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Background Chest radiation therapy (CRT) for malignant thoracic neoplasms is associated with development of valvular heart disease years later. As previous radiation exposure can complicate surgical treatment, transcatheter aortic valve replacement (TAVR) has emerged as an alternative. However, outcomes data are lacking for TAVR patients with a history of CRT. Methods We conducted a retrospective study of all patients who underwent a TAVR procedure at a single institution between September 2012 and November 2018. Among 1341 total patients, 50 had previous CRT. These were propensity-matched in a 1:2 ratio to 100 patients without history of CRT. Thirty-day adverse events were analyzed with generalized estimating equation models. Overall mortality was analyzed with stratified Cox regression modelling. Results Median clinical follow-up was 24 months (interquartile range [IQR], 12–44 months). There was no difference between CRT and non-CRT patients in overall mortality (hazard ratio [HR] 0.84 [0.37–1.90], P = 0.67), 30-day mortality (HR 3.1 [0.49–20.03], P = 0.23), or 30-day readmission rate (HR 1.0 [0.43–2.31], P = 1). There were no differences in the rates of most adverse events, but patients with CRT history had higher rates of postprocedural respiratory failure (HR 3.63 [1.32–10.02], P = 0.01) and permanent pacemaker implantation (HR 2.84 [1.15–7.01], P = 0.02). Conclusions For patients with aortic valve stenosis and previous CRT, TAVR is safe and effective, with outcomes similar to those in the general aortic stenosis population. Patients with history of CRT are more likely to have postprocedural respiratory failure and to require permanent pacemaker implantation.

BackgroundThe safety and efficacy of leadless pacemakers (LP) in transcatheter aortic valve implant (TAVI) patients is not well known due to paucity of data. Herein, we compared outcomes between leadless pacemakers to traditional dual chamber pacemakers (DCP) following TAVI.MethodsA single-center retrospective study was conducted, including a total of 27 patients with LP and 33 patients with DCP after TAVI between November 2013 to May 2021. We compared baseline demographics, pacemaker indications, percent pacing, ejection fractions, and pacemaker related complication rates.ResultsLeading indications for pacemaker implant were complete heart block (74% LP, 73% DCP) and high degree atrioventricular block (26% LP, 21% DCP). No significant differences were observed between LP and DCP in device usage and ejection fraction at 1, 6, and 12 months. Within each pacemaker group, we did not observe a significant reduction in percent ventricular pacing or ejection fraction at follow up. Three DCP patients required rehospitalization for pocket related complications.ConclusionFrom this single-center study, TAVI patients appear to have comparable pacemaker usage and ejection fraction between LP and DCP groups, suggesting that LP may be a reasonable alternative where single ventricular pacing is indicated. Larger studies are required to validate these findings.

BACKGROUND: Valve-in-valve transcatheter aortic valve replacement (ViV-TAVR) has emerged as a safe, effective alternative to redo aortic valve surgery in high-risk patients with degenerated surgical bioprosthetic valves. However, ViV-TAVR has been associated high postprocedural valvular gradients, compared with TAVR for native-valve aortic stenosis. METHODS: We performed a retrospective study of all patients who underwent ViV-TAVR for a degenerated aortic valve bioprosthesis between January 1, 2013 and March 31, 2019 at our center. The primary outcome was postprocedural mean aortic valve gradient. Outcomes were compared across surgical valve type (stented versus stentless), surgical valve internal diameter (≤19 versus >19 mm), and transcatheter aortic valve type (self-expanding vs. balloon-expandable). RESULTS: Overall, 89 patients underwent ViV-TAVR. Mean age was 69.0±12.6 years, 61% were male, and median Society of Thoracic Surgeons Predicted Risk of Mortality score was 5.4 [interquartile range, 3.2–8.5]. Bioprosthesis mode of failure was stenotic (58% of patients), regurgitant (24%), or mixed (18%). The surgical valve was stented in 75% of patients and stentless in 25%. The surgical valve’s internal diameter was ≤19 mm in 45% of cases. A balloon-expandable transcatheter valve was used in 53% of procedures. Baseline aortic valve area and mean gradients were 0.87±0.31 cm(2) and 36±18 mmHg, respectively. These improved after ViV-TAVR to 1.38±0.55 cm(2) and 18±11 mmHg at a median outpatient follow-up of 331 [67–394] days. Higher postprocedural mean gradients were associated with surgical valves having an internal diameter ≤19 mm (24±13 versus 16±8, P=0.002) and with stented surgical valves (22±11 versus 12±6, P

