Circulation: Clinical Summaries
Original Research Put Into Perspective for the Practicing Clinician
- Preoperative Serum Brain Natriuretic Peptide and Risk of Acute Kidney Injury After Cardiac Surgery
- Systemic and Vascular Oxidation Limits the Efficacy of Oral Tetrahydrobiopterin Treatment in Patients With Coronary Artery Disease
- Associations of Pregnancy Complications With Calculated Cardiovascular Disease Risk and Cardiovascular Risk Factors in Middle Age: The Avon Longitudinal Study of Parents and Children
- Associations of Maternal Prepregnancy Body Mass Index and Gestational Weight Gain With Adult Offspring Cardiometabolic Risk Factors: The Jerusalem Perinatal Family Follow-Up Study
- Long-Term Effects of Sildenafil in a Rat Model of Chronic Mitral Regurgitation: Benefits of Ventricular Remodeling and Exercise Capacity
- Renal Sympathetic Denervation Suppresses De Novo Podocyte Injury and Albuminuria in Rats With Aortic Regurgitation
- Admission International Normalized Ratio Levels, Early Treatment Strategies, and Major Bleeding Risk Among Non–ST-Segment–Elevation Myocardial Infarction Patients on Home Warfarin Therapy: Insights From the National Cardiovascular Data Registry
- Validation of the Bleeding Academic Research Consortium Definition of Bleeding in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention
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Preoperative Serum Brain Natriuretic Peptide and Risk of Acute Kidney Injury After Cardiac Surgery
Cardiovascular disease and heart failure are highly prevalent among those who undergo cardiac surgery, contributing to hemodynamic stress that may be poorly characterized by clinical history. Consequently, natriuretic peptide biomarkers that better characterize this underlying physiology have become well established in the diagnosis and management of patients with heart failure. In this study, 1139 adults who underwent cardiac surgery were evaluated from 6 centers to establish whether preoperative brain natriuretic peptide (BNP) levels predict postoperative acute kidney injury (AKI; defined by Acute Kidney Injury Network definitions; at least mild AKI was a >0.3-mg/dL [26 μmol/L] or 50% rise in creatinine, and severe AKI was either a doubling of creatinine or the requirement of acute renal replacement therapy). In this high-risk cohort, AKI was common (at least mild AKI, n=407 [36%]; severe AKI, n=58 [5.1%]). After adjustment for different preoperative characteristics, preoperative BNP was a strong and independent predictor of mild and severe AKI. Compared with the lowest BNP quintile, the highest quintile had significantly higher risk of at least mild AKI (risk ratio, 1.87) and severe AKI (risk ratio, 3.17). After adjustment for clinical predictors, the addition of BNP improved the area under the curve to predict at least mild AKI and severe AKI. Compared with clinical parameters alone, BNP also improved risk prediction of AKI cases into lower and higher risk. Preoperative BNP level is associated with postoperative AKI in high-risk patients undergoing cardiac surgery and may be a valuable component of future efforts to improve preoperative risk stratification among surgical candidates. See p 1347.
Systemic and Vascular Oxidation Limits the Efficacy of Oral Tetrahydrobiopterin Treatment in Patients With Coronary Artery Disease
Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide synthase in the vascular endothelium. Under conditions of BH4 deficiency such as the increased oxidative stress associated with atherosclerosis, endothelial nitric oxide synthase can become uncoupled, leading to the production of reactive oxygen species rather than nitric oxide, thus exacerbating oxidative stress. Accordingly, pharmacological strategies to increase BH4 levels have been proposed as therapeutic options in vascular disease states. Short-term intra-arterial infusions of BH4 have been shown to improve endothelial function; however, the effect of a long-term oral strategy in patients with coronary artery disease is unknown. In this clinical trial, we have tested the hypothesis that long-term oral BH4 treatment can increase BH4 bioavailability and improve vascular function in patients with coronary artery disease compared with placebo. Our trial results, supported by mechanistic ex vivo experiments using human blood and vascular tissue, demonstrate that exogenous BH4 is rapidly oxidized to dihydrobiopterin, which lacks endothelial nitric oxide synthase cofactor activity, and may act as a competitive inhibitor of BH4. Thus, although BH4 levels are elevated by treatment, the corresponding elevation of dihydrobiopterin levels results in no net effect of treatment on vascular redox status and hence no effect on vascular function. Therefore, future studies should address alternative therapies to target BH4-mediated vascular function or should examine strategies to ameliorate the oxidation of exogenous BH4. See p 1356.
