A randomized trial comparing axillary versus innominate artery cannulation for aortic arch surgery.

BACKGROUND: Cerebral protection remains the cornerstone of successful aortic surgery; however, there is no consensus as to the optimal strategy. OBJECTIVE: To compare the safety and efficacy of innominate to axillary artery cannulation for delivering antegrade cerebral protection during proximal aortic arch surgery. METHODS: This randomized controlled trial (The Aortic Surgery Cerebral Protection Evaluation CardioLink-3 Trial, ClinicalTrials.gov Identifier: NCT02554032), conducted across 6 Canadian centers between January 2015 and June 2018, allocated 111 individuals to innominate or axillary artery cannulation. The primary safety outcome was neuroprotection per the appearance of new severe ischemic lesions on the postoperative diffusion-weighted-magnetic resonance imaging. The primary efficacy outcome was the difference in total operative time. Secondary outcomes included 30-day all-cause mortality and postoperative stroke. RESULTS: One hundred two individuals (mean age, 63 ± 11 years) were in the primary safety per-protocol analysis. Baseline characteristics between the groups were similar. New severe ischemic lesions occurred in 19 participants (38.8%) in the axillary versus 18 (34%) in the innominate group (P for noninferiority = .0009). Total operative times were comparable (median, 293 minutes; interquartile range, 222-411 minutes) for axillary versus (298 minutes; interquartile range, 231-368 minutes) for innominate (P for superiority = .47). Stroke/transient ischemic attack occurred in 4 (7.1%) participants in the axillary versus 2 (3.6%) in the innominate group (P = .43). Thirty-day mortality, seizures, delirium, and duration of mechanical ventilation were similar in both groups. CONCLUSIONS: diffusion-weighted magnetic resonance imaging assessments indicate that antegrade cerebral protection with innominate cannulation is safe and affords similar neuroprotection to axillary cannulation during aortic surgery, although the burden of new neurological lesions is high in both groups.

Impact of empagliflozin on right ventricular parameters and function among patients with type 2 diabetes.

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibition reduces cardiovascular events in type 2 diabetes (T2DM) and is associated with a reduction in left ventricular (LV) mass index. However, the impact on right ventricular (RV) remodeling is unknown. Accordingly, the objective of this study was to assess the impact of SGLT2 inhibition on RV parameters and function in T2DM and coronary artery disease (CAD). METHODS: In EMPA-HEART CardioLink-6, 97 patients with T2DM and CAD were randomly assigned to empagliflozin 10 mg (n = 49) once daily or placebo (n = 48). Cardiac magnetic resonance imaging was performed at baseline and after 6 months. RV mass index (RVMi), RV end-diastolic and end-systolic volume index (RVEDVi, RVESVi) and RV ejection fraction (RVEF) were assessed in blinded fashion. RESULTS: At baseline, mean RVMi (± SD) (11.8 ± 2.4 g/m2), RVEF (53.5 ± 4.8%), RVEDVi (64.3 ± 13.2 mL/m2) and RVESVi (29.9 ± 6.9 mL/m2) were within normal limits and were similar between the empagliflozin and placebo groups. Over 6 months, there were no significant differences in RVMi (- 0.11 g/m2, [95% CI - 0.81 to 0.60], p = 0.76), RVEF (0.54%, [95% CI - 1.4 to 2.4], p = 0.58), RVEDVi (- 1.2 mL/m2, [95% CI - 4.1 to 1.7], p = 0.41) and RVESVi (- 0.81 mL/m2, [95% CI - 2.5 to 0.90], p = 0.35) in the empaglifozin group as compared with the placebo group. In both groups, there was no significant correlation between RVMi and LVMi changes from baseline to 6 months. CONCLUSIONS: In this post-hoc analysis, SGLT2 inhibition with empagliflozin had no impact on RVMi and RV volumes in patients with T2DM and CAD. The potentially differential effect of empagliflozin on the LV and RV warrants further investigation. CLINICAL TRIAL REGISTRATION: URL:  https://www.clinicaltrials.gov/ct2/show/NCT02998970?cond=NCT02998970&draw=2&rank=1 . Unique identifier: NCT02998970.

Sodium-Glucose Cotransporter 2 Inhibitors, All-Cause Mortality, and Cardiovascular Outcomes in Adults with Type 2 Diabetes: A Bayesian Meta-Analysis and Meta-Regression.

