Rawa Arif

Comparative investigation of the left ventricular pressure-volume relationship in rat models of type 1 and type 2 diabetes mellitus

Diabetes mellitus (DM) is associated with characteristic structural and functional changes of the myocardium, termed diabetic cardiomyopathy. As a distinct entity independent of coronary atherosclerosis, diabetic cardiomyopathy is an increasingly recognized cause of heart failure. A detailed understanding of diabetic cardiac dysfunction, using relevant animal models, is required for the effective prevention and treatment of cardiovascular complications in diabetic patients. We investigated and compared cardiac performance in rat models of type 1 DM (streptozotocin induced) and type 2 DM (Zucker diabetic fatty rats) using a pressure-volume (P-V) conductance catheter system. Left ventricular (LV) systolic and diastolic function was evaluated in vivo at different preloads, including the slope of the end-systolic P-V relation (ESPVR) and end-diastolic P-V relationship (EDPVR), preload recruitable stroke work (PRSW), maximal slope of the systolic pressure increment (dP/dt(max)), and its relation to end-diastolic volume (dP/dt(max)-EDV) as well as the time constant of LV relaxation and maximal slope of the diastolic pressure decrement. Type 1 DM was associated with decreased LV systolic pressure, dP/dt(max), slope of ESPVR and dP/dt(max)-EDV, PRSW, ejection fraction, and cardiac and stroke work indexes, indicating marked systolic dysfunction. In type 2 DM rats, systolic indexes were altered only to a lower extent and the increase of LV stiffness was more pronounced, as indicated by the higher slopes of EDPVR. Our data suggest that DM is characterized by decreased systolic performance and delayed relaxation (mainly in type 1 DM), accompanied by increased diastolic stiffness of the heart (more remarkably in type 2 DM). Based on the sophisticated method of P-V analysis, different characteristics of type 1 and type 2 diabetic cardiac dysfunction can be demonstrated.

Predictive Risk Factors for Patients With Cirrhosis Undergoing Heart Surgery

BACKGROUND Empiric experiences suggest higher mortality and complication risk for patients with cirrhosis of the liver after cardiac surgery. However, cirrhosis is not considered a risk factor in either the EuroSCORE or The Society of Thoracic Surgeons score. We report a large single-center experience of patients with cirrhosis undergoing cardiac surgery with extracorporeal circulation and aimed to evaluate the severity of cirrhosis as a predictor of outcome. METHODS During 2001 and 2011, we operated on 109 consecutive patients (average age, 64 years; 82 male) diagnosed for cirrhosis with cardiopulmonary bypass for different indications. Thirty-day mortality and long-term mortality were set as primary study end points. RESULTS Thirty-day mortality was 26%, and 5-year survival was 19%. Patients categorized as Child-Turcotte-Pugh (CHILD) C (n=6; 67% 30-day survival; 0% 5-year survival) and B (n=30; 60%; 5%) had worse 30-day and 5-year survival compared with patients categorized as CHILD A (n=73; 80%; 25%). For 30-day mortality, preoperative EuroSCORE (p=0.015), model for end-stage liver disease (MELD) score (p=0.006), albumin (p=0.023), total protein (p=0.01), and myocardial infarction (p=0.049) revealed significant differences between survivors and nonsurvivors. Multivariate logistic regression identified only MELD score (odds ratio [OR], 1.12; 95% confidence interval [CI], 1.03 to 1.23; p=0.011) and total protein (OR, 0.97; 95% CI, 0.95 to 1; p=0.049) were connected with increased 30-day mortality. Cox regression analysis revealed EuroSCORE (OR, 1.02; 95% CI, 1.01 to 1.03; p<0.0001) and MELD (OR, 1.06; 95% CI, 1.01 to 1.12; p=0.016) predicting the overall mortality. Receiver operating characteristic analysis indicated significant predictive power of MELD (p=0.001) and EuroSCORE (p=0.027) for 30-day mortality. CONCLUSIONS Patients with cirrhosis undergoing heart surgery with extracorporeal circulation have a poor prognosis. Several preoperative factors are related to outcome. EuroSCORE and MELD score may help to evaluate operation risk and indication.

The phosphodiesterase-5 inhibitor vardenafil improves cardiovascular dysfunction in experimental diabetes mellitus

Background and purpose:  Patients with diabetes mellitus exhibit generalized endothelial and cardiac dysfunction with decreased nitric oxide production. Elevated intracellular cyclic guanosine monophosphate (cGMP) levels contribute to an effective cardioprotection in different pathophysiological conditions. In this study, we investigated whether chronic treatment with the phosphodiesterase‐5 inhibitor vardenafil could improve diabetic cardiovascular dysfunction by up‐regulating the nitric oxide–cGMP pathway in the vessel wall and myocardium.

