Jolanta Biernat

Diazoxide protects myocardial mitochondria, metabolism, and function during cardiac surgery: A double-blind randomized feasibility study of diazoxide-supplemented cardioplegia

OBJECTIVES The study was designed to assess whether diazoxide-mediated cardioprotection might be used in human subjects during cardiac surgery. METHODS Forty patients undergoing coronary artery bypass grafting were randomized to receive intermittent warm blood antegrade cardioplegia supplemented with either diazoxide (100 micromol/L) or placebo (n = 20 in each group). Mitochondria were assessed before and after ischemia and reperfusion in myocardial biopsy specimens. Myocardial oxygen and glucose and lactic acid extraction ratios were measured before ischemia and in the first 20 minutes of reperfusion. Hemodynamic data were collected, and troponin I, creatine kinase-MB, and N-terminal prohormone brain natriuretic peptide levels were measured. All outcomes were analyzed by using mixed-effects modeling for repeated measures. RESULTS No deaths, strokes, or infarcts were observed. Patients received, on average, 36.2 +/- 1.2 mg of diazoxide and 37.3 +/- 1.9 mg of placebo (P = .6). Diazoxide added to cardioplegia prevented mitochondrial swelling (8899 +/- 474 vs 9273 +/- 688 pixels before and after the procedure, respectively; P = .6) compared with that seen in the placebo group (8474 +/- 163 vs 11,357 +/- 759 pixels, P = .004). No oxygen debt was observed in the diazoxide group. Glucose consumption and lactic acid production returned to preischemic values faster in the diazoxide group. The following hemodynamic parameters differed between the diazoxide and placebo groups, respectively, in the postoperative period: cardiac index, 3.0 +/- 0.09 versus 2.6 +/- 0.09 L . min(-1) . m(-2) (P = .002); left cardiac work index, 2.81 +/- 0.07 versus 2.31 +/- 0.07 kg/m(2) (P < .001); oxygen delivery index, 420 +/- 14 versus 377 +/- 13 mL . min(-1) . m(-2) (P = .03); and oxygen extraction ratio, 29.3% +/- 1.1% versus 32.6% +/- 1.1% (P = .02). Postoperative myocardial enzyme levels did not differ, but N-terminal prohormone brain natriuretic peptide levels were lower in the diazoxide group (120 +/- 27 vs 192 +/- 29 pg/mL, P = .04). CONCLUSIONS Supplementing blood cardioplegia with diazoxide is safe and improves myocardial protection during cardiac surgery, possibly through its influence on the mitochondria.

Implication of Right Ventricular Dysfunction on Long-term Outcome in Patients with Ischemic Cardiomyopathy Undergoing Coronary Artery Bypass Grafting with or without Surgical Ventricular Reconstruction

OBJECTIVE Whether right ventricular dysfunction affects clinical outcome after coronary artery bypass grafting with or without surgical ventricular reconstruction is still unknown. The aim of the study was to assess the impact of right ventricular dysfunction on clinical outcome in patients with ischemic cardiomyopathy undergoing coronary artery bypass grafting with or without surgical ventricular reconstruction. METHODS Of 1000 patients in the Surgical Treatment for Ischemic Heart Failure with coronary artery disease, left ventricular ejection fraction 35% or less, and anterior dysfunction, who were randomized to undergo coronary artery bypass grafting or coronary artery bypass grafting + surgical ventricular reconstruction, baseline right ventricular function could be assessed by echocardiography in 866 patients. Patients were followed for a median of 48 months. All-cause mortality or cardiovascular hospitalization was the primary end point, and all-cause mortality alone was a secondary end point. RESULTS Right ventricular dysfunction was mild in 102 patients (12%) and moderate or severe in 78 patients (9%). Moderate to severe right ventricular dysfunction was associated with a larger left ventricle, lower ejection fraction, more severe mitral regurgitation, higher filling pressure, and higher pulmonary artery systolic pressure (all P < .0001) compared with normal or mildly reduced right ventricular function. A significant interaction between right ventricular dysfunction and treatment allocation was observed. Patients with moderate or severe right ventricular dysfunction who received coronary artery bypass grafting + surgical ventricular reconstruction had significantly worse outcomes compared with patients who received coronary artery bypass grafting alone on both the primary (hazard ratio, 1.86; confidence interval, 1.06-3.26; P = .028) and the secondary (hazard ratio, 3.37; confidence interval, 1.36-8.37; P = .005) end points. After adjusting for all other prognostic clinical factors, the interaction remained significant with respect to all-cause mortality (P = .022). CONCLUSIONS Adding surgical ventricular reconstruction to coronary artery bypass grafting may worsen long-term survival in patients with ischemic cardiomyopathy with moderate to severe right ventricular dysfunction, which reflects advanced left ventricular remodeling.