Background This study aimed to assess the effectiveness of sodium-glucose cotransporter 2 inhibitors in reducing the incidence of mortality and cardiovascular outcomes in adults with type 2 diabetes. Methods and Results We conducted a Bayesian meta-analysis of randomized controlled trials comparing sodium-glucose cotransporter 2 inhibitors with placebo. We used meta-regression to examine the association between treatment effects and control group event rates as measures of cardiovascular baseline risk. Fifty-three randomized controlled trials were included in our synthesis. Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause mortality (empagliflozin: rate ratio [RR], 0.79; 95% credibility interval [CrI], 0.63-0.97; canagliflozin: RR, 0.86; 95% CrI, 0.69-1.05; dapagliflozin: RR, 0.86; 95% CrI, 0.72-1.01) and cardiovascular mortality (empagliflozin: RR, 0.78; 95% CrI, 0.61-1.00; canagliflozin: RR, 0.83; 95% CrI, 0.63-1.05; dapagliflozin: RR, 0.88; 95% CrI, 0.71-1.08), with a 90.1% to 98.7% probability for the true RR to be <1.00 for both outcomes. There was little evidence for ertugliflozin and sotagliflozin versus placebo for reducing all-cause and cardiovascular mortality. There was no association between treatment effects for all-cause and cardiovascular mortality and the control group event rates. There was evidence for a reduction in the incidence of heart failure for empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin versus placebo (probability RR <1.00 of ≥99.3%) and weaker, albeit positive, evidence for acute myocardial infarction for the first 3 agents (probability RR <1.00 of 89.0%-95.2%). There was little evidence of any agent except canagliflozin for reducing the incidence of stroke. Conclusions Empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause and cardiovascular mortality versus placebo. Treatment effects of sodium-glucose cotransporter 2 inhibitors versus placebo do not vary by baseline risk.

Effect of Continuous Electrocardiogram Monitoring on Detection of Undiagnosed Atrial Fibrillation After Hospitalization for Cardiac Surgery: A Randomized Clinical Trial.

Importance: Postoperative atrial fibrillation (POAF) occurring after cardiac surgery is associated with adverse outcomes. Whether POAF persists beyond discharge is not well defined. Objective: To determine whether continuous cardiac rhythm monitoring enhances detection of POAF among cardiac surgical patients during the first 30 days after hospital discharge compared with usual care. Design, Setting, and Participants: This study is an investigator-initiated, open-label, multicenter, randomized clinical trial conducted at 10 Canadian centers. Enrollment spanned from March 2017 to March 2020, with follow-up through September 11, 2020. As a result of the COVID-19 pandemic, enrollment stopped on July 17, 2020, at which point 85% of the proposed sample size was enrolled. Cardiac surgical patients with CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, prior stroke or transient ischemic attack, vascular disease, age 65-74 years, female sex) score greater than or equal to 4 or greater than or equal to 2 with risk factors for POAF, no history of preoperative AF, and POAF lasting less than 24 hours during hospitalization were enrolled. Interventions: The intervention group underwent continuous cardiac rhythm monitoring with wearable, patch-based monitors for 30 days after randomization. Monitoring was not mandated in the usual care group within 30 days after randomization. Main Outcomes and Measures: The primary outcome was cumulative AF and/or atrial flutter lasting 6 minutes or longer detected by continuous cardiac rhythm monitoring or by a 12-lead electrocardiogram within 30 days of randomization. Prespecified secondary outcomes included cumulative AF lasting 6 hours or longer and 24 hours or longer within 30 days of randomization, death, myocardial infarction, ischemic stroke, non-central nervous system thromboembolism, major bleeding, and oral anticoagulation prescription. Results: Of the 336 patients randomized (163 patients in the intervention group and 173 patients in the usual care group; mean [SD] age, 67.4 [8.1] years; 73 women [21.7%]; median [interquartile range] CHA2DS2-VASc score, 4.0 [3.0-4.0] points), 307 (91.4%) completed the trial. In the intent-to-treat analysis, the primary end point occurred in 32 patients (19.6%) in the intervention group vs 3 patients (1.7%) in the usual care group (absolute difference, 17.9%; 95% CI, 11.5%-24.3%; P < .001). AF lasting 6 hours or longer was detected in 14 patients (8.6%) in the intervention group vs 0 patients in the usual care group (absolute difference, 8.6%; 95% CI, 4.3%-12.9%; P < .001). Conclusions and Relevance: In post-cardiac surgical patients at high risk of stroke, no preoperative AF history, and AF lasting less than 24 hours during hospitalization, continuous monitoring revealed a significant increase in the rate of POAF after discharge that would otherwise not be detected by usual care. Studies are needed to examine whether these patients will benefit from oral anticoagulation therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT02793895.