Treatment of ascending aortic aneurysms using different surgical techniques: a single-centre experience with 548 patients

OBJECTIVES The proper treatment of aneurysms of the ascending aorta is still under debate. Here, we describe the early and late outcomes after composite replacement (CR), supracommissural aortic replacement (SCR) and aortic valve-sparing (AVS) operations. METHODS Five hundred and fourty-eight patients were operated on for ascending aortic aneurysm from 1994 until 2011. Two hundred and ninety-eight (54%) patients had CR, 154 (28%) underwent SCR, 96 (18%) received AVS using Davids technique [83 (15%); after October 2006] and 13 (3%) using Yacoubs technique. The average size of the aneurysms was 5.8 ± 1.3 cm and differed between groups (P < 0.001). Patients in the SCR group were older (P < 0.001), and male gender was less frequent in the Yacoub group (P = 0.004). Marfans syndrome was present more often in the AVS group (P < 0.001). RESULTS Times for operation, extracorporeal circulation and aortic cross-clamping differed significantly (P < 0.001). In the SCR group, 40% of patients additionally underwent aortic valve replacement. Rethoracotomy for bleeding was required in 33 patients. Overall, 30-day mortality was 4.8% and did not differ between groups (SCR = 7.2%, CR = 4.8%, Davids technique = 0% and Yacoubs technique = 8.3%; P = 0.12). Six patients experienced cerebral accidents. The follow-up was complete for 93%, and mean follow-up time was 3.9 ± 3.9 (0-17.8) years. Kaplan-Meier analysis revealed a significantly reduced long-term survival for women (log-rank P = 0.0052). Reoperation on the aortic root was necessary in only 6 patients from the Yacoub and SCR groups. No aortic dissection occurred. By uni- or multivariate regression analysis, age and preoperative creatinine were risk factors for 30-day mortality, and age, gender, creatinine, New York Heart Association class and chronic obstructive pulmonary disease, for long-term survival. CONCLUSIONS All four applied techniques result in low mortality and low reoperation rate and prevent aortic dissection. The David procedure yields excellent mid-term results.

Poly(ADP-Ribose) Polymerase Inhibition Improves Endothelial Dysfunction Induced by Hypochlorite

Reactive oxygen species, such as myeloperoxidase-derived hypochlorite, induce oxidative stress and DNA injury. The subsequent activation of the DNA-damage–poly(ADP-ribose) polymerase (PARP) pathway has been implicated in the pathogenesis of various diseases, including ischemia-reperfusion injury, circulatory shock, diabetic complications, and atherosclerosis. We investigated the effect of PARP inhibition on the impaired endothelium-dependent vasorelaxation induced by hypochlorite. In organ bath experiments for isometric tension, we investigated the endothelium-dependent and endothelium-independent vasorelaxation of isolated rat aortic rings using cumulative concentrations of acetylcholine and sodium nitro-prusside. Endothelial dysfunction was induced by exposing rings to hypochlorite (100–400 μM). In the treatment group, rings were preincubated with the PARP inhibitor INO-1001. DNA strand breaks were assessed by the TUNEL method. Immunohistochemistry was performed for 4-hydroxynonenal (a marker of lipid peroxidation), nitrotyrosine (a marker of nitrosative stress), and poly(ADP-ribose) (an enzymatic product of PARP). Exposure to hypochlorite resulted in a dose-dependent impairment of endothelium-dependent vasorelaxation of aortic rings, which was significantly improved by PARP inhibition, whereas the endothelium-independent vasorelaxation remained unaffected. In the hypochlorite groups we found increased DNA breakage, lipidperoxidation, and enhanced nitrotyrosine formation. The hypochloride-induced activation of PARP was prevented by INO-1001. Our results demonstrate that PARP activation contributes to the pathogenesis of hypochlorite-induced endothelial dysfunction, which can be prevented by PARP inhibitors.

