Jonathan D.W. Evans

Evidence, lack of evidence, controversy, and debate in the provision and performance of the surgery of acute type A aortic dissection

Acute type A aortic dissection is a lethal condition requiring emergency surgery. It has diverse presentations, and the diagnosis can be missed or delayed. Once diagnosed, decisions with regard to initial management, transfer, appropriateness of surgery, timing of operation, and intervention for malperfusion complications are necessary. The goals of surgery are to save life by prevention of pericardial tamponade or intra-pericardial aortic rupture, to resect the primary entry tear, to correct or prevent any malperfusion and aortic valve regurgitation, and if possible to prevent late dissection-related complications in the proximal and downstream aorta. No randomized trials of treatment or techniques have ever been performed, and novel therapies-particularly with regard to extent of surgery-are being devised and implemented, but their role needs to be defined. Overall, except in highly specialized centers, surgical outcomes might be static, and there is abundant room for improvement. By highlighting difficulties and controversies in diagnosis, patient selection, and surgical therapy, our over-arching goal should be to enfranchise more patients for treatment and improve surgical outcomes.

BMPR2 mutations and survival in pulmonary arterial hypertension: an individual participant data meta-analysis

Summary Background Mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) are the commonest genetic cause of pulmonary arterial hypertension (PAH). However, the effect of BMPR2 mutations on clinical phenotype and outcomes remains uncertain. Methods We analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation. All-cause mortality was the secondary outcome. Hazard ratios (HRs) for death or transplantation and all-cause mortality associated with the presence of BMPR2 mutation were calculated using Cox proportional hazards models stratified by cohort. Findings Overall, 448 (29%) of 1550 patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age 35·4 [SD 14·8] vs 42·0 [17·8] years), had a higher mean pulmonary artery pressure (60·5 [13·8] vs 56·4 [15·3] mm Hg) and pulmonary vascular resistance (16·6 [8·3] vs 12·9 [8·3] Wood units), and lower cardiac index (2·11 [0·69] vs 2·51 [0·92] L/min per m2; all p<0·0001). Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (3% [10 of 380] vs 16% [147 of 907]; p<0·0001). Among the 1164 individuals with available survival data, age-adjusted and sex-adjusted HRs comparing BMPR2 mutation carriers with non-carriers were 1·42 (95% CI 1·15–1·75; p=0·0011) for the composite of death or lung transplantation and 1·27 (1·00–1·60; p=0·046) for all-cause mortality. These HRs were attenuated after adjustment for potential mediators including pulmonary vascular resistance, cardiac index, and vasoreactivity. HRs for death or transplantation and all-cause mortality associated with BMPR2 mutation were similar in men and women, but higher in patients with a younger age at diagnosis (p=0·0030 for death or transplantation, p=0·011 for all-cause mortality). Interpretation Patients with PAH and BMPR2 mutations present at a younger age with more severe disease, and are at increased risk of death, and death or transplantation, compared with those without BMPR2 mutations. Funding Cambridge NIHR Biomedical Research Centre, Medical Research Council, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, Intermountain Research and Medical Foundation, Vanderbilt University, National Center for Advancing Translational Sciences, National Institutes of Health, National Natural Science Foundation of China, and Beijing Natural Science Foundation.

Short-Term Intravenous Sodium Nitrite Infusion Improves Cardiac and Pulmonary Hemodynamics in Heart Failure Patients

Background—Nitrite exhibits hypoxia-dependent vasodilator properties, selectively dilating capacitance vessels in healthy subjects. Unlike organic nitrates, it seems not to be subject to the development of tolerance. Currently, therapeutic options for decompensated heart failure (HF) are limited. We hypothesized that by preferentially dilating systemic capacitance and pulmonary resistance vessels although only marginally dilating resistance vessels, sodium nitrite (NaNO2) infusion would increase cardiac output but reduce systemic arterial blood pressure only modestly. We therefore undertook a first-in-human HF proof of concept/safety study, evaluating the hemodynamic effects of short-term NaNO2 infusion. Methods and Results—Twenty-five patients with severe chronic HF were recruited. Eight received short-term (5 minutes) intravenous NaNO2 at 10 &mgr;g/kg/min and 17 received 50 &mgr;g/kg/min with measurement of cardiac hemodynamics. During infusion of 50 &mgr;g/kg/min, left ventricular stroke volume increased (from 43.22±21.5 to 51.84±23.6 mL; P=0.003), with marked falls in pulmonary vascular resistance (by 29%; P=0.03) and right atrial pressure (by 40%; P=0.007), but with only modest falls in mean arterial blood pressure (by 4 mm Hg; P=0.004). The increase in stroke volume correlated with the increase in estimated trans-septal gradient (=pulmonary capillary wedge pressure–right atrial pressure; r=0.67; P=0.003), suggesting relief of diastolic ventricular interaction as a contributory mechanism. Directionally similar effects were observed for the above hemodynamic parameters with 10 &mgr;g/kg/min; this was significant only for stroke volume, not for other parameters. Conclusions—This first-in-human HF efficacy/safety study demonstrates an attractive profile during short-term systemic NaNO2 infusion that may be beneficial in decompensated HF and warrants further evaluation with longer infusion regimens.