The effects of saxagliptin on cardiac structure and function using cardiac MRI (SCARF).

PURPOSE: A recent large cardiovascular outcome trial in patients with type 2 diabetes (T2DM) demonstrated excess heart failure hospitalization with saxagliptin. We sought to evaluate the impact of saxagliptin on cardiac structure and function using cardiac magnetic resonance imaging (CMR) in patients with T2DM without pre-existing heart failure. METHODS: In this prospective study, patients with T2DM without heart failure were prescribed saxagliptin as part of routine guideline-directed management. Clinical assessment, CMR imaging and biomarkers were assessed in a blinded fashion and compared following 6 months of continued treatment. The primary outcome was the change in left ventricular (LV) ejection fraction (LVEF) after 6 months of therapy. Key secondary outcomes included changes in LV and right ventricular (RV) end-diastolic volume, ventricular mass, LV global strain and cardiac biomarkers [N terminal pro B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP)] over 6 months. RESULTS: The cohort (n = 16) had a mean age of 59.9 years with 69% being male. The mean hemoglobin A1c (HbA1c) was 8.3%. Mean baseline LVEF was 57% ± 3.4, with no significant change over 6 months (- 0.2%, 95% CI - 2.5, 2.1, p = 0.86). Detailed CMR analyses that included LV/RV volumes, LV mass, and feature tracking-derived strain showed no significant change (all p > 0.50). NT-proBNP and hsCRP levels did not significantly change (p > 0.20). CONCLUSIONS: In this cohort of stable ambulatory patients with T2DM without heart failure, saxagliptin treatment was not associated with adverse ventricular remodeling over 6 months as assessed using CMR and biomarkers.

Does empagliflozin modulate the autonomic nervous system among individuals with type 2 diabetes and coronary artery disease? The EMPA-HEART CardioLink-6 Holter analysis.

CONTEXT: We examined if empagliflozin was associated with modulation of cardiac autonomic tone among subjects with type 2 diabetes and stable coronary artery disease (CAD) relative to placebo. METHODS: Using ambulatory 24-h Holter electrocardiographic data prospectively collected from a randomized trial, we compared changes in heart rate variability (HRV) parameters between empagliflozin- and placebo-assigned subjects over a follow-up period of 6 months. Measured HRV domains included: standard deviation (SD) of NN intervals (SDNN), SD of average NN intervals per 5-min (SDANN), root mean square of successive RR interval differences (RMSSD), % successive NN intervals differing >50 ms (ms) (pNN50), low frequency (LF), high frequency (HF) and the LF/HF ratio (LF:HF). Differences in HRV parameters between the 2 groups were compared with analysis of covariance (ANCOVA). Statistical measures of significance were reported as adjusted differences between the 2 groups and their corresponding 95% confidence intervals. RESULTS: Sixty-six subjects completed 24-h Holter monitoring at baseline and 6-months. Over 6 months, the change in HRV was similar between subjects treated with empagliflozin vs. placebo for the following parameters: RMSSD -1.2 ms (-6.0 to 3.6 ms); pNN50 0.5% (-2.6 to 3.6%); VLF -907.8 ms2 (-2388.8 to 573.1 ms2); LF -341 ms2 (-878.7 to 196.7 ms2); HF -33.8 ms2 (-111.1 to 43.5 ms2); LF:HF -0.1 (-0.4 to 0.2). Subjects who received placebo experienced an increase in SDNN 18.6 ms (2.8-34.3 ms) and SDANN 20.2 ms (3.2-37.3 ms) relative to those treated with empagliflozin. CONCLUSION: Compared to placebo, empagliflozin did not result in changes in autonomic tone among individuals with type 2 diabetes and stable coronary artery disease.

Dynamics of dengue outbreaks in gangetic West Bengal: A trend and time series analysis.

