Audrey H. Wu

Usefulness of aortic valve calcium scores by electron beam computed tomography as a marker for aortic stenosis

This study was undertaken to determine whether aortic valve calcium (AVC) scores measured by electron beam tomography can identify patients with echocardiographically defined aortic stenosis. Electron beam tomography is increasingly being used to detect coronary artery calcium. AVC can also be measured on electron beam tomographic (EBT) scans obtained to screen for coronary calcium. Whether EBT AVC scores correlate with the presence of aortic stenosis, as assessed by echocardiography, is unknown. Results of this study suggest that AVC scores should be calculated routinely for coronary calcium screening EBT scans, and that patients with Agatston AVC scores above a certain level (e.g., >150) should be referred for echocardiography.

Uric acid level and allopurinol use as risk markers of mortality and morbidity in systolic heart failure.

BACKGROUND Previous studies have not extensively examined the association of hyperuricemia and adverse outcomes in systolic heart failure (HF) in relation to xanthine oxidase inhibitor therapy. METHODS The Prospective Randomized Amlodipine Survival Evaluation study included New York Heart Association class IIIB or IV patients with left ventricular ejection fraction <30%. For analysis, the population was divided into uric acid quartiles among nonallopurinol users (2.2-7.1, >7.1-8.6, >8.6-10.4, >10.4 mg/dL) and those using allopurinol. Multivariate Cox regression modeling was performed to identify predictors of mortality. Uric acid quartile and allopurinol groups were referenced to the lowest uric acid quartile. RESULTS A total of 1,152 patients were included. In general, patients in the allopurinol group and in the highest uric acid quartile had indicators of more severe HF, including worse renal function and greater proportion of New York Heart Association class IV patients, and greater diuretic use. The allopurinol group and highest uric acid quartile had the highest total mortality (41.7 and 42.4 per 100 person-years, respectively) and combined morbidity/mortality (45.6 and 51.0 per 100 person-years, respectively). Allopurinol use and highest uric acid quartile were independently associated with mortality (hazard ratio [HR] 1.65, 95% CI 1.22-2.23, P = .001 and HR 1.35, 95% CI 1.07-1.72, P = .01, respectively) and combined morbidity/mortality (uric acid quartile 4 vs 1: HR 1.32, 95% CI 1.06-1.66, P = .02; allopurinol use: HR 1.48, 95% CI 1.11-1.99, P = .008). CONCLUSION Elevated uric acid level was independently associated with mortality in patients with severe systolic HF, even when accounting for allopurinol use.

Cardiotoxic drugs: clinical monitoring and decision making

Through a variety of mechanisms, the heart is a target of injury for many drugs, both medically prescribed and not. Drugs with potential cardiac toxicity are particularly prominent in cancer treatment, and as survival of cancer patients continues to improve, drug toxicities feature more importantly in long term patient outcomes. This review will focus on intermediate and long term complications (in particular those related to cancer therapy), or acute effects related to drug toxicity (in particular those related to drugs of abuse), with emphasis on those toxicities that can be monitored and/or have specific treatment options. This review will not cover in detail acute complications of chemotherapeutic agents, which are typically transient and occur only during or shortly after drug administration, or toxicities related to overdose of cardiovascular drugs. Finally, note is made regarding epidemiologic associations between specific drugs and adverse cardiovascular outcomes. ### Anthracyclines The anthracyclines are used to treat a wide range of haematologic and solid malignancies, and are probably the most commonly recognised type of chemotherapy with known cardiac toxicity. Various approaches have been undertaken to reduce drug cardiotoxicity, including structural modifications to the doxorubicin molecule (epirubicin), incorporation into liposomes (doxorubicin, daunorubicin), or development of structurally related drugs (mitoxantrone).1 Long term cardiac toxicity manifests as ventricular dysfunction and clinical heart failure, and is thought to be due to direct myocardial injury from free radicals. Risk of heart failure is most directly related to cumulative dose and administration schedule. The risk of cardiomyopathy increases significantly at cumulative doses >550 mg/m2 although cardiomyopathy can still occur at lower doses. Although the reported incidence of heart failure in modern adjuvant anthracycline therapy trials is 2% or less, recent studies have reported up to 10–50% occurrence of subclinical decline in left ventricular function >10 percentage points after anthracycline treatment.2 Early …

Relation of serum uric acid to cardiovascular disease.

