Person:

Picard, Michael

Background: One third of patients who receive cardiac resynchronization therapy (CRT) are classified as nonresponders. Characteristics of responders to CRT have been studied in multiple clinical trials. Hypothesis: We aimed to examine characteristics of CRT responders in a routine clinical practice. Method: One hundred and twenty five patients were examined retrospectively from a multidisciplinary CRT clinic program. Echocardiographic CRT response was defined as a decrease in left ventricular (LV) end systolic volume (ESV) of ≥ 15% and/or absolute increase of 5% in LV ejection fraction (EF) at 6 month visit. Results: There were 81 responders and 44 nonresponders. By univariate analyses, female gender, nonischemic cardiomyopathy etiology, baseline QRS duration, the presence of left bundle branch block (LBBB) and left ventricular end-diastolic volume (LVEDV) index predicted CRT response. However, multivariate analysis demonstrated only QRS duration, LBBB and LVEDV index were independent predictors (QRS width: Odd ratio [OR] 1.027, 95% CI 1.004 – 1.050, p = 0.023; LBBB: OR 3.568, 95% CI 1.284 – 9.910, p=0.015; LV EDV index: OR 0.970, 95% CI 0.953 – 0.987, p= 0.001). While female gender and nonischemic etiology were associated with an improved CRT response on univariate analyses, after adjusting for LV volumes, they were not independent predictors. Conclusion: QRS width, LBBB and LVEDV index are independent predictors for echocardiographic CRT response. Previously reported differences in CRT response for gender and cardiomyopathy etiology are associated with differences in baseline LV volumes in our clinical practice.

Background: Because cancer patients survive longer, the impact of cardiotoxicity associated with the use of cancer treatments escalates. The present study investigates whether early alterations of myocardial strain and blood biomarkers predict incident cardiotoxicity in patients with breast cancer during treatment with anthracyclines, taxanes, and trastuzumab. Methods and Results: Eighty-one women with newly diagnosed human epidermal growth factor receptor 2–positive breast cancer, treated with anthracyclines followed by taxanes and trastuzumab were enrolled to be evaluated every 3 months during their cancer therapy (total of 15 months) using echocardiograms and blood samples. Left ventricular ejection fraction, peak systolic longitudinal, radial, and circumferential myocardial strain were calculated. Ultrasensitive troponin I, N-terminal pro–B-type natriuretic peptide, and the interleukin family member (ST2) were also measured. Left ventricular ejection fraction decreased (64 ± 5% to 59 ± 6%; P<0.0001) over 15 months. Twenty-six patients (32%, [22%–43%]) developed cardiotoxicity as defined by the Cardiac Review and Evaluation Committee Reviewing Trastuzumab; of these patients, 5 (6%, [2%–14%]) had symptoms of heart failure. Peak systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines treatment predicted the subsequent development of cardiotoxicity; no significant associations were observed for left ventricular ejection fraction, N-terminal pro–B-type natriuretic peptide, and ST2. Longitudinal strain was <19% in all patients who later developed heart failure. Conclusions: In patients with breast cancer treated with anthracyclines, taxanes, and trastuzumab, systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines therapy are useful in the prediction of subsequent cardiotoxicity and may help guide treatment to avoid cardiac side-effects.

Although multiple echocardiographic methods exist to calculate cardiac output (CO), they have not been validated in mice using a reference method. Echocardiographic and flow probe measurements of CO were obtained in mice before and after albumin infusion and inferior vena cava occlusions. Echocardiography was also performed before and after endotoxin injection. Cardiac output was calculated using LV volumes obtained from a M Mode or a 2D view, LV stroke volume calculated using the pulmonary flow, or estimated using pulmonary VTI. Close correlations were demonstrated between flow probe-measured CO and all echocardiographic measurements of CO. All echocardiographic-derived CO overestimated the flow-probe measured CO. 2D images-derived CO was associated with the smallest overestimation of CO. Interobserver variability was lowest for pulmonary VTI derived CO. In mice, CO calculated from 2D parasternal long axis images is most accurate when compared to flow probe measurements, however, pulmonary VTI-derived CO is subject to less variability.

Background—Interventions to increase brown adipose tissue (BAT) volume and activation are being extensively investigated as therapies to decrease the body weight in obese subjects. Noninvasive methods to monitor these therapies in animal models and humans are rare. We investigated whether contrast ultrasound (CU) performed in mice could detect BAT and measure its activation by monitoring BAT blood flow. After validation, CU was used to study the role of uncoupling protein 1 and nitric oxide synthases in the acute regulation of BAT blood flow. Methods and Results—Blood flow of interscapular BAT was assessed in mice (n=64) with CU by measuring the signal intensity of continuously infused contrast microbubbles. Blood flow of BAT estimated by CU was 0.5±0.1 (mean±SEM) dB/s at baseline and increased 15-fold during BAT stimulation by norepinephrine (1 µg·kg−1·min−1). Assessment of BAT blood flow using CU was correlated to that performed with fluorescent microspheres (R2=0.86, P<0.001). To evaluate whether intact BAT activation is required to increase BAT blood flow, CU was performed in uncoupling protein 1–deficient mice with impaired BAT activation. Norepinephrine infusion induced a smaller increase in BAT blood flow in uncoupling protein 1–deficient mice than in wild-type mice. Finally, we investigated whether nitric oxide synthases played a role in acute norepinephrine-induced changes of BAT blood flow. Genetic and pharmacologic inhibition of nitric oxide synthase 3 attenuated the norepinephrine-induced increase in BAT blood flow. Conclusions—These results indicate that CU can detect BAT in mice and estimate BAT blood flow in mice with functional differences in BAT.