Associations of Pregnancy Complications With Calculated Cardiovascular Disease Risk and Cardiovascular Risk Factors in Middle Age: The Avon Longitudinal Study of Parents and Children
It is increasingly recognized that women experiencing common pregnancy complications, such as gestational diabetes mellitus, preeclampsia, intrauterine growth restriction, and preterm delivery are at increased risk of cardiovascular disease (CVD). However, the manner in which their relative and absolute associations differ remains unclear. We studied associations of diabetes mellitus, hypertensive disorders of pregnancy, preterm delivery, and size for gestational age with calculated 10-year CVD risk (based on the Framingham score) and a wide range of cardiovascular risk factors measured 18 years after pregnancy in a prospective cohort of 3416 women (mean age, 48 years at outcome assessment). Gestational diabetes mellitus was positively associated with fasting glucose and insulin, even after adjustment for potential confounders, whereas hypertensive disorders of pregnancy were associated with body mass index, waist circumference, blood pressure, lipids, and insulin. Large for gestational age was associated with greater waist circumference and glucose concentrations, whereas small for gestational age and preterm delivery were associated with higher blood pressure in mothers. The association with the calculated 10-year CVD risk was odds ratio 1.31 (95% confidence interval, 1.11–1.53) for preeclampsia, 1.27 (95% confidence interval, 1.19–1.35) for gestational hypertension, 1.26 (95% confidence interval, 0.95–1.68) for gestational diabetes mellitus, and 1.10 (95% confidence interval, 1.01–1.19) for small for gestational age compared with women without these conditions. Our results suggest that hypertensive disorders of pregnancy, gestational diabetes mellitus, and small for gestational age are associated with an increased risk of CVD. These complications are widely prevalent, affecting 36% of our population, and provide an opportunity for early identification of women at increased risk of CVD later in life. Whether targeted lifestyle interventions in such women help to mitigate their future CVD risk requires further study. See p 1367.
Associations of Maternal Prepregnancy Body Mass Index and Gestational Weight Gain With Adult Offspring Cardiometabolic Risk Factors: The Jerusalem Perinatal Family Follow-Up Study
Accumulating evidence suggests that maternal prepregnancy body mass index (mppBMI) and gestational weight gain (GWG) may affect adult offspring adiposity. However, whether these maternal attributes are associated with other offspring cardiometabolic risk factors in adulthood remains unclear. We have prospectively examined the independent associations of mppBMI and GWG with offspring cardiometabolic risk factors at 32 years of age using a birth cohort of 1400 young adults born in Jerusalem. Greater mppBMI was significantly associated with higher offspring BMI, waist circumference, systolic and diastolic blood pressures, insulin, and triglycerides and with lower levels of high-density lipoprotein cholesterol. GWG was positively associated with offspring adiposity, including BMI and waist circumference. Translating these associations into mean differences of cardiometabolic outcomes between quartiles of mppBMI and GWG distributions reveals clinically meaningful differences. For example, offspring of mothers within the upper mppBMI quartile (mppBMI >26.4 kg/m2) had 4.6 kg/m2 higher BMI, 11.4 mg/dL higher triglycerides, and 3.8 mg/dL lower high-density lipoprotein cholesterol compared with offspring of mothers within the lower quartile (mppBMI <21.0 kg/m2). Differences of 1.6 kg/m2 in BMI and 2.4 cm in waist circumference were observed when offspring of mothers in the upper (GWG >14 kg) and lower (GWG <9 kg) quartiles of GWG were compared. The associations appear to be driven mainly by offspring adiposity, emphasizing the potential impact that maternal adiposity may have via offspring adiposity on predictors of long-term cardiometabolic health outcomes in offspring. Future studies that explore the mechanisms that account for these associations and clinical trials monitoring maternal size both before and during pregnancy are warranted to identify potentially novel targets for cardiometabolic risk-reduction interventions. See p 1381.
Long-Term Effects of Sildenafil in a Rat Model of Chronic Mitral Regurgitation: Benefits of Ventricular Remodeling and Exercise Capacity
Mitral regurgitation (MR) induces chronic left ventricular volume overload and leads to left ventricular contractile dysfunction, heart failure, and, finally, death. Although surgical correction of MR, the only definitive cure, carries reasonably low mortality and morbidity risks, medical therapeutics have a role in many clinical situations such as in a patient population with greater surgical risk. However, there is currently no recommended pharmacological therapy for chronic MR. Despite previous efforts, medical therapies for chronic MR have produced disappointing and conflicting results. Since the early 2000s, sildenafil, part of a class of selective inhibitors of phosphodiesterase type 5, has been under intense study in various areas. Multiple lines of preclinical and clinical evidence support a therapeutic role for phosphodiesterase type 5 inhibition with sildenafil in the management of heart failure. Accordingly, we hypothesized that sildenafil may have a beneficial effect in chronic MR. The major findings of the present study are that sildenafil prevented left ventricular remodeling and exercise intolerance caused by chronic experimental MR. To our knowledge, this is the first study that shows that sildenafil is efficacious in the presence of MR. Additionally, we proposed potential mechanisms related to the effect of sildenafil: inhibition of inflammation and apoptosis. With consideration of the beneficial effects of sildenafil in MR rats, we can expect a therapeutic potential for sildenafil in patients with MR. Future clinical studies are needed. See p 1390.