This review summarizes recent published literature on the association between serum uric acid and cardiovascular disease, a relationship which is complex and not fully elucidated. Uric acid may be a marker for risk, a causative agent in cardiovascular disease, or both. Various biologic factors can influence serum uric acid levels, and serum uric acid level itself is closely related to conditions such as hypertension, dyslipidemia, obesity, and impaired glucose metabolism, that contribute to cardiovascular disease pathophysiology. Serum uric acid levels have been found to be associated with adverse outcomes, including mortality, in the general population. In addition, serum uric acid is associated with increased risk for incident coronary heart disease, heart failure, and atrial fibrillation. In the setting of established systolic heart failure, serum uric acid is positively associated with disease severity and mortality risk. Whether targeting treatment based on uric acid levels might affect clinical outcomes is still being studied.

Association of obesity and survival in systolic heart failure after acute myocardial infarction: potential confounding by age.

To determine the association between obesity and outcomes in post‐acute myocardial infarction (AMI) patients with systolic heart failure (HF).

Sacubitril Is Selectively Activated by Carboxylesterase 1 (CES1) in the Liver and the Activation Is Affected by CES1 Genetic Variation

Sacubitril was recently approved by the Food and Drug Administration for use in combination with valsartan for the treatment of patients with heart failure with reduced ejection fraction. As a prodrug, sacubitril must be metabolized (hydrolyzed) to its active metabolite sacubitrilat (LBQ657) to exert its intended therapeutic effects. Thus, understanding the determinants of sacubitril activation will lead to the improvement of sacubitril pharmacotherapy. The objective of this study was to identify the enzyme(s) responsible for the activation of sacubitril, and determine the impact of genetic variation on sacubitril activation. First, an incubation study of sacubitril with human plasma and the S9 fractions of human liver, intestine, and kidney was conducted. Sacubitril was found to be activated by human liver S9 fractions only. Moreover, sacubitril activation was significantly inhibited by the carboxylesterase 1 (CES1) inhibitor bis-(p-nitrophenyl) phosphate in human liver S9. Further incubation studies with recombinant human CES1 and carboxylesterase 2 confirmed that sacubitril is a selective CES1 substrate. The in vitro study of cell lines transfected with wild-type CES1 and the CES1 variant G143E (rs71647871) demonstrated that G143E is a loss-of-function variant for sacubitril activation. Importantly, sacubitril activation was significantly impaired in human livers carrying the G143E variant. In conclusion, sacubitril is selectively activated by CES1 in human liver. The CES1 genetic variant G143E can significantly impair sacubitril activation. Therefore, CES1 genetic variants appear to be an important contributing factor to interindividual variability in sacubitril activation, and have the potential to serve as biomarkers to optimize sacubitril pharmacotherapy.

Management of patients with non-ischaemic cardiomyopathy

The term “cardiomyopathy” refers to specific diseases affecting the myocardium which generally lead to clinical manifestations of heart failure, including exercise intolerance, dyspnoea, and fluid retention. The causes of cardiomyopathy can be broadly divided into two categories, ischaemic and non-ischaemic. In ischaemic cardiomyopathy, ventricular dysfunction is a consequence of myocardial ischaemia and infarction related to coronary arteriosclerosis, while there are many potential causes of non-ischaemic cardiomyopathy (NICM), including haemodynamic pathology, infection, immunologic abnormalities, toxic injury, or genetic factors. Determining the prevalence of NICM is made difficult by the heterogeneity in definitions and diagnostic criteria, selection bias in populations studied, and geographic variation. Many epidemiological and clinical studies simply classify patients as having NICM if heart failure is present but there is no clinical or electrocardiographic evidence of coronary disease. In addition, there are clear differences in population characteristics between community-based studies versus analyses of populations from referral centres. Finally, there appears to be geographic variation in the prevalence of specific aetiologies of NICM. Estimates of the prevalence of NICM range from 2–15% in community or hospital settings, and up to 50% in large clinical trials.1 Although the causes of NICM are many and varied, they generally culminate in a final common pathway of myocardial injury leading to ventricular dysfunction and clinical heart failure. In many cases of NICM a specific aetiology is never identified, or if one is, then frequently no aetiology-specific treatment is available; thus, treatment of NICM frequently includes standard management for systolic heart failure. While a minority of cardiomyopathies manifest with preserved systolic function, this article specifically reviews management of NICM manifesting with left ventricular (LV) systolic dysfunction. Many types of NICM are not treatable with specific therapies beyond those used for heart failure in general. A significant proportion of patients with NICM have idiopathic dilated …

Relation of Body Mass Index to Mortality After Development of Heart Failure Due to Acute Coronary Syndrome