BACKGROUND AND AIMS: Dengue is a vector-borne viral disease which is one of the major causes of public health problem in India, and its control is often the major challenges of municipal bodies in the country, especially in West Bengal. The previous outbreaks of the disease can be used to forecast the future occurrence and burden, so that authorities may optimize the available resources in order to contain and minimize the impact. MATERIALS AND METHODS: Weekly disease outbreak data were extracted from Integrated Disease Surveillance Programme website and arranged as monthly data. Mann-Kendall test was used to determine the significance of the disease trends in various districts of Gangetic West Bengal. Time series analysis was done by using Seasonal ARIMA method to predict the number of Dengue outbreak cases for the year 2020. RESULTS: Murshidabad was the only district of Gangetic West Bengal that had a significant upward Dengue cases outbreak trend. Nadia had a downward trend but it was not statistically significant. Model SARIMA (1,0,0) (1,0,0) 12 was chosen to forecast the Dengue outbreak cases which showed that the cases might start from the month of June, peak in August and wane off in October 2020. However, this prediction was not significant. CONCLUSION: Gangetic West Bengal might experience similar dengue cases as the previous year, but their numbers would be low. Only the district of Murshidabad would have upward trend. Knowledge in advance about periods of disease occurrence may enable health authorities to initiate control measures during the start of the outbreak season.

Mechanistic insights regarding the role of SGLT2 inhibitors and GLP1 agonist drugs on cardiovascular disease in diabetes.

The treatment landscape for patients with established or at high risk for cardiovascular disease and type 2 diabetes mellitus has entirely changed over the past decade, with the introduction of several anti-hyperglycemic agents. Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are two anti-hyperglycemic classes which have been of special interest after multiple large cardiovascular disease (CVD) outcomes studies have demonstrated superiority of these agents compared to placebo for major adverse CVD events and in some cases, hospitalization for heart failure. Despite the dramatic results of these trials, only recently have we began to understand the mechanisms underlying these CVD benefits. Here we review the underlying mechanisms which have the greatest plausibility for both of these agents including the impact of ventricular loading conditions, direct effects on cardiac structure and function, myocardial energetics and sodium/hydrogen exchange for SGLT2 inhibitors, and the anti-atherosclerotic, anti-inflammatory, and modulation of endothelial function for GLP-1 agonists.

Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial.

BACKGROUND: SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease. METHODS: Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m2. The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide). RESULTS: Among the 97 participants (90 men [93%], mean [standard deviation] age 62.8 [9.0] years, type 2 diabetes mellitus duration 11.0 [8.2] years, estimated glomerular filtration rate 88.4 [16.9] mL/min/1.73m2, LV mass indexed to body surface area 60.7 [11.9] g/m2), 90 had evaluable imaging at follow-up. Mean LV mass indexed to body surface area regression over 6 months was 2.6 g/m2 and 0.01 g/m2 for those assigned empagliflozin and placebo, respectively (adjusted difference -3.35 g/m2; 95% CI, -5.9 to -0.81g/m2, P=0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference -6.8mmHg, 95% CI -11.2 to -2.3mmHg, P=0.003), diastolic blood pressure (adjusted difference -3.2mmHg; 95% CI, -5.8 to -0.6mmHg, P=0.02) and elevation of hematocrit (P=0.0003). CONCLUSIONS: Among people with type 2 diabetes mellitus and coronary artery disease, SGLT2 inhibition with empagliflozin was associated with significant reduction in LV mass indexed to body surface area after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02998970.

Practical definitions of severe versus familial hypercholesterolaemia and hypertriglyceridaemia for adult clinical practice.

Diagnostic scoring systems for familial hypercholesterolaemia and familial chylomicronaemia syndrome often cannot differentiate between adults who have extreme dyslipidaemia based on a simple monogenic cause versus people with a more complex cause involving polygenic factors and an environmental component. This more complex group of patients carries a substantial risk of atherosclerotic cardiovascular disease in the case of marked hypercholesterolaemia and pancreatitis in the case of marked hypertriglyceridaemia. Complications are mainly a function of the degree of disturbance in lipid metabolism resulting in elevated lipid levels, so the added value of knowing the precise genetic cause in clinical decision making is unclear and does not lead to clinically meaningful benefit. We propose that for severe elevations of plasma low density lipoprotein cholesterol or triglyceride, the primary factor driving intervention should be the biochemical perturbation rather than the clinical risk score. This underscores the importance of expanding the definition of severe dyslipidaemias and to not rely solely on clinical scoring systems to identify individuals who would benefit from appropriate treatment approaches. We advocate for the use of simple, practical, clinical, and largely biochemically based definitions for severe hypercholesterolaemia (eg, LDL cholesterol >5 mmol/L) and severe hypertriglyceridaemia (triglyceride >10 mmol/L), which complement current definitions of familial hypercholesterolaemia and familial chylomicronaemia syndrome. Irrespective of the precise genetic cause, individuals diagnosed with severe hypercholesterolaemia and severe hypertriglyceridaemia require intensive therapy, including special consideration for new effective but more expensive therapies.

