Impact of lipid levels and high-intensity statins on vein graft patency after CABG: Midterm results of the ACTIVE trial.

BACKGROUND: High-dose atorvastatin did not improve 1-year vein graft patency in the recent Aggressive Cholesterol Therapy to Inhibit Vein Graft Events trial. However, it remains unknown whether high-intensity statins may impact graft disease in the years that follow. METHODS: In the trial, patients (N = 173) were randomized to receive atorvastatin 10 or 80 mg for 1 year after coronary bypass surgery (CABG). Beyond 1 year, the choice of statin was left to the patient's physician. In this study of participants who agreed to follow-up (N = 76), low-density lipoprotein (LDL) levels were measured and graft patency was assessed 3 years after surgery. RESULTS: The rate of vein graft disease 3 years after surgery was not significantly reduced with atorvastatin 80 mg during the first postoperative year or the use of open-label high-intensity statin thereafter (p = NS). However, a trend was observed between higher LDL levels during the first postoperative year and a greater incidence of vein graft disease at 3 years (p = .12). Among patients who had LDL levels more than 90 mg/dl in the first year after CABG, 38.5% had vein graft disease at 3 years, compared to 19.0% for those with LDL levels less than 90 mg/dl (p = .15). Higher mean LDL levels during the first postoperative year were associated with a higher rate of vein disease 3 years after surgery both at the graft level (p = .03) and at the patient level (p = .03) in multivariate analysis. CONCLUSIONS: Higher LDL levels during the first postoperative year were associated with significantly greater vein graft disease 3 years after CABG.

Can heat therapy help patients with heart failure?

To review and analyze the clinical outcomes of thermal therapy (≤1.4°C increase in core body temperature) in patients with heart failure (HF). A systematic review and meta-analysis regarding the effects of thermal therapy on HF was done by searching PubMed, Ovid Medline, Ovid Embase, Scopus, and internal databases up to date (2019). Improvement in the New York Heart Association (NYHA) class: Ten studies with 310 patients showed significant improvement in NYHA class. Only 7 among 40 patients remained in Class IV and 99 patients in Class III from 155 patients. Increased patients in lower classes indicate that more patients showed improvement. Sixteen studies on 506 patients showed an overall improvement of 4.4% of left ventricular ejection fraction (LVEF). Four studies reported improved endothelial dysfunction by 1.7% increase in flow-mediated dilation (FMD) on 130 patients. Reduction in blood pressure: Thermal therapy reduced both systolic blood pressure (SBP) and diastolic blood pressure by 3.1% and 5.31%, respectively, in 431 patients of 15 studies. Decrease in cardiothoracic ratio (CTR): Eight studies reported an average of 5.55% reduction of CTR in a total of 347 patients. Improvement in oxidative stress markers: Plasma brain natriuretic peptide (BNP) levels significantly decreased (mean difference of 14.8 pg/dL) in 303 patients of 9 studies. Improvement of quality of life: Among 65 patients, thermal therapy reduced cardiac death and rehospitalization by 31.3%. A slight increase in core body temperature is a promising, noninvasive, effective, and complementary therapy for patients with HF. Further clinical studies are recommended.

Intensive versus moderate statin therapy and early graft occlusion after coronary bypass surgery: The Aggressive Cholesterol Therapy to Inhibit Vein Graft Events randomized clinical trial.

OBJECTIVE: Statins prevent saphenous vein graft (SVG) disease and improve outcomes after coronary artery bypass graft surgery. However, the optimal postoperative statin dose remains unclear. The Aggressive Cholesterol Therapy to Inhibit Vein Graft Events trial was undertaken to evaluate whether early postoperative high-dose statin therapy reduces SVG occlusion compared with conventional moderate-dose therapy. METHODS: In this pilot, multicenter, double-blind randomized trial, 173 patients who had coronary artery bypass graft surgery with SVG were randomized to receive 10 mg or 80 mg atorvastatin daily for 1 year. The primary outcome was SVG occlusion at 1 year. Secondary outcomes were SVG stenosis and major adverse cardiovascular events. RESULTS: During trial enrollment, patients randomized to 80 mg atorvastatin achieved significantly lower low-density lipoprotein cholesterol levels (P < .00001). One-year graft assessment was performed in 145 patients (83.8%). The primary outcome, SVG occlusion at 1 year, did not significantly differ between the 2 groups (12.9% vs 11.4% for 10 mg atorvastatin vs 80 mg atorvastatin; P = .85). The incidence of vein graft stenosis also did not significantly differ between the groups (P = .54). However, there was a trend toward fewer patients developing vein graft disease (either occlusion or stenosis) in the 80 mg atorvastatin group (29.2% vs 19.2%, 10 mg atorvastatin vs 80 mg atorvastatin; P = .18). Freedom from major adverse cardiovascular events at 1 year was similar between the groups (P = .27). CONCLUSIONS: Compared with 10 mg atorvastatin, 80 mg atorvastatin did not significantly reduce vein graft occlusion 1 year after coronary artery bypass graft surgery in this pilot trial.