Several studies have suggested that obesity may be associated with a survival advantage in heart failure (HF). The duration of HF likely influences disease severity and may introduce lead-time bias into analyses of outcomes. The aim of this study was to analyze a cohort in which the exact time of HF onset could be determined: patients in the University of Michigan subset of the acute coronary syndromes (ACS) database of the Global Registry of Acute Coronary Events (GRACE) who developed new-onset HF (no history of HF and left ventricular ejection fraction <or=40% or qualitatively diminished) with their index ACS events from January 1999 to March 2006 (n = 446). For analysis, body mass index (BMI) was categorized as normal (18.5 to <25 kg/m(2)), overweight (25 to <30 kg/m(2)), and obese (>or=30 kg/m(2)). Underweight patients (BMI <or=18.5 kg/m(2)) were excluded. Separate multivariate Cox regression models were performed to examine the effect of BMI group and other potential confounders on all-cause mortality and on the combined outcome of all-cause death, cardiac transplantation, or ventricular assist device implantation. BMI groups were not associated with different risks for the combined outcome, although overweight BMI approached statistical significance for lower risk for the combined outcome. Overweight BMI was significantly associated with lower risk for all-cause death (hazard ratio 0.63, 95% confidence interval 0.42 to 0.94, p = 0.02), although obese BMI was not (hazard ratio 1.06, 95% confidence interval 0.69 to 1.64, p = 0.8). In conclusion, these findings suggest a U-shaped relation between mortality and BMI in the setting of new-onset HF after ACS.

The Effect of Continuous Infusion Loop Diuretics in Patients With Acute Decompensated Heart Failure With Hypoalbuminemia

Purpose: Hypoalbuminemia is believed to decrease diuretic effectiveness and contribute to diuretic resistance that is observed in patients with nephrotic syndrome. Hypoalbuminemia is also seen in patients with acute decompensated heart failure (ADHF). However, the role of hypoalbuminemia on the effectiveness of continuous infusion diuretics in patients with ADHF is not known. Methods: To evaluate hypoalbuminemia (albumin ≤3 g/dL) and diuretic effectiveness, we performed a retrospective study in 162 patients admitted to a tertiary care center for treatment of ADHF over a 3-year period. All patients received continuous infusion diuretic for at least a 2-day time period. Results: A total of 33 patients were determined to have hypoalbuminemia. Average net urine output over a 2-day study period was similar between patients with and without hypoalbuminemia (−1462 ± 1734 vs −1233 ± 1560 mL, P = .46, respectively). In addition, diuretic doses (furosemide equivalent/24 hours) were similar between the 2 groups (788 ± 671 vs 778 ± 713 mg, P = .91, respectively) as was baseline serum creatinine (1.6 ± 0.6 vs 1.6 ± 0.6 mg/dL, P = .5, respectively). Conclusion: Overall, hypoalbuminemia did not decrease the diuretic effectiveness when measured by the net urine output in patients receiving continuous infusion diuretics for the treatment of ADHF.

Changes in serial B-type natriuretic peptide level independently predict cardiac allograft rejection

BACKGROUND Despite positive associations with rejection, the clinical value of B-type natriuretic peptide (BNP) monitoring in heart transplant recipients has not been established. We sought to determine the predictive value of changes in serial BNP level for identifying patients with acute allograft rejection. METHODS BNP, hemodynamics and biopsies were obtained for 205 transplant recipients who underwent a total of 4,007 endomyocardial biopsy procedures. Samples analyzed were collected ≥ 180 days post-transplant, without evidence of rejection on the immediately preceding biopsy. Using a repeated-measures multivariate model, we assessed the association of change in BNP with Grade ≥ 3A (2R) rejection. We also determined predictive values of various cut-off thresholds of change in serial BNP levels to predict Grade ≥ 3A rejection. RESULTS There were 47 episodes of Grade ≥ 3A rejection among the 1,350 samples analyzed. Median change in serial BNP (ΔBNP) for those with Grade ≥ 3A rejection was 20 pg/ml (IQR -26 to 169 pg/ml) and among those with Grade <3A rejection was -4 pg/ml (IQR -34 to 22 pg/ml, p = 0.003). On multivariate analysis, ΔBNP remained the most potent independent predictor of Grade ≥ 3A rejection (p = 0.001). ΔBNP >100 pg/ml predicted increased risk of Grade ≥ 3A rejection (OR = 5.3, p < 0.001) with high specificity (93.3%) and positive predictive value (13.0%) and excellent negative predictive value (97.3%). CONCLUSIONS Change in serial BNP level is an independent predictor of cardiac allograft rejection. With wide availability, rapid turnaround, low cost, favorable positive predictive value and excellent negative predictive value, serial BNP monitoring has several advantages for non-invasive monitoring of heart transplant recipients for acute cardiac allograft rejection.