Axillary versus innominate artery cannulation for antegrade cerebral perfusion in aortic surgery: design of the Aortic Surgery Cerebral Protection Evaluation (ACE) CardioLink-3 randomised trial.

INTRODUCTION: Neurological injury remains the major cause of morbidity and mortality following open aortic arch repair. Systemic hypothermia along with antegrade cerebral perfusion (ACP) is the accepted cerebral protection approach, with axillary artery cannulation being the most common technique used to establish ACP. More recently, innominate artery cannulation has been shown to be a safe and efficacious method for establishing ACP. Inasmuch as there is a lack of high-quality data comparing axillary and innominate artery ACP, we have designed a randomised, multi-centre clinical trial to compare both cerebral perfusion strategies with regards to brain morphological injury using diffusion-weighted MRI (DW-MRI). METHODS AND ANALYSIS: 110 patients undergoing elective aortic surgery with repair of the proximal arch requiring an open distal anastamosis will be randomised to either the innominate artery or the axillary artery cannulation strategy for establishing unilateral ACP during systemic circulatory arrest with moderate levels of hypothermia. The primary safety endpoint of this trial is the proportion of patients with new radiologically significant ischaemic lesions found on postoperative DW-MRI compared with preoperative DW-MRI. The primary efficacy endpoint of this trial is the difference in total operative time between the innominate artery and the axillary artery cannulation group. ETHICS AND DISSEMINATION: The study protocol and consent forms have been approved by the participating local research ethics boards. Publication of the study results is anticipated in 2018 or 2019. If this study shows that the innominate artery cannulation technique is non-inferior to the axillary artery cannulation technique with regards to brain morphological injury, it will establish the innominate artery cannulation technique as a safe and potentially more efficient method of antegrade cerebral perfusion in aortic surgery. TRIAL REGISTRATION NUMBER: NCT02554032.

The emerging role of proprotein convertase subtilisin/kexin type-9 inhibition in secondary prevention: from clinical trials to real-world experience.

PURPOSE OF REVIEW: The recent advent of a highly efficacious class of low-density lipoprotein cholesterol (LDL-C) lowering agents, the proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors, has transformed dyslipidaemia management in patients with cardiovascular disease as well as those with familial hypercholesterolemia. RECENT FINDINGS: Recent positive results of the landmark Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk cardiovascular outcome trial with evolocumab as an add-on to statin therapy demonstrate further reduction of cardiovascular events. Additional safety outcomes from this large randomized trial, as well as the EBBINGHAUS substudy, allay fears of neurocognitive disorder as an adverse effect of achieving very low LDL-C levels with these agents. SUMMARY AND IMPLICATIONS: Widespread clinical adoption of PCSK9 inhibitors will depend on the results from ongoing and planned cardiovascular efficacy and safety trials with PCSK9 inhibitors. In addition, understanding the practical challenges and barriers to usage of these injectable agents by high cardiovascular risk patients will also affect clinical adoption of this class of agents. Analysis of cost-benefit models, along with anticipated updates to practice guidelines for dyslipidaemia management are likely to strengthen the clinical utility of PCSK9 inhibitors. Importantly, the potency of this new class of agents provides a huge opportunity to extend further the 'lower LDL-C is better' hypothesis in an effort to reduce rates of cardiovascular morbidity and mortality on a population level.

Advances in aortic disease management: a year in review.