Nanoengineered Electroconductive Collagen-Based Cardiac Patch for Infarcted Myocardium Repair.

We have prepared and tested in vivo a novel nanoengineered hybrid electroconductive cardiac patch for treating the infarcted myocardium. Of the prepared and tested patches, only those containing spherical nanogold were able to increase connexin-43 expression in neonatal rat cardiomyocytes cultured under electrical stimulation. In vivo data indicated that only nano-gold-containing patches were able to recover cardiac function. Histological analysis also revealed that connexin-43 levels and blood vessel density were increased, while the scar size was reduced for animals that received the nanogold patch. Thus, our study indicates that the incorporation of electroconductive properties into a collagen-based cardiac patch can improve its therapeutic potential for treating myocardial infarction.

Intensive versus moderate atorvastatin therapy and one-year graft patency after CABG: Rationale and design of the ACTIVE (Aggressive Cholesterol Therapy to Inhibit Vein Graft Events) randomized controlled trial (NCT01528709).

RATIONALE: Saphenous vein graft disease remains a major limitation of coronary artery bypass graft surgery (CABG). Statin therapy inhibits the development of vein graft disease and improves outcomes after CABG. However, it is unclear whether treatment with high-dose statins will further slow the process of vein graft disease and improve graft patency, as compared to conventional moderate doses. Therefore, the goal of this study will be to evaluate the efficacy of high-dose statin therapy versus moderate-dose statin therapy for the prevention of saphenous vein graft occlusion following CABG. STUDY DESIGN: The Aggressive Cholesterol Therapy to Inhibit Vein Graft Events (ACTIVE) trial is a multi-center double-blind randomized controlled trial enrolling patients who have undergone multi-vessel CABG with at least one saphenous vein graft. Patients will be randomized to receive either atorvastatin 80mg daily or atorvastatin 10mg daily for one year starting within 5days after surgery. The target enrollment is 100 patients in each arm (200 patients total). Lipid levels will be assessed every 3months. After one year, patients will undergo computed tomography (CT) coronary angiography to assess the incidence of vein graft occlusion and stenosis. CONCLUSION: This trial is the first prospective study to evaluate the impact of early postoperative high-dose statin therapy on graft patency after CABG. Should high-dose statin therapy reduce the incidence of postoperative graft occlusion, the results will add to the growing evidence supporting the role of high-intensity statins for modern lipid management after coronary surgical revascularization (ClinicalTrials.govNCT01528709).

Minimally invasive coronary artery bypass grafting via a small thoracotomy versus off-pump: a case-matched study.

OBJECTIVE: The minimally invasive coronary artery bypass grafting (MICS CABG) operation performed via a small thoracotomy has not previously been examined in a direct comparison to sternotomy off-pump coronary artery bypass grafting (OPCAB). METHODS: We matched, according to age, gender, left ventricular function, and median number of distal anastomoses, 150 patients who underwent MICS CABG via small left thoracotomy, and 150 patients who received sternotomy OPCAB. All operations were performed by the same surgeon. RESULTS: There was no perioperative mortality (0/300). In the MICS CABG group, pump assistance was used in 28/150 (19%) patients, and conversion to sternotomy occurred in 10/150 (6.7%) patients. In the OPCAB group, conversion to on-pump occurred in 3/150 (2.0%) patients. There were four (2.7%) reoperations for bleeding and one (0.7%) for anastomotic revision in each group. The median hospital length of stay was 5 days for MICS CABG (average 5.4), and 6 days for OPCAB (average 7.2) (P=0.02). New-onset atrial fibrillation occurred in 35 (23%) MICS CABG patients and in 42 (28%) OPCAB patients (P=0.3). No wound infection occurred with MICS CABG versus six (4.0%) with OPCAB (P=0.03). A self-limiting left pleural effusion developed in 22 (15%) MICS CABG patients and in six (4.0%) OPCAB patients (P=0.002). The median time to return to full physical activity was 12 days in MICS CABG patients versus >5 weeks in OPCAB patients (P<0.001). CONCLUSIONS: MICS CABG is a valuable alternative for patients in need of multivessel CABG. The operation appears at least as safe as OPCAB, and associated with shorter hospital length of stay, less wound infections, and faster postoperative recovery than OPCAB.