Diazoxide provides protection to human myocardium in vitro that is concentration dependent

BACKGROUND Diazoxide has been shown to confer significant myocardial protection in many experiments. This study was designed to assess its influence on the structural injury and functional recovery of human myocardium subjected to hypoxia/reoxygenation in vitro. METHODS The isolated electrically driven human right atrial trabeculae, obtained during cardiac surgery, were studied. The tissue bath was oxygenated with 95% oxygen and 5% carbon dioxide, hypoxia being obtained by replacing oxygen with argon. The influence of diazoxide on atrial contractility was studied first. Next, the two trabeculae from one atrial appendage were studied simultaneously, adding diazoxide to the tissue bath 10 minutes before hypoxia in one, with another serving as a control. We tested 10(-4.5) mol/L and 10(-4) mol/L diazoxide in three sets of experiments testing 30, 60, and 90 minutes of hypoxia. We continued reoxygenation for 120 minutes (in 60-minute and 90-minute hypoxia experiments) and subsequently tested reaction to 10(-4) mol/L norepinephrine. Apart from continuous recording of the contraction force, we measured the troponin I release into the tissue bath after ischemia and reoxygenation. RESULTS Diazoxide exerted a negative inotropic effect in human atrial muscle (pD(2)=3.96 +/- 0.18). Both concentrations of diazoxide studied resulted in better functional recovery of atrial trabeculae subjected to 30 minutes of hypoxia. With longer hypoxia, only the higher diazoxide concentration provided significant protection as assessed by contractility. After 120 minutes of reoxygenation, only diazoxide-treated muscle was viable enough to respond to norepinephrine. Only 10(-4) mol/L diazoxide resulted in lower troponin I release during hypoxia and reoxygenation. CONCLUSIONS This study shows that diazoxide provides significant concentration-dependent protection against hypoxia/reoxygenation injury to human myocardium in vitro.

Statistical agreement of left ventricle measurements using cardiac magnetic resonance and 2D echocardiography in ischemic heart failure

Summary Background The aim of this study was to compare cardiac magnetic resonance imaging (CMR) with 2-dimensional echocardiography (2D echo) in the assessment of left ventricle (LV) function parameters and mass in patients with ischemic heart disease and severely depressed LV function. Although 2D echo is commonly used to assess LV indices, CMR is the state-of-the-art technique. Agreement between these 2 methods in these patients has not been well established. Material/Methods LV indexed end systolic and diastolic volumes (EDVi and ESVi), indexed mass (LVMi) and ejection fraction (EF) were assessed in 67 patients (12 women), using 2D echo and CMR. Results According to statistical analysis (Bland-Altman), 2D echo underestimated LV EDV and ESV and overestimated EF and LVMi compared to CMR. The highest correlation between 2D echo and CMR was found for EDVi (R2=0.73, p<0.0001) and ESVi (R2=0.69, p<0.0001) and the lowest for EF (R2=0.21, p=0.001) and LVMi (R2=0.20, p=0.002). The maximal differences between 2D echo and CMR were found for highest mesurements of LV volumes and mass, and for lowest EF values. Conclusions There is moderate to strong correlation between CMR and 2D echo in the assessment of LV function parameters and mass in patients with ischemic heart failure. Between-method agreement depends on the degree of LV dysfunction. The results of assessment of the severely damaged LV obtained by the use of 2D echo should be interpreted with caution.

Frailty Syndrome in Heart Failure Patients who are Receiving Cardiac Resynchronization.

We hypothesized that patients with de novo cardiac resynchronization therapy (CRT) implantation had a more intense frailty syndrome when compared to the patients who qualified for a system upgrade.

Left internal mammary artery improves 5-year survival in patients under 40 subjected to surgical revascularization.