PURPOSE OF REVIEW: The medical and surgical management of aortic disease is continually changing in search for improved outcomes. Our objective is to highlight recent advances in a few select areas pertaining to aortic disease and aortic surgery: the genetics of aortopathy, medical therapy of aortic aneurysms, advances in cardiac imaging, and operative strategies for the aortic arch. RECENT FINDINGS: As our understanding of the genetic basis for aortopathy continues to improve, routine genetic testing may be of value in assessing patients with genetically triggered forms of aortic disease. With regard to medical advances, treating patients with Marfan syndrome with either losartan or atenolol at an earlier stage in their disease course improves outcomes. In addition, novel imaging indices such as wall shear stress and aortic stiffness assessed by MRI may become useful markers of aortopathy and warrant further study. With regard to the optimal technique for cerebral perfusion in aortic arch surgery, high-quality data are still lacking. Finally, in patients with complex, multilevel aortic disease, the frozen elephant trunk is a viable single-stage option compared with the conventional elephant trunk, although with an increased risk for spinal cord injury. SUMMARY: Based on recent advances, continued studies in genetics, cardiac imaging, and surgical trials will further elucidate the etiology of aortopathy and ultimately guide management, both medically and surgically.

Innominate and Axillary Cannulation in Aortic Arch Surgery Provide Similar Neuroprotection.

BACKGROUND: Contemporaneous trends in cerebral protection during aortic arch surgery include moderate hypothermia (22°C-28°C) and continuous antegrade cerebral perfusion (ACP). Innominate artery cannulation is a simplified, alternative route for ACP; however, clinical outcomes have yet to be evaluated against the gold standard of axillary cannulation. METHODS: Between 2008 and 2015, 140 consecutive patients underwent hemiarch reconstruction with moderate hypothermia and continuous ACP at 2 institutions. Axillary cannulation was used in 74 patients (31.1% female, 64.8 ± 12.7 years) and the remaining 66 patients (24.2% female, 60.8 ± 10.5 years) had direct cannulation of the innominate artery for delivery of ACP. RESULTS: Although there were no statistically significant differences in complications, neurological events were almost twice as frequent in innominate (19.7%) than in axillary (10.8%; P = 0.142) whereas prolonged mechanical ventilation was much more common with axillary (17.6%) vs innominate (7.6%; P = 0.078). There were no mortalities in the axillary group and 1 in the innominate group (0% vs 1.5%; P > 0.471) and no statistically significant differences in any other postoperative complications or hospital length of stay. There was a reduction in total operating room time in the innominate group (axillary 454 ± 115 minutes, innominate 318 ± 125 minutes; P < 0.001), and in the matched subgroup analysis of patients who underwent Bentall and hemiarch reconstruction (axillary 456 ± 109 minutes, innominate 370 ± 106 minutes; P = 0.003). CONCLUSIONS: Axillary and innominate artery cannulation for ACP during proximal aortic arch reconstructive surgery resulted in similarly excellent neurological outcomes. Innominate artery cannulation might reduce total surgical time. Possible clinically relevant differences in neurological and respiratory complications require assessment in randomized controlled trials.

Direct innominate artery cannulation for selective antegrade cerebral perfusion during deep hypothermic circulatory arrest in aortic surgery.

OBJECTIVE: To demonstrate a novel, reproducible, and effective method of direct innominate artery cannulation using a 14 F pediatric venous cannula to establish antegrade cerebral protection (ACP) in patients undergoing aortic surgery that requires an open distal anastomosis or hemiarch replacement. METHODS: We reviewed prospectively gathered data on all patients who had undergone replacement of the ascending aorta or hemiarch with an open distal anastomosis using deep hypothermic circulatory arrest and direct innominate artery cannulation with a 14 F pediatric venous cannula at our institution. After central cannulation and cooling to 25 °C to 28 °C, all patients had ACP initiated by way of a direct innominate cannula placed over a guidewire. RESULTS: Fifty patients underwent direct innominate artery cannulation with our technique from 2010 to 2012. The operative mortality was 2% (n = 1), and the rates of neurologic morbidity were acceptable and similar to those with other methods of ACP delivery: stroke (2%, n = 1), seizure (0%, n = 0), and delirium (18%, n = 9). The mean operative time was 31 ± 9, 19 ± 5, 100 ± 39, 141 ± 39, and 259 ± 63 minutes for cooling, circulatory arrest, crossclamp, cardiopulmonary bypass, and total operative time, respectively. No local or arterial complications were observed. CONCLUSIONS: Direct cannulation of the innominate artery using a 14 F pediatric venous cannula is a simple, reproducible, safe, and effective technique for establishing ACP in patients undergoing aortic surgery that requires an open distal anastomosis or hemiarch replacement. This technique avoids the additional time and potential local complications associated with other established methods for delivering ACP, such as axillary cannulation.

miRNA-141 is a novel regulator of BMP-2-mediated calcification in aortic stenosis.