Objectives Using a large nationally representative database, we aimed to examine risk factors for acute kidney injury (AKI) and its association with outcomes in patients undergoing percutaneous left atrial appendage closure (LAAC). Background Previous small-scale studies have reported poor outcomes with AKI following percutaneous LAAC. Methods We queried the Nationwide Readmission Database to identify LAAC procedures performed from 2016 to 2017. Multivariable logistic and linear regression models were used to identify risk factors for AKI and determine the association between AKI and clinical outcomes. The primary outcome of interest was in-hospital mortality. Results Of 20,703 patients who underwent LAAC during the study period, 1,097 (5.3%) had a diagnosis of AKI. Chronic kidney disease, non-elective admission, coagulopathy, weight loss, prior coronary artery disease, heart failure, diabetes mellitus, and anemia were independently associated with an increased risk of AKI after LACC. In patients undergoing LAAC, AKI was associated with an increased risk of in-hospital mortality (adjusted odds ratio [aOR], 16.01; 95% CI, 8.48-30.21), stroke/transient ischemic attack (aOR, 2.50; 95% CI, 1.69-3.70), systemic embolization (aOR, 3.78; 95% CI, 1.64-8.70), bleeding/transfusion (aOR, 1.96; 95% CI, 1.50-2.56), vascular complications (aOR, 3.53; 95% CI, 1.94-6.42), pericardial tamponade requiring intervention (aOR, 6.83; 95% CI, 4.37-10.66), index length of stay (adjusted parameter estimate, 7.46; 95% CI, 7.02-7.92), and 180-day all-cause readmissions (aOR, 1.43; 95% CI, 1.09-1.88). Conclusion AKI in the setting of LAAC is uncommon but is associated with poor clinical outcomes. Further studies are needed to determine if a similar association exists for long-term outcomes.

Inflammation plays a key role in clearing cellular debris and recovery after acute myocardial infarction (AMI). Dysregulation of or prolonged inflammation may result in adverse cardiac remodeling and major adverse clinical events (MACE). Several pre-clinical studies and moderate sized clinical trials have investigated the role of immunomodulation in improving clinical outcomes in patients with AMI. Clinical data from the Canakinumab Atherothrombosis Outcome (CANTOS) and Colchicine Cardiovascular Outcomes Trial (COLCOT) have provided encouraging results among patients with AMI. Several other clinical and pre-clinical trials have brought about the prospect of modulating inflammation at various junctures of the inflammatory cascade including inhibition of complement cascade, interleukins, and matrix metalloproteinases. In patients with AMI, modulation of residual inflammation via various inflammatory pathways and mediators may hold promise for further reducing MACE. Learning from current data and understanding the nuances of immunomodulation in AMI are key for future trials and before widespread dissemination of such therapies.

Radiation treatment of thoracic malignancies is linked with development of valvular disease years after exposure. Given the challenges to surgical treatment related to previous radiation exposure, TAVR has emerged as an alternative. However, outcomes data for patients with history of mediastinal

Background: Significant improvement of computed tomography (CT) technology in the last decade has led to more use of this modality for evaluating infective endocarditis (IE) especially since the introduction of high resolution electrocardiogram (ECG) synchronized multiphasic (4D) acquisition. While there are a number of reports on the accuracy and value of 4D CT for evaluation of IE, there is no published data regarding the performance of single-phase ECG gated CT for assessment of IE. The purpose of this study is to evaluate the sensitivity and specificity of preoperative single-phase ECG-gated CT imaging versus transesophageal echocardiography (TEE) in the assessment of complications related to IE, with comparison to surgical findings. Methods: Among 899 patients with surgically proven IE in our database, 122 underwent contrast-enhanced ECG cardiac CT and were included in the study; 84 of these patients also underwent TEE. Results: Overall, there was no significant difference between CT and TEE in the identification of pseudoaneurysm/abscess and dehiscence. For the detection of pseudoaneurysm/abscess in prosthetic valves, CT demonstrated higher sensitivity (81% vs . 64%) and specificity (75% vs . 33%) in patients with mechanical aortic valves; TEE demonstrated marginally higher sensitivity (72% vs . 63%) and specificity (80% vs . 73%) in patients with bioprosthetic aortic valves, although the differences are not statistically significant. TEE demonstrated significantly higher sensitivity (85% vs . 16%) in identifying vegetation in all patients (P vs . 19%). The combined imaging findings of CT and TEE demonstrated improved sensitivity in identifying pseudoaneurysm/abscess and slightly improved detection of prosthesis dehiscence. Conclusions: Preoperative single-phase gated CT can be seen as complementary to TEE in assessing complications of suspected IE or may be substituted for TEE when vegetation or dehiscence is depicted on transthoracic echocardiography and the patient has a contraindication to TEE.

To rock: to move back and forth in or as if in a cradle; to rouse to excitement—Merriam Webster Dictionary [(1)][1] The left ventricle (LV), when imaged in horizontal plane, may exhibit 3 types of motion: inward (reflective of muscle thickening); along the long axis (reflecting piston-like

Endothelial dysfunction and impaired angiogenesis constitute a hallmark of hypercholesterolemia. This study was designed to examine the effects of resveratrol, an antioxidant with lipid-lowering properties similar to those of statins, on neovascularization along with caveolar interaction with proangiogenic molecules in hypercholesterolemic rats. Animals were divided into: rats maintained on a normal diet (control group); rats maintained on a 5% high-cholesterol diet for 8 weeks (HC group); and rats maintained on a 5% high-cholesterol diet for 8 weeks and administered resveratrol (20 mg/kg) orally for 2 weeks (HCR group). Myocardial infarction was induced by ligating the left anterior descending artery. Herein we examined a novel method for stimulating myocardial angiogenesis by pharmacological preconditioning with resveratrol at both the capillary and arteriolar levels and the potential role of hemeoxygenase-1, endothelial nitric oxide synthase and caveolin-1 in mediating such a response. We also investigated the functional relevance of such treatment by assessing whether the induced neovascularization can help preserve left ventricle-contractile functional reserve in the setting of a chronic hypercholesterolemic condition. Four weeks after sham surgery and left anterior descending artery occlusion, rats underwent echocardiographic evaluation, which revealed improvement in ejection fraction and fractional shortening in the HCR group compared with the HC group. Left ventricular tissue sections displayed increased capillary and arteriolar density in the HCR group compared with the HC group. Western blot analysis revealed downregulation of vascular endothelial growth factor and hemeoxygenase-1 and increased association of caveolin-1 eNOS in the HC group, decreasing the availability of eNOS to the system; which was reversed with resveratrol treatment in the HCR group. This study was further validated in cardiac-specific hemeoxygenase-1-overexpressed mice assuming molecular cross-talk between the targets. Hence, our data identified potential regulators that primarily attenuate endothelial dysfunction by resveratrol therapy in hypercholesterolemic myocardium.

