Mitochondrial Dysregulation in the Pathogenesis of Diabetes: Potential for Mitochondrial Biogenesis-Mediated Interventions

Muscle mitochondrial metabolism is a tightly controlled process that involves the coordination of signaling pathways and factors from both the nuclear and mitochondrial genomes. Perhaps the most important pathway regulating metabolism in muscle is mitochondrial biogenesis. In response to physiological stimuli such as exercise, retrograde signaling pathways are activated that allow crosstalk between the nucleus and mitochondria, upregulating hundreds of genes and leading to higher mitochondrial content and increased oxidation of substrates. With type 2 diabetes, these processes can become dysregulated and the ability of the cell to respond to nutrient and energy fluctuations is diminished. This, coupled with reduced mitochondrial content and altered mitochondrial morphology, has been directly linked to the pathogenesis of this disease. In this paper, we will discuss our current understanding of mitochondrial dysregulation in skeletal muscle as it relates to type 2 diabetes, placing particular emphasis on the pathways of mitochondrial biogenesis and mitochondrial dynamics, and the therapeutic value of exercise and other interventions

Sternal reentry in a patient with previous deep sternal wound infection managed with horizontal titanium plate fixation

Redo open-heart surgery and sternal reentry in patients with previous deep sternal wound infection (DSWI) and absence of sternal integrity can be a delicate and morbid task due the lack of a dissection plane between the heart and the surrounding soft tissues. Delayed sternal reconstruction and osteosynthesis with horizontal titanium plating fixation (Synthes) following vacuum assisted therapy (KCI) has recently been proposed and adopted for the treatment of DSWI. We present such a case of a patient who was successfully reoperated for valve replacement three years after coronary artery bypass grafting complicated by DSWI and initially treated with titanium plate fixation

Impact of valve prosthesis-patient mismatch on short-term mortality after aortic valve replacement

Background— The prosthesis used for aortic valve replacement (AVR) can be too small in relation to body size, thus causing valve prosthesis-patient mismatch (PPM) and abnormally high transvalvular pressure gradients. This study examined if there is a relation between PPM and short-term mortality after operation. Methods and Results— The indexed valve effective orifice area (EOA) was estimated for each type and size of prosthesis being implanted in 1266 consecutive patients and used to define PPM as not clinically significant if 0.85 cm2/m2, as moderate if 0.65 cm2/m2 and 0.85 cm2/m2, and as severe if 0.65 cm2/m2; it was correlated with 30-day mortality and compared with other relevant variables. Moderate or severe PPM was present in 38% of patients. Thirty-day mortality was 4.6% (58/1266 patients) and the strongest independent predictors in multivariate analysis were left ventricular ejection fraction 40% (P 0.007), infectious endocarditis (P 0.002), emergent/salvage operation (P 0.002), cardiopulmonary bypass time 120 minutes (P 0.001), and PPM (P 0.003). Relative risk of mortality was increased 2.1-fold (95% confidence interval, 1.2 to 3.7) in patients with moderate PPM and 11.4-fold (4.4 to 29.5) in those with severe PPM. Moreover, risk of mortality for every category of PPM was higher in patients with a left ventricular ejection fraction 40% as compared with 40% (nonsignificant PPM, 2.7 versus 1.0; moderate PPM, 7.1 versus 1.8; severe PPM, 77.1 versus 11.3). Conclusion— PPM is a strong and independent predictor of short-term mortality among patients undergoing AVR, and its impact is related both to its degree of severity and the status of left ventricular function. In contrast to other risk factors, moderate-severe PPM can be largely avoided with the use of a prospective strategy at the time of operation

A single center experience with the freestyle bioprosthesis : midterm results at the Québec Heart Institute

Stentless bioprostheses show excellent early hemodynamic performance. However, longevity still remains unknown. This study reports midterm follow-up in 419 patients in which a Freestyle bioprosthesis (Medtronic Heart Valves, Minneapolis, MN) was inserted between January 1993 and January 2000 at the Quebec Heart Institute (Ste-Foy, Québec, Canada). Mean age at implantation was 68.0 +/- 8.2 years. Implantation was subcoronary in 81.9% of the patients, as a root replacement in 16.5%, and as a root inclusion in 1.7%. Mortality at 30 days was 6.2% for the whole cohort (2.8% for isolated subcoronary aortic valve replacement). Female gender, root implantation, valve sizes 19 to 21 mm, previous surgery, a history of stroke and diabetes were identified as predictors of 30-day mortality. Actuarial freedom from all death causes was 81.5% at 7 years; freedom from valve-related deaths 97.0%, and freedom from cardiac deaths 92.7%. Freedom from thromboembolic events was 86.1% at 7 years (55.1% of events were < 30 days). Freedom from endocarditis and hemorrhagic complications were respectively 98.5% and 95.6% at 7 years. Six patients required reoperations for valve explantation: 2 for endocarditis, 2 for structural dysfunction, and 2 for nonstructural dysfunction. Incidence of moderate or severe valve insufficiency at annual echocardiographic follow-up was: discharge: 0.6%; year 1: 0.7%; year 2: 1.3%; year 3: 3.3%; year 4: 3.7%; year 5: 2.6%; year 6: 0%. At 6 years after implantation, mean transvalvular gradient and effective valve orifice area were comparable to the year 1 values. This single center experience with the Medtronic Freestyle prosthesis shows preserved hemodynamic performance and low valve-related complications at midterm

Impact of aortic stenosis severity and its interaction with prosthesis-patient mismatch on operative mortality following aortic valve replacement.