Renal Sympathetic Denervation Suppresses De Novo Podocyte Injury and Albuminuria in Rats With Aortic Regurgitation
There is increasing awareness of the cardiorenal syndrome in patients with myocardial disease. The presence of chronic kidney disease is a significant and independent risk factor for poor prognosis in patients with chronic heart failure. In the present study, we demonstrated that inappropriate activation of the sympathetic nervous system and intrarenal renin-angiotensin system mediates de novo albuminuria in rats subjected to aortic regurgitation. Renal denervation reduced intrarenal angiotensinogen and angiotensin II levels and decreased podocyte injury and albuminuria in aortic regurgitation rats. Furthermore, treatment with olmesartan, to block renin-angiotensin system activity, enhanced the suppressive effects of renal denervation on albuminuria. Renal denervation also significantly reduced the induction of genes involved in fetal gene programming such as β-myosin heavy chain and brain natriuretic peptide and reduced markers of cardiac fibrosis such as collagen I and III mRNA levels and collagen content in the left ventricle. Our results imply that patients with cardiac dysfunction may be at increased risk for de novo renal dysfunction or worsening of preexisting asymptomatic renal dysfunction through sympathetic nerve hyperactivity. Recent clinical trials have demonstrated that catheter-based renal denervation can safely reduce blood pressure in treatment-resistant hypertensive patients without significant adverse events. The molecular mechanism underlying this pathophysiological condition may provide a new therapeutic target for patients with cardiovascular disease to prevent further renal injury while providing stronger protection of both organs. See p 1402.
Admission International Normalized Ratio Levels, Early Treatment Strategies, and Major Bleeding Risk Among Non–ST-Segment–Elevation Myocardial Infarction Patients on Home Warfarin Therapy: Insights From the National Cardiovascular Data Registry
Little is known about the contemporary treatment patterns and bleeding risks of non–ST-segment–elevation myocardial infarction patients on home warfarin therapy. Although expert opinion from consensus guidelines suggests withholding parenteral anticoagulant therapy in patients with admission international normalized ratio (INR) levels ≥2.0, we found that 45% of these patients were prescribed early heparin in the first 24 hours of hospitalization. Additionally, although guidelines suggest initiation of antiplatelet therapy among those with admission INR levels ≥2.0, we found that only 35% and 14% of these patients were prescribed early clopidogrel and glycoprotein IIb/IIIa inhibitor, respectively. Patients with admission INR ≥2.0 were less likely to receive an early invasive strategy despite higher ischemic risk. These findings highlight the challenge that clinicians face in balancing ischemic benefit and bleeding risk when selecting a treatment for these patients. We found that early use of antiplatelet and antithrombin therapy was associated with increased bleeding risk among non–ST-segment–elevation myocardial infarction patients on home warfarin; however, an early invasive strategy was not. After adjustment, patients with admission INR levels >3.0 were at highest risk of in-hospital major bleeding followed by those with admission INR of 2.0 to 3.0. Early antithrombotic treatment was associated with increased bleeding risk regardless of admission INR level. Future clinical trials are critically needed to guide treatment decisions, to determine the optimal use and timing of anticoagulant therapy, and to formulate more definitive guideline recommendations that balance the prevention of adverse ischemic events with the risk of major bleeding in this vulnerable population. See p 1414.
Validation of the Bleeding Academic Research Consortium Definition of Bleeding in Patients With Coronary Artery Disease Undergoing Percutaneous Coronary Intervention
Available evidence demonstrates that occurrence of bleeding in patients undergoing percutaneous coronary intervention (PCI) signifies a worse clinical outcome compared with patients who do not bleed. Differences in the bleeding definition represent an important confounding factor that hinders the ascertainment of true bleeding occurrence and its association with clinical outcome and implementation of preventive/reducing strategies. Recently, a consensus report from the Bleeding Academic Research Consortium (BARC) proposed a standardized bleeding definition with a hierarchical approach of describing bleeding severity in patients receiving antithrombotic therapy. The BARC document is a consensus report rather than a data-based analysis and has not yet been validated. In this study, we investigated the relationship between bleeding as defined by the BARC consensus document and 1-year mortality in patients undergoing PCI and assessed whether the BARC bleeding definition is superior to Thrombolysis in Myocardial Infarction (TIMI) and Randomized Evaluation in PCI Linking Angiomax to Reduced Clinical Events (REPLACE-2) bleeding definitions. The study represents a pooled patient-level analysis of 12 459 patients recruited in 6 Intracoronary Stenting and Antithrombotic Regimen (ISAR) clinical trials. The present study found a close association between bleeding defined by BARC and 1-year mortality after PCI. The BARC bleeding definition criteria offer a balanced combination of laboratory and clinical metrics for bleeding recognition and a detailed hierarchical grading system of its severity that is closely associated with increased risk of death up to 1 year after PCI. However, all 3 bleeding definitions (BARC, TIMI, and REPLACE-2) provide comparable prognostic information with respect to 1-year mortality in patients with coronary artery disease undergoing PCI. See p 1424.
- © 2012 American Heart Association, Inc.
- Preoperative Serum Brain Natriuretic Peptide and Risk of Acute Kidney Injury After Cardiac Surgery
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