant increase in fatty acid metabolism, and the inherent alterations in the proteins of the electron transport chain used to create the gradient needed to drive mitochondrial ATP production, results in a decrease in efficiency of cardiac work and a relative increase in oxygen usage. These changes in cardiac mitochondrial metabolism are potential therapeutic targets for the treatment and prevention of obesity-related heart failure.

Increase in parasympathetic tone by pyridostigmine prevents ventricular dysfunction during the onset of heart failure.

Heart failure (HF) is characterized by elevated sympathetic activity and reduced parasympathetic control of the heart. Experimental evidence suggests that the increase in parasympathetic function can be a therapeutic alternative to slow HF evolution. The parasympathetic neurotransmission can be improved by acetylcholinesterase inhibition. We investigated the long-term (4 wk) effects of the acetylcholinesterase inhibitor pyridostigmine on sympathovagal balance, cardiac remodeling, and cardiac function in the onset of HF following myocardial infarction. Myocardial infarction was elicited in adult male Wistar rats. After 4 wk of pyridostigmine administration, per os, methylatropine and propranolol were used to evaluate the cardiac sympathovagal balance. The tachycardic response caused by methylatropine was considered to be the vagal tone, whereas the bradycardic response caused by propranolol was considered to be the sympathetic tone. In conscious HF rats, pyridostigmine reduced the basal heart rate, increased vagal, and reduced sympathetic control of heart rate. Pyridostigmine reduced the myocyte diameter and collagen density of the surviving left ventricle. Pyridostigmine also increased vascular endothelial growth factor protein in the left ventricle, suggesting myocardial angiogenesis. Cardiac function was assessed by means of the pressure-volume conductance catheter system. HF rats treated with pyridostigmine exhibited a higher stroke volume, ejection fraction, cardiac output, and contractility of the left ventricle. It was demonstrated that the long-term administration of pyridostigmine started right after coronary artery ligation augmented cardiac vagal and reduced sympathetic tone, attenuating cardiac remodeling and left ventricular dysfunction during the progression of HF in rats.

Spironolactone improves the arrhythmogenic substrate in heart failure by preventing ventricular electrical activation delays associated with myocardial interstitial fibrosis and inflammation.

INTRODUCTION: Mineralocorticoid receptor antagonism reduces sudden cardiac death in heart failure, but the underlying mechanism is unclear. Our previous studies indicate that treatment with a mineralocorticoid receptor antagonist prevents adverse ventricular electrophysiological remodeling and reduces ventricular tachyarrhythmia inducibility in the rapid ventricular pacing-induced heart failure model. This study's aim was to determine whether chronic spironolactone treatment prevents formation of local electrical activation delays in the cardiomyopathic ventricle by attenuating inflammatory pathways and myocardial fibrosis. METHODS AND RESULTS: Dogs subjected to rapid ventricular pacing at 220 bpm for 5 weeks in the absence or presence of spironolactone treatment were assessed by echocardiography, electrophysiology study, ventricular fibrosis measurements and inflammatory cytokine mRNA expression analysis. Spironolactone failed to prevent LV systolic dysfunction or chamber enlargement in dogs that underwent rapid ventricular pacing. Spironolactone prevented ventricular electrogram widening after premature stimulation at short coupling intervals, electrogram fractionation, interstitial fibrosis, and inflammatory cytokine (interleukin-6, tumor necrosis factor-α) gene overexpression in ventricular paced dogs with heart failure. CONCLUSIONS: Our findings establish an important link between inflammatory cytokine gene expression, interstitial fibrosis and myocardial electrical activation delays during premature excitation and provide insight into the mechanisms by which mineralocorticoid receptor antagonism may prevent development of an arrhythmogenic ventricular substrate in systolic heart failure.

Eplerenone attenuated cardiac steatosis, apoptosis and diastolic dysfunction in experimental type-II diabetes.

BACKGROUND: Cardiac steatosis and apoptosis are key processes in diabetic cardiomyopathy, but the underlying mechanisms have not been elucidated, leading to a lack of effective therapy. The mineralocorticoid receptor blocker, eplerenone, has demonstrated anti-fibrotic actions in the diabetic heart. However, its effects on the fatty-acid accumulation and apoptotic responses have not been revealed. METHODS: Non-hypertensive Zucker Diabetic Fatty (ZDF) rats received eplerenone (25 mg/kg) or vehicle. Zucker Lean (ZL) rats were used as control (n = 10, each group). After 16 weeks, cardiac structure and function was examined, and plasma and hearts were isolated for biochemical and histological approaches. Cultured cardiomyocytes were used for in vitro assays to determine the direct effects of eplerenone on high fatty acid and high glucose exposed cells. RESULTS: In contrast to ZL, ZDF rats exhibited hyperglycemia, hyperlipidemia, insulin-resistance, cardiac steatosis and diastolic dysfunction. The ZDF myocardium also showed increased mitochondrial oxidation and apoptosis. Importantly, eplerenone mitigated these events without altering hyperglycemia. In cultured cardiomyocytes, high-concentrations of palmitate stimulated the fatty-acid uptake (in detriment of glucose assimilation), accumulation of lipid metabolites, mitochondrial dysfunction, and apoptosis. Interestingly, fatty-acid uptake, ceramides formation and apoptosis were also significantly ameliorated by eplerenone. CONCLUSIONS: By blocking mineralocorticoid receptors, eplerenone may attenuate cardiac steatosis and apoptosis, and subsequent remodelling and diastolic dysfunction in obese/type-II diabetic rats.

Brain sigma-1 receptor stimulation improves mental disorder and cardiac function in mice with myocardial infarction.

Mental disorder after myocardial infarction (MI) is reported by many epidemiological studies and is associated with a poor prognosis. The reduction of brain sigma-1 receptor (S1R) plays an important role in the pathogenesis of mental disorder, and we recently demonstrated that the reduction of brain S1R causes sympathoexcitation. However, the role of brain S1R in the association between MI and mental disorder, such as depression or cognitive impairment, remains unclear. To investigate this, we performed left coronary artery ligation on mice to produce an MI model (MI-mice). Compared with sham-operated controls (Sham-mice), MI-mice showed augmented sympathetic activity, decreased cardiac function, and lower S1R expression in both the hypothalamus and hippocampus. Furthermore, MI-mice displayed decreased Y-maze spontaneous alternation (a maker of spatial working memory), decreased circadian variation in locomotor activity, and increased immobility time in the tail suspension test (markers of depression-like behavior). Intracerebroventricular infusion of the S1R agonist PRE084 in MI-mice improved both mental disorder and cardiac function with lowered sympathetic activity and the recovery of the S1R expression in both the hypothalamus and hippocampus. These results indicate that brain S1R is decreased in MI-mice and that this plays an important role in the coexistence of increased heart failure via sympathoexcitation and mental disorders, such as depression or cognitive impairment.