Sildenafil citrate (SC), a drug for erectile dysfunction, is now emerging as a cardiopulmonary drug. Our study aimed to determine a novel role of sildenafil on cardioprotection through stimulating angiogenesis during ischaemia (I) reperfusion (R) at both capillary and arteriolar levels and to examine the role of vascular endothelial growth factor (VEGF) and angiopoietin-1 (Ang-1) in this mechanistic effect. Rats were divided into: control sham (CS), sildenafil sham (SS), control + IR (CIR) and sildenafil + IR (SIR). Rats were given 0.7 mg/kg, (i.v) of SC or saline 30 min. before occlusion of left anterior descending artery followed by reperfusion (R). Sildenafil treatment increased capillary and arteriolar density followed by increased blood flow (2-fold) compared to control. Treatment with sildenafil demonstrated increased VEGF and Ang-1 mRNA after early reperfusion. PCR data were validated by Western blot analysis. Significant reduction in infarct size, cardiomyocyte and endothelial apoptosis were observed in SC-treated rats. Increased phosphorylation of Akt, eNOS and expression of anti-apoptotic protein Bcl-2, and thioredoxin, hemeoxygenase-1 were observed in SC-treated rats. Echocardiography demonstrated increased fractional shortening and ejection fraction following 45 days of reperfusion in the treatment group. Stress testing with dobutamine infusion and echocardiogram revealed increased contractile reserve in the treatment group. Our study demonstrated for the first time a strong additional therapeutic potential of sildenafil by up-regulating VEGF and Ang-1 system, probably by stimulating a cascade of events leading to neovascularization and conferring myocardial protection in in vivo I/R rat model.

Hypercholesterolemia (HC) is a common health problem that significantly increases risk of cardiovascular disease. Both statin (S) and resveratrol (R) demonstrated cardioprotection through nitric oxide-dependent mechanism. Therefore, the present study was undertaken to determine whether combination therapy with statin and resveratrol is more cardioprotective than individual treatment groups in ischemic rat heart model. The rats were fed with 2% high cholesterol diet and after 8 weeks of high cholesterol diet the animals were treated with statin (1 mg/kg bw/day) and resveratrol (20 mg/kg bw/day) for 2 weeks. The rats were assigned to: (1) Control (C), (2) HC, (3) HCR, (4) HCS and (5) HCRS. The hearts, subjected to 30-min global ischemia followed by 120-min reperfusion were used as experimental model. The left ventricular functional recovery (+dp/dt(max)) was found to be significantly better in the HCRS (1926+/-43), HCR (1556+/-65) and HCS (1635+/-40) compared to HC group (1127+/-16). The infarct sizes in the HCRS, HCS and HCR groups were 37+/-3.6, 43+/-3.3 and 44+/-4.2 respectively compared to 53+/-4.6 in HC. The lipid level was found to be decreased in all the treatment groups when compared to HC more significantly in HCS and HCRS groups when compared to HCR. Increased phosphorylation of Akt and eNOS was also observed in all the treatment groups resulting in decreased extent of cardiomyocyte apoptosis but the extent of reduction in apoptosis was more significant in HCRS group compared to all other groups. In vivo rat myocardial infarction (MI) model subjected to 1 week of permanent left descending coronary artery (LAD) occlusion documented increased capillary density in HCR and HCRS treated group when compared to HCS treatment group. We also documented increased beta-catenin translocation and increased VEGF mRNA expression in all treatment groups. Thus, we conclude that the acute as well as chronic protection afforded by combination treatment with statin and resveratrol may be due to pro-angiogenic, anti-hyperlipidemic and anti-apoptotic effects and long-term effects may be caused by increased neo-vascularization of the MI zone leading to less ventricular remodeling.