The optimal timing of aortic valve replacement (AVR) in patients with severe aortic stenosis (AS) is a source of debate. Moreover, it has been shown previously that prosthesis-patient mismatch (PPM) is an independent predictor of operative mortality after AVR. The study aim was to assess the effect of the preoperative severity of AS and its interaction with PPM with respect to operative mortality after AVR

Sustained postoperative anaemia is associated with an impaired outcome after coronary artery bypass graft surgery:insights from the IMAGINE trial

Objective To investigate the association between sustained postoperative anaemia and outcome after coronary artery bypass graft (CABG) surgery. Design Retrospective analysis of the IMAGINE trial, which tested the effect of the ACE inhibitor quinapril on cardiovascular events after CABG. Setting Thoracic surgery clinic/outpatient department. Patients 2553 stable patients with left ventricular ejection fraction >40% 2-7 days after scheduled CABG. Interventions Randomisation to quinapril or placebo. Main outcome measures Cox regression analysis for the association between postoperative anaemia and cardiovascular events and the effect of quinapril on the incidence of anaemia. Results Postoperative anaemia was sustained for >50 days in 44% of patients. Sustained postoperative anaemia was associated with an increased incidence of cardiovascular events during the first 3 months (adjusted HR (adjHR) 1.77, 95% CI 1.10 to 2.85, p=0.012) and during the maximum follow-up of 43 months (adjHR 1.37, 95% CI 1.14 to 1.65, p=0.008). When haemoglobin (Hb) was considered as a continuous variable, every 1 mg/dl decrease in Hb was associated with a 13% increase in cardiovascular events (adjHR 0.87, 95% CI 0.81 to 0.95, p=0.003) and a 22% increase in all-cause mortality (adjHR 0.78, 95% CI 0.60 to 0.99, p=0.034). Quinapril was associated with a slower postoperative recovery of Hb levels and a higher incidence of cardiovascular events in patients with anaemia (adjHR 1.60, 95% CI 1.1 to 2.4, p=0.024). Conclusions Postoperative anaemia is common, frequently persists for months after CABG surgery and is associated with an impaired outcome. In patients with anaemia, ACE inhibitors slowed recovery from postoperative anaemia and increased the incidence of cardiovascular events after CABG

Impact of previous percutaneous transluminal coronary angioplasty and/or stenting revascularization on outcomes after surgical revascularization: insights from the imagine study

Aim To determine the impact of previous coronary artery revascularization by percutaneous transluminal coronary angioplasty and/or stenting (PCI) on outcome after subsequent coronary artery bypass grafting (CABG). Methods and results The ischaemia management with Accupril post-bypass Graft via Inhibition of the coNverting Enzyme (IMAGINE) trial, conducted between November 1999 and September 2004, tested whether early initiation of an angiotensin-converting enzyme inhibitor post-CABG, in stable patients with LVEF >= 40%, would reduce cardiovascular events. Of the 2489 patients included in the IMAGINE trial, undergoing their first operation, 430 had a history of PCI prior to surgery (PCI group), and 2059 were referred to surgery without previous PCI (non-PCI group). There was a significant increase in the primary IMAGINE endpoint in the PCI group, HR = 1.53 [1.17-1.98], P = 0.0016. Coronary revascularization, HR = 1.80 [1.13-2.87], P = 0.014, unstable angina requiring hospitalization, HR = 2.43 [1.52-3.89], P = 0.0002, were the two individual components that significantly increased in the PCI group, even when adjusted for baseline characteristics (age, sex, history of myocardial infarction or stroke, diabetes, treatment group, or off-pump surgery). Conclusion Patients with left ventricular ejection fraction >= 40% having a history of PCI prior to surgery had a worse outcome post-CABG than those with no prior PCI. Further studies are needed to investigate whether these results apply for drug eluting stents

Effects of angiotensin-converting enzyme inhibition in low-risk patients early after coronary artery bypass surgery

Background-Early after coronary artery bypass surgery (CABG), activation of numerous neurohumoral and endogenous vasodilator systems occurs that could be influenced favorably by angiotensin-converting enzyme inhibitors. Methods and Results-The Ischemia Management with Accupril post -bypass Graft via Inhibition of the coNverting Enzyme (IMAGINE) trial tested whether early initiation (= 40%. The trial was a double-blind, placebo-controlled study of 2553 patients randomly assigned to quinapril, target dose 40 mg/d, or placebo, who were followed up to a maximum of 43 months. The mean (SD) age was 61 (10) years. The incidence of the primary composite end point (cardiovascular death, resuscitated cardiac arrest, nonfatal myocardial infarction, coronary revascularization, unstable angina or heart failure requiring hospitalization, documented angina, and stroke) was 13.7% in the quinapril group and 12.2% in the placebo group (hazard ratio 1.15, 95% confidence interval 0.92 to 1.42, P = 0.212) over a median follow-up of 2.95 years. The incidence of the primary composite end point increased significantly in the first 3 months after CABG in the quinapril group (hazard ratio 1.52, 95% confidence interval 1.03 to 2.26, P = 0.0356). Adverse events also increased in the quinapril group, particularly during the first 3 months after CABG. Conclusions-In patients at low risk of cardiovascular events after CABG, routine early initiation of angiotensin-converting enzyme inhibitor therapy does not appear to improve clinical outcome up to 3 years after CABG; however, it increases the incidence of adverse events, particularly early after CABG. Thus, early after CABG, initiation of angiotensin-converting enzyme inhibitor therapy should be individualized and continually reassessed over time according to risk