Urgent replacement of a mechanical mitral prosthesis in an anticoagulated patient with Bombay red blood cell phenotype.

PURPOSE: Bombay red blood cell phenotype is an extremely rare blood type for which patients can receive only autologous or Bombay phenotype red blood cells. We report a case of urgent repeat sternotomy for replacement of a mechanical mitral prosthesis in a patient with Bombay phenotype anticoagulated with warfarin, to emphasize the transfusion challenges in such patients. CLINICAL FEATURES: A male of Indian descent presented to hospital with New York Heart Association IV symptoms. His medical history revealed previous mitral valve replacement with a mechanical prosthesis in 2005 and Bombay phenotype blood. Preoperative transthoracic echocardiography demonstrated thrombus obstruction of the mitral prosthesis despite anticoagulation with warfarin. Right ventricular systolic pressure was >100 mmHg with 3+ tricuspid regurgitation. The patient's condition was temporized with diuretics, bronchodilators, and bi-level positive airway pressure ventilation while transfusion medicine and cardiac surgery were consulted for urgent surgery. The patient received vitamin K and prothrombin complex concentrate prior to repeat sternotomy and successful mitral prosthesis replacement. After cardiopulmonary bypass, heparinization was corrected with protamine and followed by a second dose of prothrombin complex concentrate and recombinant activated factor VIIa. Postoperatively, the patient received four units of packed red blood cells, two autologous units and two units of Bombay specific red blood cells. Right ventricular pressures stabilized at 40 mmHg following surgery. The patient recovered following several days of inotropic support with milrinone, diuretics, and bronchodilators. CONCLUSION: Patients with Bombay phenotype red blood cells present as type O, but they are unable to receive red blood cells from any phenotype other than Bombay phenotype. They are able to receive all other blood products, including fresh frozen plasma, cryoprecipitate, platelets, prothrombin complex concentrate, and recombinant activated factor VIIa. Coordination between Canadian Blood Services, transfusion medicine, surgery, and anesthesia is important in managing these patients.

Impairment of human cell-based vasculogenesis in rats by hypercholesterolemia-induced endothelial dysfunction and rescue with L-arginine supplementation.

OBJECTIVE: Clinical efficacy of cardiac cell therapy may be compromised by its target population, patients with endothelial dysfunction. In vivo inhibition by endothelial dysfunction has been demonstrated for protein angiogenesis but remains unclear for cell therapy. We examined whether hypercholesterolemia inhibits vasculogenic effects of transplanted human circulating progenitor cells in ischemic tissue and whether L-arginine, a nitric oxide donor, might prevent impairment. METHODS: Athymic rats were fed either normal (group A) or high-cholesterol diets, the latter without (group B) or with (group C) oral L-arginine supplementation. Two weeks later, these rats underwent left femoral artery ligation followed by injection of 2 x 10(6) human circulating progenitor cells into left hind-limb muscle. A fourth group (group D) received supplemented high-cholesterol diets but no cells. RESULTS: Group B had biochemical evidence of endothelial dysfunction and reduced tissue endothelial nitric oxide synthase expression, whereas group A levels were the same as in group C. By 21 postoperative days, left hind-limb perfusion had recovered fully in groups A and C, partially in D, and not at all in B (38% lower than group A, P < or = .004). Lower arteriolar densities were found in groups and B and D than in groups A and C (P < or = .02). Engrafted human cell numbers were equivalent in all cell-transplanted groups after 3 weeks. CONCLUSIONS: Endothelial dysfunction inhibited effects of cell therapy, specifically vasculogenesis, suggesting a role for substrate modification to overcome this inhibition. Involved mechanisms appear related to use of cells but not engraftment and require further investigation.