Robert & Suzanne Tomsich Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave./J1-5 Cleveland, OH 44195, USA *Author for correspondence: Tel.: +1 216 444 8429; Fax: +1 216 445 6164; colliep@ccf.org

Therapeutic angiogenesis represents a novel approach for the prevention and treatment of ischemic heart disease. This study examined a novel method of stimulating myocardial angiogenesis using secoisolariciresinol diglucoside (SDG), a plant lignan isolated from flaxseed. SDG has been shown to decrease serum cholesterol and reduce the extent of atherosclerosis. In the present study, the angiogenic properties of SDG were investigated in three different models. First, in the in vitro model, human coronary arteriolar endothelial cells (HCAEC) treated with SDG (50 and 100 microM) showed a significant increase in tubular morphogenesis compared with control. Western blot analysis indicated an increased expression of vascular endothelial growth factor (VEGF), kinase insert domain-containing receptor (KDR), Flt-1, angiopoietin-1 (Ang-1), Tie-1, and phosphorylated endothelial nitric oxide synthase (p-eNOS) in the SDG-treated cells. Second, in the ex vivo ischemia/reperfusion model, SDG-treated rats (20 mg/kg b.wt./day for 2 weeks orally) showed an increased level of aortic flow and functional recovery after 2 h of reperfusion following 30 min of ischemia compared with the control group [dP/dt (mm Hg/s) of 2110 +/- 35 versus 1752 +/- 62]. SDG reduced infarct size compared with the control group by 32% (38 versus 26%) and also decreased cardiomyocyte apoptosis. Increased protein expression of VEGF, Ang-1, and p-eNOS was also observed in the SDG-treated group. Third, in the in vivo myocardial infarction model, SDG increased capillary density and myocardial function as evidenced by increased fractional shortening and ejection fraction. In conclusion, these results suggest that SDG has potent angiogenic and antiapoptotic properties that may contribute to its cardioprotective effect in ischemic models.

Heart failure (HF) readmissions are a common and serious problem of heterogeneous etiology. Left ventricular (LV) ejection fraction has not been found to be a consistent risk marker. However, LV strain has been shown to predict outcomes in other settings, so the aim of this study was to determine the association of LV strain with 30-day HF readmission, independent of and incremental to clinical and basic echocardiographic parameters.A total of 468 patients who underwent echocardiography at the time of the first admission for HF from July 2009 to June 2012 were retrospectively studied. Clinical parameters were comprehensively assessed, and standard echocardiographic parameters and two strain parameters (global longitudinal strain [GLS] and global circumferential strain) were measured using speckle-tracking. Patients were followed for all-cause 30-day hospital readmission or death after discharge, and the associations of parameters with outcome were assessed using Cox proportional hazards models.Readmission within 30 days (n = 92 patients [20%]) was associated with greater impairment of LV GLS (-8.6% [interquartile range, -10.9% to -5.9%] vs -11.1% [interquartile range, -14.6% to -7.7%], P .01). The association of GLS with readmission (hazard ratio, 1.13; 95% confidence interval, 1.07-1.19; P .01) was independent of age, male gender, systolic blood pressure, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use, and comorbidity, as well as renal function, sodium, hematocrit, LV mass, left atrial size, and mitral regurgitation. Global circumferential strain was associated with outcome but not was independent after adjustment with echocardiographic parameters. In sequential models for 30-day outcome, GLS added incremental information to clinical parameters and LV ejection fraction and significantly improved reclassification (categorical net reclassification improvement, 0.34; P = .04) when LV ejection fraction was50%.GLS is associated with HF readmission, independent of and incremental to clinical and basic echocardiographic parameters.

Objective In adults with an interarterial and intramural course of an anomalous right coronary artery from the left sinus (AAORCA), surgical unroofing is recommended in the setting of myocardial ischaemia. However, data regarding functional testing are limited, and the management of adults without ischaemia is unclear. To evaluate these patients, we employed an exercise N13-ammonia positron emission tomography (PET) protocol. We hypothesised that patients with typical angina and exertional dyspnoea would be more likely to have ischaemia and that patients without ischaemia could be managed conservatively. Methods Between July 2008 and December 2014, we retrospectively identified 27 consecutive patients >18 years old with an interarterial and intramural course of an AAORCA who had exercise N13-ammonia PET. Results The majority of patients had anatomic delineation with cardiac CT (25, 93%), and most patients had chest pain (24, 89%). Myocardial ischaemia with PET was common (13, 48%), and ischaemia was more likely in patients with typical angina and exertional dyspnoea (p

The utility of Atrio-Ventricular (AV) delay optimization following Cardiac Resynchronization Therapy (CRT) remains unclear. We aimed to determine the utility and outcome of interrogating and selectively optimizing AV synchrony using Echo-Doppler-Guided (EDG) AV optimization following CRT. All

Background— The present study evaluated the reversal of diabetes-mediated impairment of angiogenesis in a myocardial infarction model of type 1 diabetic rats by intramyocardial administration of an adenoviral vector encoding thioredoxin-1 ( Ad.Trx1 ). Various studies have linked diabetes-mediated impairment of angiogenesis to dysfunctional antioxidant systems in which thioredoxin-1 plays a central role. Methods and Results— Ad.Trx1 was administered intramyocardially in nondiabetic and diabetic rats immediately after myocardial infarction. Ad.LacZ was similarly administered to the respective control groups. The hearts were excised for molecular and immunohistochemical analysis at predetermined time points. Myocardial function was measured by echocardiography 30 days after the intervention. The Ad.Trx1 -administered group exhibited reduced fibrosis, oxidative stress, and cardiomyocyte and endothelial cell apoptosis compared with the diabetic myocardial infarction group, along with increased capillary and arteriolar density. Western blot and immunohistochemical analysis demonstrated myocardial overexpression of thioredoxin-1, heme oxygenase-1, vascular endothelial growth factor, and p38 mitogen-activated protein kinase-β, as well as decreased phosphorylated JNK and p38 mitogen-activated protein kinase-α, in the Ad.Trx1 -treated diabetic group. Conversely, we observed a significant reduction in the expression of vascular endothelial growth factor in nondiabetic and diabetic animals treated with tin protoporphyrin (SnPP, a heme oxygenase-1 enzyme inhibitor), even after Ad.Trx1 therapy. Echocardiographic analysis after 4 weeks of myocardial infarction revealed significant improvement in myocardial functional parameters such as ejection fraction, fractional shortening, and E/A ratio in the Ad.Trx1 -administered group compared with the diabetic myocardial infarction group. Conclusions— This study demonstrates for the first time that impairment of angiogenesis and myocardial dysfunction can be regulated by Ad.Trx1 gene therapy in streptozotocin-induced diabetic rats subjected to infarction.