BACKGROUND The population of young patients under 40 requiring coronary bypass surgery is characterized by an extremely and unusually rapid progression of coronary heart disease. The aim of the present study was to assess the clinical status and quality of life in these patients after surgery in relation to the type of conduit used to revascularize the left anterior descending artery (LAD). METHODS One hundred seventeen patients under 40 (range, 30-40 years) underwent coronary artery bypass grafting (CABG) at our institution between 1991 and 1999. Ninety-one patients received LIMA to LAD graft (group A), and in 26 patients the saphenous vein was used to graft this vessel (group B). Seventy-eight patients (63 in group A and 15 in group B) were assessed after a mean time of 71 +/- 26 months. They were asked to fill out a questionnaire aimed at their subjective assessment of their quality of life as compared with their preoperative status. RESULTS Five-year actuarial survival was higher in patients with LIMA to LAD graft (log rank test: P < .004). The functional status of patients in group B was significantly worse in comparison to group A: respectively, CCS 2.2 +/- 1.1 versus 1.5 +/- 0.7; (P = .02), NYHA 2.2 +/- 1.1 versus 1.3 +/- 0.5; (P = .002). Patients in group B more frequently required reinstitution of nitroglycerine treatment (93% versus 56%; P = .025). We failed to show differences between the 2 groups as far as subjective quality of life is concerned. In summary, 63% of patients perceived it to be worse, 29% to be better, and 8% felt it had not changed. CONCLUSION The use of LIMA is crucial in patients undergoing CABG under the age of 40 in order to achieve the best possible surgical results. Quicker recurrence of coronary disease symptoms is observed when a vein is used to graft the LAD. It may reflect an earlier progress of atherosclerosis in venous grafts.

Sex difference in patients with ischemic heart failure undergoing surgical revascularization results from the STICH trial (surgical treatment for ischemic heart failure)

Background: Female sex is conventionally considered a risk factor for coronary artery bypass grafting (CABG) and has been included as a poor prognostic factor in multiple cardiac operative risk evaluation scores. We aimed to investigate the association of sex and the long-term benefit of CABG in patients with ischemic left ventricular dysfunction enrolled in the prospective STICH trial (Surgical Treatment for Ischemic Heart Failure Study). Methods: The STICH trial randomized 1212 patients (148 [12%] women and 1064 [88%] men) with coronary artery disease and left ventricular ejection fraction ⩽35% to CABG+medical therapy (MED) versus MED alone. Long-term (10-year) outcomes with each treatment were compared according to sex. Results: At baseline, women were older (63.4 versus 59.3 years; P=0.016) with higher body mass index (27.9 versus 26.7 kg/m2; P=0.001). Women had more coronary artery disease risk factors (diabetes mellitus, 55.4% versus 37.2%; hypertension, 70.9% versus 58.6%; hyperlipidemia, 70.3% versus 58.9%) except for smoking (13.5% versus 21.8%) and had lower rates of prior CABG (0% versus 3.4%; all P<0.05) than men. Moreover, women had higher New York Heart Association class (class III/IV, 66.2% versus 57.0%), lower 6-minute walk capacity (300 versus 350 m), and lower Kansas City Cardiomyopathy Questionnaire overall summary scores (51 versus 63; all P<0.05). Over 10 years of follow-up, all-cause mortality (49.0% versus 65.8%; adjusted hazard ratio, 0.67; 95% confidence interval, 0.52–0.86; P=0.002) and cardiovascular mortality (34.3% versus 52.3%; adjusted hazard ratio, 0.65; 95% confidence interval, 0.48–0.89; P=0.006) were significantly lower in women compared with men. With randomization to CABG+MED versus MED treatment, there was no significant interaction between sex and treatment group in all-cause mortality, cardiovascular mortality, or the composite of all-cause mortality or cardiovascular hospitalization (all P>0.05). In addition, surgical deaths were not statistically different (1.5% versus 5.1%; P=0.187) between sexes among patients randomized to CABG per protocol as initial treatment. Conclusions: Sex is not associated with the effect of CABG+MED versus MED on all-cause mortality, cardiovascular mortality, the composite of death or cardiovascular hospitalization, or surgical deaths in patients with ischemic left ventricular dysfunction. Thus, sex should not influence treatment decisions about CABG in these patients. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00023595.

‘Opioidergic postconditioning’ of heart muscle during ischemia/reperfusion injury