Background: Non-diagnostic dobutamine stress echocardiography (ndDSE, failure to achieve 85% of maximal predicted heart rate (HR) without evidence of inducible ischemia) is an important limitation affecting quality of DSE testing. The objectives of this study were to identify the clinical variables associated with a non-diagnostic Dobutamine Stress Echocardiogram (ndDSE) and further evaluate the patterns of subsequent testing for myocardial ischemia. Methods: Consecutive DSE’s over a 17 month period (January 2008 to June 2009) were studied. Baseline demographics, medical history, and vital signs were collected. Subsequent testing was determined for up to 6 months after the initial DSE. Univariate and multivariate logistic regression analysis was performed to identify clinical factors associated with ndDSE. Results: Of 467 total DSE, 314 (67%) were negative for ischemia, 69 (15%) were positive, and 84 (18%) were ndDSE. Of those recommended for further nuclear MPI testing 12 (14%) had an ndDSE compared to 16 (4%) patients with a diagnostic DSE (P = 0.001). Fifty percent of the ndDSE nuclear MPI tests were positive for ischemia. In the univariate analysis, Diabetes Mellitus (DM; P = 0.003), calcium channel antagonist (CCA) use (P = 0.047), Hypertension (HTN; P = 0.06), low baseline HR (P < 0.001), and younger age group (P = 0.02) were predictive of ndDSE. Of these, all except CCA use remained independent predictors of ndDSE in multivariate analysis. A 4 variable model for predicting ndDSE was developed from the multivariate logistic regression displayed in Table 1 (age and baseline HR were categorized and scored 0-2; DM and HTN were scored as 0 (absent) or 1 (present)). Figure 2 demonstrates how risk of ndDSE correlated with a higher score, with each increment having an odds ratio of 2.1 (P < 0.001). Conclusions: DM, HTN, younger age, and lower baseline HR affect the quality of DSE testing, resulting in non-diagnostic tests. A model combining these factors can identify patients most likely to have this outcome. Identification of this cohort may improve referral patterns and improve the quality of stress testing.

BACKGROUND: Biomarkers may play an important role in identifying patients at risk for cancer therapy cardiotoxicity. Our objectives were to define the patterns of change in biomarkers with cancer therapy and their associations with cardiotoxicity. METHODS: In a multicenter cohort of 78 breast cancer patients undergoing doxorubicin and trastuzumab therapy, 8 biomarkers were evaluated at baseline and every 3 months over a maximum follow-up of 15 months. These biomarkers, hypothesized to be mechanistically relevant to cardiotoxicity, included high-sensitivity cardiac troponin I (hs-cTnI), high-sensitivity C-reactive protein (hsCRP), N-terminal pro–B-type natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor-1 (sFlt-1), and galectin 3 (gal-3). We determined if biomarker increases were associated with cardiotoxicity at the same visit and the subsequent visit over the entire course of therapy. Cardiotoxicity was defined by the Cardiac Review and Evaluation Criteria; alternative definitions were also considered. RESULTS: Across the entire cohort, all biomarkers except NT-proBNP and gal-3 demonstrated increases by 3 months; these increases persisted for GDF-15, PlGF, and hs-cTnI at 15 months. Increases in MPO, PlGF, and GDF-15 were associated with cardiotoxicity at the same visit [MPO hazard ratio 1.38 (95% CI 1.10–1.71), P = 0.02; PlGF 3.78 (1.30–11.0), P = 0.047; GDF-15 1.71 (1.15–2.55), P = 0.01] and the subsequent visit. MPO was robust to alternative outcome definitions. CONCLUSIONS: Increases in MPO are associated with cardiotoxicity over the entire course of doxorubicin and trastuzumab therapy. Assessment with PlGF and GDF-15 may also be of value. These findings motivate validation studies in additional cohorts.