Background Hypertension, the major risk factor for many cardiovascular diseases, is a result of multiple causes along with excessive generation of reactive oxygen species (ROS) resulting in imbalance of redox status. Methods In this study, we investigated the therapeutic potential of Adenoviral-Thioredoxin-1 (Adeno-Trx-1) in spontaneous hypertensive rats (SHRs) at a dosage of 1 x 10(9) pfu. The rats were assigned as normotensive Wistar-Kyoto (WKY), SHR, SHR + Adeno-Lac-Z (SHRLac-Z), and SHR + Adeno-Trx-1 (SHRTrx-1). Echo-guided injection of adeno virus was done 48 h before permanent myocardial infarction (MI) by left anterior descending coronary artery (LAD) occlusion. Results Decreased infarct size (52 +/- 4.1% vs. 67 +/- 6.1%), number of apoptotic cardiomyocytes (161 +/- 14.8 vs. 240 +/- 22.2), left ventricular inner diameter (7 +/- 0.33 vs. 9 +/- 0.46 mm), increased ejection fraction (52 +/- 6.3 vs. 42 +/- 3.3%), and fractional shortening (28 +/- 1.8 vs. 22 +/- 2.04 %) was observed in the SHRTrx-1 compared to SHR. Western Blot and immunohistochemical analysis demonstrated increased expression of Trx-1, HO-1, and Bcl-2 in the SHRTrx-1 compared to SHR. In addition, increased HO-1 activity was also observed in SHRTrx-1 as compared to SHR and SHRLac-Z groups. Conclusion Our study demonstrates that the cardioprotective effect of Adeno-Trx-1 gene therapy in SHR is Trx-1/HO-1/Bcl-2 mediated and may represent future target to develop therapy against hypertension associated cardiac failure.

Hypercholesterolemia (HC) related decrease in eNOS phosphorylation & endothelial dysfunction may account for impaired angiogenesis and subsequent increased ventricular remodeling. Over expression of Caveolin-1 (Cav-1) and Lectin-like oxidized LDL receptor (LOX-1) has been demonstrated during HC but the mechanism needs to be elucidated. To investigate this we randomized the rats into control (normal diet) and HC (5% high cholesterol diet for 8 weeks). The cholesterol, triglycerides & LDL levels were increased & the HDL levels decreased in HC compared to control. After the experimental diet period the rats were subjected to Left Anterior Descending Artery (LAD) ligation. We evaluated the expression of Cav-1, LOX-1, Heme Oxygenase (HO-1), HSP-90, phospho(p)-Akt & p-eNOS in HC and control. Significant increase in Cav-1, LOX-1 (2, 1.8 fold) & decrease in HO-1, HSP-90, p-Akt, p-eNOS & VEGF (0.5, 0.6, 0.4, 0.5 & 0.6 fold) was observed in HC compared to control. The LV functional reserve was evaluated by measuring the ejection fraction (EF), fractional shortening (FS) & LV internal diameter (LVID) after 30 days of LAD ligation. Significant increase in LVID ( 8.6 vs 7) and decrease in EF (39 vs 53%), FS (20 vs 28%), LVID (2 vs 2.7mm) as well as capillary (1888 vs 2424) & arteriolar density (1.5 vs 2.5) counts/mm2 was observed in HC compared to control. Earlier we have reported that over expression of HO-1 mediates eNOS activation & cardioprotection in MI model. To investigate the mechanism involved in HO-1 mediated cardioprotection we generated cardiac specific HO-1 over expressed transgenic (Tg) mice. Immunohistochemical analysis of HO-1 Tg mice has clearly demonstrated decreased Cav-1-eNOS interaction. Immunoblot analysis has shown to decrease Cav-1 (0.6 fold) & increased HSP-90, p-Akt, p-eNOS & VEGF expression (1.5, 1.6, 1.4 & 1.5 fold) as compared to control. These findings demonstrated that HO-1 over expression regulates HSP-90 & Cav-1 for eNOS activation. In conclusion, we demonstrate a novel mechanism of HO-1/HSP-90 mediated Cav-1-eNOS regulation leading to increased neovascularization & reduced ventricular remodeling during HC for the regression of clinical complications which would be crucial for cardiovascular drug therapy.

