Purpose Anthracycline-induced congestive heart failure (CHF) is a rare but serious toxicity associated with this commonly employed anti-cancer therapy. The ability to predict which patients might be at increased risk prior to exposure would be valuable to optimally counsel risk to benefit ratio for each patient. Herein we present a genome wide approach for biomarker discovery with two validation cohorts to predict CHF from adult patients planning to receive an anthracycline. Experimental Design We performed a genome wide association study (GWAS) in 3431patients from the randomized phase III adjuvant breast cancer trial E5103 to identify SNP genotypes associated with an increased risk of anthracycline-induced CHF. We further attempted candidate validation in two independent phase III adjuvant trials, E1199 and BEATRICE. Results When evaluating for cardiologist adjudicated CHF, 11 SNPs had a p-value <10−5 of which nine independent chromosomal regions were associated with increased risk. Validation of the 2 top SNPs in E1199 revealed one SNP, rs28714259 that demonstrated a borderline increased CHF risk (p=0.04, OR=1.9). rs28714259 was subsequently tested in BEATRICE and was significantly associated with a decreased left ventricular ejection fraction (p=0.018, OR=4.2). Conclusion rs28714259 represents a validated SNP that is associated with anthracycline-induced CHF in three independent, phase III adjuvant breast cancer clinical trials.
Circulation Journal Official Journal of the Japanese Circulation Society http://www. j-circ.or.jp valuation of left ventricular (LV) systolic function is a critical component of the practice of cardiology and a fundamental function of the echocardiographic examination. Although LV systolic function is commonly defined by ejection fraction (EF), there are numerous technical and hemodynamic limitations to EF. A qualitative "eyeball" estimate has high variability, and quantitative measurements are subject to endocardial border definition and formulas that make assumptions in geometry of the LV. The EF denotes global LV function and does not convey any regional differences in function that may exist in patients with various cardiomyopathies. Hyperkinetic segments can distort a global measurement, leading to an underestimation of the significance of regional abnormalities. There are several alternative techniques that can either supplement or replace EF, including tissue Doppler recordings of the mitral annulus and measurements such as the TEI or myocardial performance index. Doppler-Derived Strain RateThe newest technique for evaluating the LV uses the concept of strain or strain rate. This technique assesses myocardial mechanics by measuring the relationship between 2 points within the myocardium as if they were connected by a rubber band. When the 2 points move away from each other (myocardial lengthening during diastole), strain values are positive. When the 2 points move toward each other (myocardial shortening during systole), strain is decreased, generating negative strain. Strain and strain rate can be derived from either tissue Doppler or speckle tracking 2-or 3-dimensional (D) echocardiography. Using tissue Doppler, which is a form of pulsed Doppler, specific points within the myocardium can be identified. 1 Tracking these Doppler points enables measurement of strain rate. Because Doppler is velocity or distance divided by time, the initial measurement is strain rate. Integrating the strain rate gives strain.There are limitations to the Doppler-based strain rate. As with all Doppler applications, the Doppler-derived strain rate is angledependent. The Doppler strain rate sample volume is also fixed while the myocardium is moving. Thus the sample volume may not stay within the myocardium throughout the cardiac cycle. Strain rate is a derivative of strain and tends to be noisy. Figure 1 shows one way of recording strain rate using "curved M-mode". A resting normal 4-chamber view shows yellowishbrown strain rate during ventricular systole. The strain rate recording of the apex is not reliable, because the apex is perpendicular to the ultrasonic beam, so there is no Doppler signal. With exercise the systolic strain rate turns reddish brown, indicating a higher degree of negativity or contraction in the basal segments. This patient has a blockage in the left anterior descending coronary artery. With exercise, there is a delay in the onset of contraction of the apical half of the septal and lateral walls, a failur...
Left ventricular (LV) mass is a strong predictor of cardiovascular disease (CVD) events; increased LV mass is common among US firefighters and plays a major role in firefighter sudden cardiac death. We aim to identify significant predictors of LV mass among firefighters. Cross-sectional study of 400 career male firefighters selected by an enriched randomization strategy. Weighted analyses were performed based on the total number of risk factors per subject with inverse probability weighting. LV mass was assessed by echocardiography (ECHO) and cardiac magnetic resonance, and normalized (indexed) for height. CVD risk parameters included vital signs at rest, body mass index (BMI)–defined obesity, obstructive sleep apnea risk, low cardiorespiratory fitness, and physical activity. Linear regression models were performed. In multivariate analyses, BMI was the only consistent significant independent predictor of LV mass indexes (all, p <0.001). A 1-unit decrease in BMI was associated with 1-unit (g/m1.7) reduction of LV mass/height1.7 after adjustment for age, obstructive sleep apnea risk, and cardiorespiratory fitness. In conclusion, after height-indexing ECHO-measured and cardiac magnetic resonance–measured LV mass, BMI was found to be a major driver of LV mass among firefighters. Our findings taken together with previous research suggest that reducing obesity will improve CVD risk profiles and decrease on-duty CVD and sudden cardiac death events in the fire service. Our results may also support targeted noninvasive screening for LV hypertrophy with ECHO among obese firefighters.
This study showed that 100% of patients had reduced RV function early after transplant. Two thirds of patients had partial recovery of RV function during the first year. In all patients, however, RV function remained significantly lower than in controls.
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