BACKGROUND Ischemic preconditioning and postconditioning are the novel strategies of attaining cardioprotection against ischemia/reperfusion (I/R) injury. Previous studies suggested the role of opioid pathway, however the class of opioid receptors responsible for this effect in humans remains unknown. The aim of the study was to assess the influence of opioids on simulated I/R injury outcomes in the hu-man myocardium. METHODS Trabeculae of the human right atrium were electrically driven in organ bath and subjected to simulated I/R injury. Morphine (10-4M, 10-5M, 10-6M) or d-opioid receptor agonist DADLE (10-8M, 10-7M, 10-6M) was used at the time of re-oxygenation. Additional trabecula was subjected to hypoxia protocol only (Control). Contractive force of the myocardium was assessed as the maximal force of a contraction (Amax), the rate of rise of the force of a contraction (Slope L) and relaxation as the rate of decay of the force of a contraction (Slope T). RESULTS Application of morphine 10-4M resulted in increase of Amax, Slope L and Slope T during re-oxygenation period as compared to Control (77.99 ± 1.5% vs. 68.8 ± 2.2%, p < 0.05; 45.72 ± 2.9% vs. 34.12 ± 5.1%, p < 0.05; 40.95 ± 2.5% vs. 32.37 ± 4.3%, p < 0.05). Parameters were not significantly different in the lower morphine concentrations. Application of DADLE 10-6M resulted in decrease of Amax and Slope L as compared to Control (68.13 ± 5.5% vs. 76.62 ± 6.6%, p < 0.05; 28.29 ± 2.2 vs. 34.80 ± 3.9%, p < 0.05). CONCLUSIONS At re-oxygenation, morphine improves systolic and diastolic function of the human myo-cardium in the dose-dependent manner. Delta-opioid receptor stimulation attenuates systolic function of human heart muscle which remains in contrast to previous reports with animal models of I/R injury. (Cardiol J 2017; 24, 4: 419-425).

The co-application of hypoxic preconditioning and postconditioning abolishes their own protective effect on systolic function in human myocardium.

BACKGROUND Ischemic preconditioning (IPC) and postconditioning (POC) are well documented to trigger cardioprotection against ischemia/reperfusion (I/R) injury, but the effect oftheir both co-application remains unclear in human heart. The present study sought to assessthe co-application of IPC and POC on fragments of human myocardium in vitro. METHODS Muscular trabeculae of the human right atrial were electrically driven in the organbath and subjected to simulated I/R injury - hypoxia/re-oxygenation injury in vitro. To achieveIPC of trabeculae the single brief hypoxia period preceded the applied lethal hypoxia, and to achieve POC triple brief hypoxia periods followed the lethal hypoxia. Additional muscular trabeculae were exposed only to the hypoxic stimulation (Control) or were subjected to the non-hypoxic stimulation (Sham). 10 μM norepinephrine (NE) application ended every experiment to assess viability of trabeculae. The contraction force of the myocardium assessed as a maximal amplitude of systolic peak (%Amax) was obtained during the whole experiments period. RESULTS Co-application of IPC and POC resulted in decrease in %Amax during the re-oxygentaionperiod and after NE application, as compared to Control (30.35 ± 2.25 vs. 41.89 ± 2.25, 56.26 ± 7.73 vs. 65.98 ± 5.39, respectively). This was in contrary to the effects observed when IPC and POC were applied separately. CONCLUSIONS The co-application of IPC and POC abolishes the cardioprotection of either intervention alone against simulated I/R injury in fragments of the human right heart atria.

Total arterial revascularization for multiple vessel coronary artery disease: with or without cardiopulmonary bypass.

BACKGROUND To assess the usefulness of off-pump technique for more technically demanding coronary artery bypass procedures using exclusively arterial conduits. METHODS Analysis of perioperative data of 324 consecutive patients in whom total arterial revascularization for multiple- vessel coronary artery disease was performed--181 cases on-pump and 143 cases off-pump. RESULTS On average in the on-pump group 2.7 +/- 0.8 (range, 2-5) grafts per patient were constructed versus 2.4 +/- 0.7 (range, 2-4) grafts per patient in the off-pump group (P < .001). Of the total number of 490 anastomoses performed on-pump, 83 (17%) were side-to-side and of 349 anastomoses performed off-pump, 51(15%) were side-to-side, a nonsignificant difference (P = .4). The aorta was used as a site for proximal anastomosis of 1 or more arterial conduits in 105 patients (58%) who underwent on-pump surgery and in 57 patients (40%) who underwent off-pump surgery (P = .002). In the off-pump group, the right internal thoracic artery (RITA) was rarely (12%) routed through the transverse sinus to circumflex branches compared with the on-pump group (34%) (P = .017). RITA in off-pump patients was more often used to revascularize the anterior wall (47% versus 29%; P = .08). We observed no difference in mortality (1.7% versus 0%; P = .3), incidence of perioperative myocardial infarction (8.8% versus 7.7%; P = .8), stroke (1.7% versus 1.4%; P = .8), or atrial fibrillation (24% versus 19%; P = .3). We observed less inotropic support and less blood-product use in off-pump patients. CONCLUSION Total arterial revascularization for multiple-vessel coronary artery disease may be safely performed off-pump. We observed tendency to somewhat smoother postoperative course in the off-pump group.