Statin based lowering of low density lipoprotein (LDL) cholesterol has been considered as one of the major factors of cardiovascular risk reduction. Independent of lipid lowering, statins up-regulates the endothelial nitric oxide production through caveolin-1 (Cav-1) downregulation. The novel receptor, lectin like Ox-LDL receptor-1 (LOX-1) is known to bind, internalize and degrade Ox-LDL for its action. This study was designed to investigate the molecular mechanism of statin mediated Cav-1 & LOX-1 regulation. Rats were randomized into: control (normal diet); HC (5% high cholesterol diet for 8 weeks) and HC + Pravastatin (S) (1mg/kg) administered orally for 2 weeks (HCS). Statin reduced the cholesterol, LDL & increased the HDL levels compared to non-treated HC. Hearts were subjected to permanent left anterior descending coronary artery occlusion (MI). LV functions by echocardiography was examined 30 days after MI. Decreased LV inner diameter (7.4 vs 9 mm), increased ejection fraction (47 vs 39 %) and fractional shortening (25 vs 20 %) was observed in HCS compared to HC. Cav-1, LOX-1 protein expression was upregulated in HC (2, 1.8 fold) compared to control which were decreased to 1.2 and 1.1 fold on statin treatment. We have observed in HCS increased Heme Oxygenase-1 (HO-1, 1.9 fold), HSP-90 expression (1.7 fold) and phosphorylation of eNOS (p-eNOS) by 1.6 fold whereas in HC 0.4, 0.5 and 0.4 fold respectively as compared to control. Over expression of HO-1 and HSP-90 by statin treatment might have facilitated for the stimulated displacement of eNOS from Cav-1 for its activation. Further to examine how HO-1 and HSP-90 regulate the eNOS activation we have generated cardiac specific HO-1 over expressed mice. Immunohistochemical analysis of HO-1 mice clearly demonstrated decreased Cav-1-eNOS interaction and increased p-eNOS (1.8 fold) as shown by immunoblot analysis compared to wild type. Moreover, we observed increased HSP-90 (2 fold) which is known for the serine phosphorylation of eNOS. These results indicate for the first time; a novel mechanism of action by statins in regulation of the caveolar platform by Cav-1, LOX-1, HO-1/HSP-32 & HSP-90 for eNOS activation which would be a novel treatment strategy to prevent HC mediated cardiovascular complications.

This study examined the hypothesis that the ubiquitin proteasome system (UPS) degrades proteins damaged by exposure to hyperglycemia. Experimental hyperglycemia was induced in male rats by treatment with streptozotocin. After 30 days, echocardiography confirmed the presence of cardiomyopathy as ejection fraction, fractional shortening, and diastolic function (E/A ratio) were decreased, and chamber diameter was increased in hyperglycemic animals. Proteasome non-ATP-dependent chymotryptic activity was increased over 2-fold in hyperglycemic hearts, but the ATP-dependent activity was decreased and levels of ubiquitinated proteins were increased. Protein levels of the PA28alpha of the 11S-activator ring were increased by 128% and the PA28beta subunit increased by 58% in the hyperglycemic hearts. The alpha3 subunit of the 20S-proteasome was increased by 82% while the catalytic beta5 subunit was increased by 68% in hyperglycemic hearts. Protein oxidation as indicated by protein carbonyls was significantly higher in hyperglycemic hearts. These studies support the conclusion that the UPS becomes dysfunctional during long term hyperglycemia. However, 11S-activated proteasome was increased suggesting a response to oxidative protein damage and a potential role for this form of the proteasome in a cardiac pathophysiology.

Hypertension the major risk factor for many cardiovascular diseases is a result of multiple causes along with excessive generation of reactive oxygen species resulting in imbalance of redox status. Thioredoxin-1 (Trx-1) is a redox regulatory multifunctional protein with anti-inflammatory, anti-apoptotic and antioxidant effects. In the present study we investigated the therapeutic potential of Adeno-Trx-1 in spontaneously hypertensive rats (SHR). The rats were assigned to four different groups (n = 24) such as (1) normotensive Wistar Kyoto (WKY) (2) SHR (3) SHR +Adeno-Lac-Z (SHRLac-Z) and (4) SHR +Adeno-Trx-1 (SHRTrx-1). Echo-guided gene delivery to the anterior wall of left ventricle was performed using 1x109 pfu of adenovirus constructed with Trx-1 and Lac-Z. Two days after injection of adeno virus, the hearts were subjected to permanent left anterior descending coronary artery occlusion (MI). Left ventricular functions by Echocardiography were examined after 30 days of MI as the significant changes in left ventricle were observed after 4 weeks of MI. Decreased left ventricular inner diameter (7 vs 9 mm) and increased ejection fraction (52 vs 42 %), fractional shortening (28 vs 22 %) was observed in SHRTrx-1 compared to SHR. Infarct size, cardiomyocyte apoptosis and protein expression profiles (by Confocal and Western blot analysis) were observed at predetermined time points i.e after 24 and 48 hours of MI respectively. Decreased infarct size (52% vs 67%), cardiomyocyte apoptosis by TUNEL assay (161 vs 240) and increased expression of Trx-1 and HO-1 were observed in SHRTrx-1 compared to SHR. Confocal results were also confirmed by Western blot analysis. Results documented increased expression of Trx-1 (1.8 fold) and HO-1 (1.4 fold) in SHRTrx-1 as compared to SHR. In addition, we have also observed increased expression of anti-apoptotic protein Bcl-2 (1.7 fold) in SHRTrx-1 treated group compared SHR. Thus our results demonstrate for the first time that the cardioprotective effect of Adeno-Trx-1 therapy in SHR is Trx-1/HO-1/Bcl-2 mediated and may represent a novel mechanism for therapy against hypertension induced post infarction heart failure.