Dose-dependent effects of a selective phosphodiesterase-5-inhibitor on endothelial dysfunction induced by peroxynitrite in rat aorta

Reactive oxygen species, such as peroxynitrite, induce oxidative stress and DNA injury leading to endothelial dysfunction. It has been proposed, that elevated intracellular cyclic GMP (cGMP)-levels may contribute to an effective cytoprotection against nitro-oxidative stress. We investigated the dose-dependent effects of vardenafil, an inhibitor of phosphodiesterase-5, on endothelial dysfunction induced by peroxynitrite. In organ bath experiments, we investigated the endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside, SNP) vasorelaxation of isolated aortic rings of rats. Endothelial dysfunction was induced by peroxynitrite. In the treatment groups, rats received low doses (0.01-5 microg/kg) or high doses (5-300 microg/kg) of vardenafil. DNA strand breaks were assessed by the TUNEL method. Immunohistochemical analysis was performed for cGMP and nitrotyrosine. Exposure to peroxynitrite resulted in an impairment of endothelium-dependent vasorelaxation of aortic rings. Pre-treatment with lower doses of vardenafil led to an improvement of endothelial function as reflected by the higher maximal vasorelaxation (R(max)) to acetylcholine. Interestingly, at higher doses, R(max) to acetylcholine was attenuated leading to U-shaped dose-response curves. The endothelium-independent vasorelaxation to SNP under peroxynitrite stress showed a significant left-shift of the SNP concentration-response curves in the vardenafil groups without any alterations of the R(max). Vardenafil-pre-treatment significantly reduced DNA-breakage, reduced nitrosative stress, and increased cGMP score in the aortic wall. Our working hypothesis is that improvement of endothelial function could be mainly due to the cytoprotection of endothelium by vardenafil. This work supports the view that acute PDE5-inhibition might be advantageous in the treatment of endothelial dysfunction induced by disturbed NO-cGMP pathway due to nitro-oxidative stress.

Female Gender and Differences in Outcome after Isolated Coronary Artery Bypass Graft Surgery: Does Age Play a Role?

Introduction Female gender is a known risk factor for early and late mortality after coronary artery bypass graft surgery (CABG). Higher age of women at operation may influence outcome, since age per se is also an important risk factor. The purpose of our study was to analyze possible gender differences in outcome after isolated CABG in different age groups to delineate the impact of female gender and age. Methods All patients over 60 years of age undergoing isolated CABG at our department during 2001 and 2011 were included and categorized by age into sexagenarians (2266, 16.6% women), septuagenarians (2332, 25.4% women) and octogenarians (374, 32% women) and assessed by gender for 30-day and 180-day mortality. Results Thirty-day mortality was significantly higher in women only amongst septuagenarians (7.1 vs. 4.7%, p = 0.033). Same differences apply for 180-day mortality (12.3 vs. 8.2%, p = 0.033) and estimated one-year survival (81.6 ± 4.2 vs. 86.9 ± 2.2%, p = 0.001). Predictive factors for 30-day mortality of septuagenarian were logistic EuroSCORE (ES) (p = 0.003), perioperative myocardial infarction (MI) (p<0.001), pneumonia (p<0.001), abnormal LV-function (p<0.04) and use of LIMA graft (p<0.001), but not female gender. However, female gender was found to be an independent predictor for 180-day mortality (HR 1.632, p = 0.001) in addition to ES, use of LIMA graft, perioperative MI, pneumonia and abnormal LV function (HR 1.013, p = 0.004; HR 0.523, p<0.001; HR 2.710, p<0.001; HR 3.238, p<0.001; HR 2.013, p<0.001). Conclusion Women have a higher observed probability of early death after CABG in septuagenarians. However, female gender was not found to be an independent risk factor for 30-day, but for 180-day survival. Therefore, reduction of high impact risk factors such as perioperative MI and enhancement of LIMA use should be future goals. In view of our findings, decision for surgical revascularization should not be based on gender.

Vascular dysfunction induced by hypochlorite is improved by the selective phosphodiesterase-5-inhibitor vardenafil