Concomitant treatment with oral L-arginine improves the efficacy of surgical angiogenesis in patients with severe diffuse coronary artery disease: the Endothelial Modulation in Angiogenic Therapy randomized controlled trial.

OBJECTIVE: Endothelial dysfunction and decreased nitric oxide bioavailability may explain why therapeutic angiogenesis and cell therapy have mostly failed in humans. Building from previous large animal work, the Phase I Endothelial Modulation in Angiogenic Therapy trial tested the hypothesis that L-arginine, a nitric oxide donor, may be safe and effective in potentiating surgical angiogenesis in humans. METHODS: Patients with surgical triple-vessel coronary disease and a severely diffusely diseased left anterior descending artery were randomized in 2 x 2 factorial fashion to receive ten 200-microg injections of vascular endothelial growth factor-165 plasmid DNA or placebo in the anterior myocardium along the proximal and mid-left anterior descending arteries, plus oral L-arginine supplementation at a dose of 6 g per day or placebo for 3 months. The distal left anterior descending artery and other coronary arteries were grafted. End points included 3-month changes in myocardial perfusion and contractility of the anterior myocardium, using (13)N-ammonia positron emission tomography and echocardiography. Baseline scans were obtained 3 to 7 days postoperatively to delineate treatment effects from the effects of coronary artery bypass grafting. RESULTS: Patient (N = 19) characteristics were equivalent between groups. There was no perioperative or late mortality. Patients who received the combination of vascular endothelial growth factor and L-arginine had improved anterior wall perfusion on positron emission tomography (P = .02), a trend toward smaller perfusion defects (P = .10), and better anterior wall contractility (P = .02, Kruskal-Wallis) at 3 months versus baseline. This was corroborated by a trend toward better disease perception at 3 months versus baseline on the Seattle Angina Questionnaire (score improvement of 47 +/- 35, combination treatment group; P = .1, Kruskal-Wallis). CONCLUSION: To our knowledge, this is the first study to examine concomitant substrate modification in patients undergoing new biosurgical therapies by using vascular endothelial growth factor angiogenesis. The results suggest safety and efficacy. Concomitant endothelial modulation with L-arginine not only has the potential to make angiogenesis effective but also may have implications for cell therapy trials.

Surgery for chronic thromboembolic pulmonary hypertension--inclusive experience from a national referral center.

BACKGROUND: Chronic thromboembolic pulmonary hypertension represents a unique form of pulmonary hypertension amenable to curative intervention with a pulmonary thromboendarterectomy (PTE). Canada's first successful and sustainable program for PTE surgery was established at the University of Ottawa Heart Institute in 1995. Inclusive results from similarly sized programs are not readily available owing to selective reporting, therefore making it difficult to benchmark outcomes. The purpose of this report is to provide a review of the inclusive results from our moderately sized national program for all PTE, with a particular emphasize on the aspects of the learning curve in terms of patient management. METHODS: Since 1995, 180 patients have been referred for consideration of PTE, and 106 patients have undergone surgery with a perioperative 30-day mortality rate of 9.4%. RESULTS: There was a significant improvement in all hemodynamic parameters except right ventricular ejection fraction in nonsurvivors (mean pulmonary artery pressure pre 47 +/- 12 mm Hg versus post 28 +/- 9 mm Hg, p < 0.0001; pulmonary vascular resistance pre 814 +/- 429 dynes x sec(-1) x cm(-5), post 224 +/- 145 dynes x sec(-1) x cm(-5), p < 0.0001; cardiac index pre 2.0 +/- 0.7 L x min(-1) x m(-2), post 3.2 +/- 0.7 L x min(-1) x m(-2), p < 0.0001). A postoperative pulmonary vascular resistance of 500 dynes x sec(-1) x cm(-5) or more was associated with increased perioperative mortality (odds ratio, 12 +/- 8.7; p = 0.001). On average, these procedures were associated with significant resource use involving operating room time (610 +/- 243 minutes), intensive care unit and hospital days (11.2 +/- 13.7 and 19.5 +/- 15.6 days), and ventilation time (7.8 +/- 10.0 days). There was no significant change in hospital or intensive care unit length of stay, or the mortality rate during this first decade. CONCLUSIONS: PTE programs are resource-intensive surgical specialty services that demand excellence in cardiothoracic expertise. The initial decade reflected an expanding referral basis and likely parallel increases in patient complexity and expertise. The current results at a national referral center have emphasized the importance of centralization of resources to optimize patient outcome.