Hypercholesterolemia (HC) induced endothelial cell dysfunction and decreased endothelial nitric oxide formation results in impaired angiogenesis and subsequent cardiovascular disorders. Therapeutic angiogenesis is known to be a novel strategy for treatment of patients with ischemic heart disease. We have shown that secoisolariciresinol diglucoside (SDG) is angiogenic as well as cardioprotective against myocardial ischemia. In the present study, we examined the efficacy of SDG in a hypercholesterolemic myocardial infarction (MI) model. The rats were maintained on a normal and high cholesterol diet (2%) for 8 weeks followed by oral administration of SDG (20 mg/kg) for 2 weeks. The rats were divided into four groups ( n = 24 in each): Control (C); SDG control (SDG); HC; and HC + SDG (HSDG). Isolated hearts subjected to 30 min of global ischemia followed by 120 min of reperfusion were used to measure the cardiac functions, infarct size and to examine the protein expression profile. After treatment, MI was induced by ligating the left anterior descending artery. Echocardiographic parameters were examined 30 days after MI. Significant reduction in total cholesterol, LDL-cholesterol, triglycerides and an increase in HDL-cholesterol levels were observed in HSDG as compared to the HC. Decreased infarct size was observed in the HSDG group (43%) compared to the HC (54%). Increased phosphorylation of endothelial nitric oxide synthase (p-eNOS) (3.1-fold), vascular endothelial growth factor (1.9-fold) and heme oxygenase-1 (2.3-fold) was observed in the HSDG group as compared to the HC group. Significant improvement in left ventricular functions was also observed in the HSDG group as evidenced by increased ejection fraction (55% vs. 45%), fractional shortening (28% vs. 22%) and decreased left ventricular inner diameter in systole (8 vs. 6 mm) in HSDG compared to HC. Moreover, MI model has shown increased capillary density (2531 vs. 1901) and arteriolar density (2.6 vs. 1.8) in SDG-treated rats as compared to the HC. The increased capillary and arteriolar density along with increased left ventricular functions on SDG treatment might be due to increased HO-1, VEGF and p-eNOS expression. In conclusion, our study demonstrates for the first time that SDG treatment reduces ventricular remodeling by neovascularization of the infarcted HC myocardium.

Reactive oxygen species (ROS) generated during ischemia-reperfusion (I/R) enhance myocardial injury, but brief periods of myocardial ischemia followed by reperfusion [ischemic preconditioning (IP)] induce cardioprotection. Ischemia is reported to stimulate glucose uptake through the translocation of GLUT-4 from the intracellular vesicles to the sarcolemma. In the present study we demonstrated involvement of ROS in IP-mediated GLUT-4 translocation along with increased expression of caveolin (Cav)-3, phospho (p)-endothelial nitric oxide synthase (eNOS), p-Akt, and decreased expression of Cav-1. The rats were divided into the following groups: 1) control sham, 2) N-acetyl-l-cysteine (NAC, free radical scavenger) sham (NS), 3) I/R, 4) IP + I/R (IP), and 5) NAC + IP (IPN). IP was performed by four cycles of 4 min of ischemia and 4 min of reperfusion followed by 30 min of ischemia and 3, 24, 48 h of reperfusion, depending on the protocol. Increased mRNA expression of GLUT-4 and Cav-3 was observed after 3 h of reperfusion in the IP group compared with other groups. IP increased expression of GLUT-4, Cav-3, and p-AKT and p-eNOS compared with I/R. Coimmunoprecipitation demonstrated decreased association of Cav-1/eNOS in the IP group compared with the I/R group. Significant GLUT-4 and Cav-3 association was also observed in the IP group. This association was disrupted when NAC was used in conjunction with IP. It clearly documents a significant role of ROS signaling in Akt/eNOS/Cav-3-mediated GLUT-4 translocation and association in IP myocardium. In conclusion, we demonstrated a novel redox mechanism in IP-induced eNOS and GLUT-4 translocation and the role of caveolar paradox in making the heart euglycemic during the process of ischemia, leading to myocardial protection in a clinically relevant rat ischemic model.