OBJECTIVE: Bone morphogenetic protein-2 (BMP-2) is a major regulator of aortic valve calcification. MicroRNAs (miRNAs) are essential post-transcriptional modulators of gene expression and miRNA-141 is a known repressor of BMP-2-mediated osteogenesis. We hypothesized that miRNA-141 is a key regulator of aortic valve calcification. METHODS: Porcine valvular interstitial cells were isolated, transfected with miRNA-141 or control, and stimulated with transforming growth factor-ß. The BMP-2, extracellular signal-regulated kinase 1/2, and runt-related transcription factor 2 levels were determined by immunoblotting and reverse transcriptase polymerase chain reaction. To determine the role of miRNA-141 in bicuspid aortic valve disease, human bicuspid (n = 19) and tricuspid (n = 17) aortic valve leaflets obtained intraoperatively were submitted for GenoExplorer human microRNA array, immunoblotting, and histologic and immunohistochemical analyses. RESULTS: Stimulation of porcine aortic valvular interstitial cells with transforming growth factor-ß induced morphologic alterations consistent with myofibroblastic transformation, BMP-2 signaling, and calcification. Transfection with miRNA-141 restored transforming growth factor-ß-induced valvular interstitial cell activation, BMP-2 signaling, and alkaline phosphatase activity (3.55 ± 0.18 vs 4.01 ± 0.21, P < .05), suggesting upstream regulation by miRNA-141. miRNA microarray demonstrated differential expression of 35 of 1583 miRNA sequences in the bicuspid versus tricuspid aortic valve leaflets, with a 14.5-fold decrease in miRNA-141 in the bicuspid versus tricuspid leaflets (P < .05). This was associated with significantly increased BMP-2 protein expression in bicuspid aortic valve compared with the tricuspid aortic valve leaflets (P < .001). CONCLUSIONS: We report a completely novel role of miRNA-141 as a regulator of BMP-2-dependent aortic valvular calcification and demonstrate marked attenuation of miRNA-141 expression in patients with bicuspid aortic valve-associated aortic stenosis. Therapeutic targeting of miRNA-141 could serve as a novel strategy to limit progressive calcification in aortic stenosis.

BRCA2 protein deficiency exaggerates doxorubicin-induced cardiomyocyte apoptosis and cardiac failure.

The tumor suppressor breast cancer susceptibility gene 2 (BRCA2) plays an important role in the repair of DNA damage, and loss of BRCA2 predisposes carriers to breast and ovarian cancers. Doxorubicin (DOX) remains the cornerstone of chemotherapy in such individuals. However, it is often associated with cardiac failure, which once manifests carries a poor prognosis. Because BRCA2 regulates genome-wide stability and facilitates DNA damage repair, we hypothesized that loss of BRCA2 may increase susceptibility to DOX-induced cardiac failure. To this aim, we generated cardiomyocyte-specific BRCA2 knock-out (CM-BRCA2(-/-)) mice using the Cre-loxP technology and evaluated their basal and post-DOX treatment phenotypes. Although CM-BRCA2(-/-) mice exhibited no basal cardiac phenotype, DOX treatment resulted in markedly greater cardiac dysfunction and mortality in CM-BRCA2(-/-) mice compared with control mice. Apoptosis in left ventricular (LV) sections from CM-BRCA2(-/-) mice compared with that in corresponding sections from wild-type (WT) littermate controls was also significantly enhanced after DOX treatment. Microscopic examination of LV sections from DOX-treated CM-BRCA2(-/-) mice revealed a greater number of DNA double-stranded breaks and the absence of RAD51 focus formation, an essential marker of double-stranded break repair. The levels of p53 and the p53-related proapoptotic proteins p53-up-regulated modulator of apoptosis (PUMA) and Bax were significantly increased in samples from CM-BRCA2(-/-) mice. This corresponded with increased Bax to Bcl-2 ratios and elevated cytochrome c release in the LV sections of DOX-treated CM-BRCA2(-/-) mice. Taken together, these data suggest a critical and previously unrecognized role of BRCA2 as a gatekeeper of DOX-induced cardiomyocyte apoptosis and susceptibility to overt cardiac failure. Pharmacogenomic studies evaluating cardiac function in BRCA2 mutation carriers treated with doxorubicin are encouraged.