High-Sensitivity Cardiac Troponin Concentration and Risk of First-Ever Cardiovascular Outcomes in 154,052 Participants

Background High-sensitivity assays can quantify cardiac troponins I and T (hs-cTnI, hs-cTnT) in individuals with no clinically manifest myocardial injury. Objectives The goal of this study was to assess associations of cardiac troponin concentration with cardiovascular disease (CVD) outcomes in primary prevention studies. Methods A search was conducted of PubMed, Web of Science, and EMBASE for prospective studies published up to September 2016, reporting on associations of cardiac troponin concentration with first-ever CVD outcomes (i.e., coronary heart disease [CHD], stroke, or the combination of both). Study-specific estimates, adjusted for conventional risk factors, were extracted by 2 independent reviewers, supplemented with de novo data from PROSPER (Pravastatin in Elderly Individuals at Risk of Vascular Disease Study), then pooled by using random effects meta-analysis. Results A total of 28 relevant studies were identified involving 154,052 participants. Cardiac troponin was detectable in 80.0% (hs-cTnI: 82.6%; hs-cTnT: 69.7%). In PROSPER, positive associations of log-linear shape were observed between hs-cTnT and CVD outcomes. In the meta-analysis, the relative risks comparing the top versus the bottom troponin third were 1.43 (95% confidence interval [CI]: 1.31 to 1.56) for CVD (11,763 events), 1.67 (95% CI: 1.50 to 1.86) for fatal CVD (7,775 events), 1.59 (95% CI: 1.38 to 1.83) for CHD (7,061 events), and 1.35 (95% CI: 1.23 to 1.48) for stroke (2,526 events). For fatal CVD, associations were stronger in North American studies (p = 0.010) and those measuring hs-cTnT rather than hs-cTnI (p = 0.027). Conclusions In the general population, high cardiac troponin concentration within the normal range is associated with increased CVD risk. This association is independent of conventional risk factors, strongest for fatal CVD, and applies to both CHD and stroke.

Socioeconomic Deprivation and Survival After Heart Transplantation in England

Background—Socioeconomic deprivation (SED) is associated with shorter survival across a range of cardiovascular and noncardiovascular diseases. The association of SED with survival after heart transplantation in England, where there is universal healthcare provision, is unknown. Methods and Results—Long-term follow-up data were obtained for all patients in England who underwent heart transplantation between 1995 and 2014. We used the United Kingdom Index of Multiple Deprivation (UK IMD), a neighborhood level measure of SED, to estimate the relative degree of deprivation for each recipient. Cox proportional hazard models were used to examine the association between SED and overall survival and conditional survival (dependant on survival at 1 year after transplantation) during follow-up. Models were stratified by transplant center and adjusted for donor and recipient age and sex, ethnicity, serum creatinine, diabetes mellitus, and heart failure cause. A total of 2384 patients underwent heart transplantation. There were 1101 deaths during 17 040 patient-year follow-up. Median overall survival was 12.6 years, and conditional survival was 15.6 years. Comparing the most deprived with the least deprived quintile, adjusted hazard ratios for all-cause mortality were 1.27 (1.04–1.55; P=0.021) and 1.59 (1.22–2.09; P=0.001) in the overall and conditional models, respectively. Median overall survival and conditional survival were 3.4 years shorter in the most deprived quintile than in the least deprived. Conclusions—Higher SED is associated with shorter survival in heart transplant recipients in England and should be considered when comparing outcomes between centers. Future research should seek to identify modifiable mediators of this association.

A single-center analysis of abdominal imaging in the evaluation of kidney transplant recipients

Many transplantation programs utilize noninvasive abdominal and pelvic imaging in the pre‐operative evaluation of recipient candidates. Practice patterns vary, and consensus guidelines addressing the risks and benefits of computed tomography (CT) and magnetic resonance imaging (MRI) in the pre‐transplant evaluation process do not currently exist. In this single‐center study, we examined the frequency, clinical significance, and associated costs of CT and MRI findings during the pre‐transplant evaluation of renal transplant recipients. A retrospective chart review of 3041 adult patients who underwent a CT/CTA or MRI/MRA of the abdomen and pelvis for pre‐transplant evaluation between 2005 and 2010 was performed. Pre‐transplant imaging with MRI offered a more sensitive evaluation in comparison with CT, with the notable exception of abnormalities in which calcium was detected. Patients imaged with CT had a significantly greater proportion of subsequent clinical actions arising from imaging findings. The total financial cost of MRI was greater than that of CT. No cases of nephrogenic systemic fibrosis (NSF) in patients who received MultiHance gadolinium contrast were reported. In conclusion, the risks, benefits, and costs of CT/CTA and MRI/MRA must be carefully considered to optimize the pre‐operative evaluation of renal transplant recipients.

Human Second Window Pre-Conditioning and Post-Conditioning by Nitrite Is Influenced by a Common Polymorphism in Mitochondrial Aldehyde Dehydrogenase

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