Excessive oxidative stress has been implicated in the pathology and complications of diabetes, which leads to myocardial ischemia reperfusion injury. The present study was designed to examine whether resveratrol (trans-3,5,4'-trihydroxystilbene), a polyphenolic compound present in red wine has a direct cardioprotective effect on diabetic myocardium. Resveratrol (2.5 mg/kg body wt/day) and L-NAME (25 mg/kg body wt/day) were administered orally for 15 days to streptozotocin (65 mg/kg)-induced diabetic rats. Sprague Dawley rats were divided into 5 groups: (i) control, (ii) diabetic, (iii) diabetic+resveratrol, (iv) diabetic+resveratrol+L-NAME (nitric oxide synthase inhibitor), and (v) diabetic+L-NAME. In our present study resveratrol demonstrated significant reduction in glucose level in diabetic rats. After the treatment, the hearts were excised and subjected to 30 min of global ischemia followed by 2 h of reperfusion. Resveratrol-treated diabetic rats demonstrated significant reduction in glucose levels as compared to the nontreated diabetic animals, and improved left ventricular function throughout reperfusion compared to the diabetic or L-NAME-treated animals (dp/dt(max) 1457+/-51 vs 999+/-44 mm Hg/s at 120 min reperfusion). Cardioprotection from ischemic injury in resveratrol-treated diabetic rats showed decreased infarct size (42% vs 51%) and cardiomyocyte apoptosis (35% vs 40%) as compared with diabetic animals. Resveratrol produced significant induction of p-AKT, p-eNOS, Trx-1, HO-1, and VEGF in addition to increased activation of MnSOD activity in diabetic animals compared to nondiabetic animals. However treatment with L-NAME in resveratrol-treated and nontreated diabetic animals demonstrated significant downregulation of the above-noted protein expression profile and MnSOD activity. In the present study we found that the mechanism(s) responsible for the cardioprotective effect of resveratrol in the diabetic myocardium include upregulation of Trx-1, NO/HO-1, and VEGF in addition to increased MnSOD activity and reduced blood glucose level. Thus this study shows a novel mechanism of pharmacological preconditioning with resveratrol in the diabetic myocardium.

Background/Objective: The burden of coronary in-stent restenosis (ISR) remains a problem in spite of advances in technology and advent of drug-eluting stents (DES). The aim of this observational study is to evaluate the trends of ISR requiring target lesion revascularisation (TLR). Methods: All consecutive patients undergoing percutaneous coronary intervention (PCI) between January, 2007 and December, 2014 were included. The incidence of ISR and the use of DES were analysed. Results: Of the 3791 patients who underwent PCI during the study period, 132 patients (3.5%) underwent TLR for ISR. There were 101 males and 31 females with the mean age of 65.5 years. ISR requiring TLR was most commonly seen in patients with BMS (n=95). Of the 132 patients, the commonest clinical presentation was Acute Coronary Syndrome (51%) irrespective of the stent type. The use of DES was noted to increase over the 8-year period from 24.6% to 54.2%, inversely correlating with incidence of TLR. A slight increase in the incidence was seen after 2011 (1.95% to 2.65%) which may correspond to increasing number of complex cardiac interventions being routinely performed in this hospital including rotational atherectomy, PCI formulti-vessel disease and chronic total occlusions. Conclusions: Over the 8-year period, the incidence of ISR had dramatically decreased with the increasing use of DES consistent with its known clinical effects. The likely hypothesis for the recent increase in the incidence is increasingPCIs for complex coronary lesions as we enter into an era of complex interventional cardiology.

Background: Diabetic heart disease (DHD) is one of the major causes of mortality and morbidity in people with diabetes. DHD is characterised by the excessive loss of cardiovascular cells including cardiac stem cells. However, the exact mechanism leading to this loss remains unknown. Autophagy is a cellular degradation pathway that plays an important role in cellular homeostasis which becomes pathological when the balance is lost. Our recent studies conducted using mouse model of type-2 diabetes showed pathological autophagy in the diabetic heart. Current study aimed to understand if similar mechanism exists in the human diabetic heart. Methods: We collected right atrial appendage samples from 11 patients with type-2 diabetes (54-83 years of age), who underwent on-pump coronary artery bypass graft surgery at Dunedin Hospital. Samples from age-matched non-diabetic individuals served as the control. Total proteins were extracted and quantitative western blot analysis was carried out to study the expression pattern of the autophagy inducer beclin-1 and autophagy marker LC3-II proteins. Results: Clinical data showed no significant difference between diabetic and non-diabetic groups. However, quantitative western blot analysis of the right atrial appendage showed significant (p < 0.05, n = 11) increase in the autophagy markers, beclin-1 (1.26 0.6) and LC3-P (1.18 0.2) in the diabetic heart as compared to the non-diabetic heart. Conclusion: For the first time we demonstrate the existence of pathological autophagy in the human diabetic heart. These observations, therefore, invite a larger study to investigate the correlation between autophagy and functional alterations in the diabetic heart.

We reported a case of a 28-year-old Caucasian woman with hypereosinophilic syndrome (HES) associated with ulcerative colitis who presented on separate occasions with Loeffler's endocarditis. She was admitted in 2008 with fever, headache, confusion and visual loss. Diagnostic workup uncovered an eosinophilia of 3.1×10⁹/L and major ECG abnormalities. Subsequent echocardiography revealed left ventricular wall motion abnormalities with mural thrombus. MRI brain scan showed multiple white matter lesions consistent with acute infarcts. She recovered rapidly with corticosteroids and anticoagulation. Four years later she re-presented with headache, fatigue and an eosinophilia of 13.4×10⁹/L. This occurred 3 months after cessation of immunosuppression and within 12 months of total colectomy for fulminant ulcerative colitis. Echocardiography was suggestive of hypereosinophilic endomyocardial fibrosis with left ventricular thrombus. Anticoagulation and corticosteroids were resumed with good effect. This report highlights the findings, treatment and outcome of ulcerative colitis-associated HES manifesting as recurrent Loeffler's endocarditis.