Reactive oxygen species, such as hypochlorite induce oxidative stress, which impairs nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) signalling and leads to vascular dysfunction. It has been proposed, that elevated cGMP-levels may contribute to an effective cytoprotection against oxidative stress. We investigated the effects of vardenafil, a selective inhibitor of the cGMP-degrading phosphodiesterase-5 enzyme on vascular dysfunction induced by hypochlorite. In organ bath experiments for isometric tension, we investigated the endothelium-dependent and endothelium-independent vasorelaxation of isolated rat aortic rings using cumulative concentrations of acetylcholine and sodium nitroprusside (SNP). Vascular dysfunction was induced by exposing rings to hypochlorite (100-400 µM). In the treatment groups, rats were pretreated with vardenafil (30 and 300 µg/kg i.v.). Immunohistochemical analysis was performed for the oxidative stress markers nitrotyrosine, poly(ADP-ribose) and for apoptosis inducing factor (AIF). Exposure to hypochlorite resulted in a marked impairment of acetylcholine-induced endothelium-dependent vasorelaxation of aortic rings. Pretreatment with vardenafil led to improved endothelial function as reflected by the higher maximal vasorelaxation (Rmax) to acetylcholine. Regarding endothelium-independent vasorelaxation, hypochlorite exposure led to a left-shift of SNP concentration-response curves in the vardenafil groups without any alterations of the Rmax. In the hypochlorite groups immunohistochemical analysis showed enhanced poly(ADP-ribose)-formation and nuclear translocation of AIF, which were prevented by vardenafil-pretreatment. Our results support the view that cytoprotective effects of PDE-5-inhibitors on the endothelium may underlie the improved endothelial function, however, a slight sensitisation of vascular smooth muscle to NO was also confirmed. PDE-5-inhibition may represent a potential therapy approach for treating vascular dysfunction induced by oxidative stress.

Gender-specific differences in outcome of ascending aortic aneurysm surgery.

Objectives Gender specific differences receive increasing attention and are known to affect the outcome of cardiovascular diseases. We investigated possible risk-factors for gender-specific differences in ascending aortic aneurysm surgery. Methods 548 consecutive patients (male: n = 390, age: 58.3±14.4 years; female: n = 158, age: 65.3±12.9 years) with aneurysms of the ascending aorta eligible for cardiac surgery were retrospectively analyzed. Results Women were significantly older when operation was indicated (p<0.001) and presented with significantly more hypertension (p=0.04) and chronic obstructive pulmonary disease (COPD; p = 0.017), whereas men had significantly more previous cardiac operations (p = 0.016). Normalized aortic diameters (diameter / body surface area) were significantly larger in women (3.10±0.6 cm) vs. (2.75±0,5 cm, p≤0.001) in men, without differences in absolute values (5.74±1.04 cm vs. 5.86±1.34 cm). The aortic arch was significantly more involved in aneurysm formation in women (p = 0.04). Follow-up was available in 93% of the patients with a mean follow-up time of 3.9±3.9 (0-17.8) years. 30-day mortality was 3.5% in men (n=12) and 7.9% in women (n=11; p = 0.058). Univariate regression analysis shows gender specific risk factors for 30-day mortality in men to be age: p = 0.028; myocardial infarction: p = 0.0.24 and in women diameter of the ascending aorta: p=0.014; renal insufficiency: p=0.007. Long-term survival was significantly reduced in women (log-rank p = 0.0052). Conclusions The outcome after surgery for ascending aortic aneurysm is less favourable in women with significantly reduced long-term survival and a trend to increased 30-day mortality in this cohort. Larger normalized aortic diameters, higher incidence of involvement of the aortic arch and differences in comorbidities may contribute to gender differences. Women undergo surgery at higher age and more progressed state of aortic disease. Therefore, gender-specific guidelines for ascending replacement may be useful to improve outcome in women.

Long-term results after surgical treatment of postinfarction ventricular septal rupture

OBJECTIVES Postinfarction ventricular septal rupture is a serious complication associated with high hospital mortality rates. The present study aimed to identify predictors of early and late outcome in patients with postinfarction ventricular septal defect over a period of 30 years. METHODS We retrospectively analysed clinical and operative data, predictors of early mortality and long-term survival in a series of 52 consecutive patients (male, n = 26; mean age, 67 ± 10 years) with postinfarction ventricular septal rupture that was surgically repaired at our institution between September 1982 and December 2012. The overall logistic EuroSCORE was 41 ± 24% and the follow-up rate was 100%. RESULTS The 30-day mortality rate was 36% (n = 19), and these 19 survivors were followed up for a mean of 7.8 ± 7.7 (median, 6.0) years. The actuarial survival rates of these 19 patients at 1, 5 and 10 years were 91, 75 and 31%, respectively. Univariate predictors of 30-day mortality comprised renal insufficiency, shock at surgery, emergency surgery, logistic EuroSCORE, three-vessel disease, significant left circumflex coronary arterial stenosis, significant right coronary arterial stenosis, incomplete revascularization, surgical duration and cardiopulmonary bypass time and multivariate analysis selected only incomplete coronary revascularization as an independent risk factor of 30-day mortality. CONCLUSIONS Early mortality rates after surgical repair of postinfarction septal rupture remained poor in this series. Most patients who survived for <30 days had a preoperative shock status. Preoperative improvement in shock status and aggressive coronary revascularization are mandatory for patients with ventricular septal rupture.