Effects of L-arginine on fibroblast growth factor 2-induced angiogenesis in a model of endothelial dysfunction.

BACKGROUND: Nitric oxide availability, which is decreased in advanced coronary artery disease associated with endothelial dysfunction, is an important mediator of fibroblast growth factor-2 (FGF-2)-induced angiogenesis. This could explain the disappointing results of FGF-2 therapy in clinical trials despite promising preclinical studies. We examined the influence of L-arginine supplementation to FGF-2 therapy on myocardial microvascular reactivity and perfusion in a porcine model of endothelial dysfunction. METHODS AND RESULTS: Eighteen pigs were fed either a normal (NORM, n=6) or high cholesterol diet, with (HICHOL-ARG, n=6) or without (HICHOL, n=6) L-arginine. All pigs underwent ameroid placement on the circumflex artery and 3 weeks later received surgical FGF-2 treatment. Four weeks after treatment, endothelial-dependent coronary microvascular responses and lateral myocardial perfusion were assessed. Endothelial cell density was determined by immunohistochemistry. FGF-2, fibroblast growth receptor-1, endothelial-derived nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), and syndecan-4 levels were determined by immunoblotting. Pigs from the HICHOL group showed endothelial dysfunction in the circumflex territory, which was normalized by L-arginine supplementation. FGF-2 treatment was ineffective in the HICHOL group (circumflex/left anterior descending blood flow ratios: 1.01 (rest) and 1.01 (pace), after and before treatment). Addition of L-arginine improved myocardial perfusion in response to FGF-2 at rest (ratio 1.13, P=0.02 versus HICHOL) but not during pacing (ratio 0.94, P=NS), and was associated with increased protein levels of iNOS and eNOS. CONCLUSIONS: L-arginine supplementation can partially restore the normal response to endothelium-dependent vasorelaxants and myocardial perfusion in response to FGF-2 treatment in a swine model of hypercholesterolemia-induced endothelial dysfunction. These findings suggest a role for L-arginine in combination with FGF-2 therapy for end-stage coronary artery disease.

Normalization of coronary microvascular reactivity and improvement in myocardial perfusion by surgical vascular endothelial growth factor therapy combined with oral supplementation of l-arginine in a porcine model of endothelial dysfunction.

OBJECTIVE: Vascular endothelial growth factor acts in part through nitric oxide release, the availability of which is decreased in endothelial dysfunction associated with advanced coronary artery disease. This could explain the relatively disappointing results of vascular endothelial growth factor therapy in clinical studies compared with animal studies. We examined the influence of L-arginine supplementation to vascular endothelial growth factor therapy on myocardial microvascular reactivity and perfusion in a porcine model of endothelial dysfunction. METHODS: Twenty-four pigs were fed either a normal (NORM, n = 8) or high-cholesterol diet with (CHOL-ARG, n = 8) or without (CHOL, n = 8) L-arginine. All pigs underwent ameroid placement on the circumflex artery and then 3 weeks later received surgical vascular endothelial growth factor treatment. Four weeks after treatment, endothelial-dependent coronary microvascular responses and lateral myocardial perfusion were assessed. Endothelial cell density was determined by means of immunohistochemistry. Vascular endothelial growth factor, endothelial nitric oxide synthase, and Akt levels were determined by means of immunoblotting. RESULTS: Pigs from the CHOL group showed endothelial dysfunction in the circumflex territory, which was normalized by L-arginine supplementation. Vascular endothelial growth factor treatment was ineffective in the CHOL group (circumflex/left anterior descending coronary artery blood flow ratios: 0.95 [rest] and 0.74 [pace] before-after treatment; P < .05 compared with the NORM group). Addition of L-arginine restored the angiogenic effect of vascular endothelial growth factor (ratios: 1.13 [rest] and 1.20 [pace]; P < .05) and was associated with increased endothelial cell density, as well as vascular endothelial growth factor, endothelial nitric oxide synthase, and Akt protein levels in the ischemic territory. CONCLUSIONS: L-Arginine supplementation can restore normal endothelium-dependent vasorelaxation and angiogenic response to vascular endothelial growth factor in a swine model of chronic myocardial ischemia with hypercholesterolemia-induced endothelial dysfunction. These findings suggest a putative role for L-arginine in combination with vascular endothelial growth factor therapy for end-stage coronary artery disease.