Background: Although illicit anabolic-androgenic steroid (AAS) use is widespread, the cardiac effects of long-term AAS use remain inadequately characterized. We compared cardiac parameters in weightlifters reporting long-term AAS use to those in otherwise similar weightlifters without prior AAS exposure. Methods & Results: We performed 2-dimensional, tissue-Doppler, and speckle-tracking echocardiography to assess left ventricular (LV) ejection fraction, LV systolic strain, and conventional indices of diastolic function in long-term AAS users (n=12) and otherwise similar AAS non-users (n=7). AAS users (median [Q1,Q3] cumulative lifetime AAS exposure 468 [169–520] weeks) closely resembled non-users in age, prior duration of weightlifting, and current intensity of weight training. LV structural parameters were similar between the two groups. However, AAS users had significantly lower LV ejection fraction (50.6% [48.4, 53.6] versus 59.1% [58.0, 61.7]; p = 0.003 by Wilcoxon rank sum test, two-tailed); longitudinal strain (16.9% [14.0, 19.0] versus 21.0% [20.2, 22.9]; p = 0.004), and radial strain (38.3 [28.5, 43.7] versus 50.1 [44.3, 61.8]; p = 0.02). Ten of the 12 AAS users showed LV ejection fractions below the accepted limit of normal (≥55%). AAS users also demonstrated decreased diastolic function compared to non-users, as evidenced by a markedly lower E′ velocity (7.4 [6.8, 7.9] versus 9.9 [8.3, 10.5]; p = 0.005) and E/A ratio (0.93 [0.88, 1.39] versus 1.80 [1.48, 2.00]; p = 0.003). Conclusions: Cardiac dysfunction in long-term AAS users appears more severe than previously reported, and may be sufficient to increase the risk of heart failure.

There is a preponderance of evidence that, in the setting of an acute coronary syndrome, an invasive approach using coronary revascularization has a morbidity and mortality benefit. However, recent stable ischemic heart disease (SIHD) randomized clinical trials testing whether the addition of coronary revascularization to guideline-directed medical therapy (GDMT) reduces death or major cardiovascular events have been negative. Based on the evidence from these trials, the primary role of GDMT as a front line medical management approach has been clearly defined in the recent SIHD clinical practice guideline; the role of prompt revascularization is less precisely defined. Based on data from observational studies, it has been hypothesized that there is a level of ischemia above which a revascularization strategy might result in benefit regarding cardiovascular events. However, eligibility for recent negative trials in SIHD has mandated at most minimal standards for ischemia. An ongoing randomized trial evaluating the effectiveness of randomization of patients to coronary angiography and revascularization as compared to no coronary angiography and GDMT in patients with moderate-severe ischemia will formally test this hypothesis. The current review will highlight the available evidence including a review of the published and ongoing SIHD trials.

Objectives: The aim of this study was to determine if individual or multiple biomarkers are associated with cardiotoxicity in patients with breast cancer undergoing cancer therapy. Background: Current methods to identify patients at risk for cardiotoxicity from cancer therapy are inadequate. Methods: We measured 8 biomarkers in a multicenter cohort of 78 patients with breast cancer undergoing doxorubicin and trastuzumab therapy: ultrasensitive troponin I (TnI), high-sensitivity C-reactive protein (CRP), N-terminal pro–B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, myeloperoxidase (MPO), placental growth factor (PlGF), soluble fms-like tyrosine kinase receptor (sFlt)-1, and galectin (gal)-3. Cardiotoxicity, defined by the Cardiac Review and Evaluation Committee criteria, was assessed every 3 months for up to 15 months. Hazard ratios (HRs) of cardiotoxicity risk were assessed for each biomarker at baseline, at visit 2 (3 months), and as a function of the difference between visit 2 and baseline. Joint models were assessed for the most promising biomarkers. Results: TnI, CRP, GDF-15, MPO, PlGF, and sFlt-1 levels increased from baseline to visit 2 (p < 0.05). A greater risk of cardiotoxicity was associated with interval changes in TnI (HR: 1.38 per SD; 95% confidence interval: 1.05 to 1.81; p = 0.02) and MPO (HR: 1.34 per SD; 95% confidence interval: 1.00 to 1.80; p = 0.048) and in models combining both markers (p = 0.007 and p = 0.03, respectively). The risk of cardiotoxicity was 46.5% in patients with the largest changes in both markers (ΔTnI >121.8 μg/l; ΔMPO >422.6 pmol/l). Conclusions: Early increases in TnI and MPO levels offer additive information about the risk of cardiotoxicity in patients undergoing doxorubicin and trastuzumab therapy. Independent validation of these findings is necessary before application to clinical practice.

Patients with diabetes and heart failure (HF) have worse clinical outcomes compared to patients with HF without diabetes after cardiac resynchronization therapy (CRT). Patients with HF and diabetes represent a growing population at high risk for cardiovascular events and are increasingly treated with CRT. Although patients with diabetes and HF appear to benefit from CRT, their clinical outcomes are worse than those of patients without diabetes after CRT. The aim of this study was to identify clinical predictors that explain the differential hazard in patients with diabetes. We studied 442 patients (169 with diabetes) with systolic HF referred to the Massachusetts General Hospital CRT clinic from 2003 to 2010 to identify predictors of outcomes after CRT in patients with HF and diabetes. Patients with diabetes were more likely to have ischemic causes of HF than those without diabetes, but there was no difference in the left ventricular ejection fraction or HF classification at implantation. Patients with diabetes had poorer event-free survival (death or HF hospitalization) compared to those without diabetes (log-rank p = 0.04). The presence of diabetes was the most important independent predictor of differential outcomes in the entire population (hazard ratio 1.65, 95% confidence interval 1.10 to 2.51). Patients with diabetes receiving insulin therapy had poorer survival, whereas those not receiving insulin therapy had similar survival to patients without diabetes. Patients with peri-implantation glycosylated hemoglobin >7% had worse outcomes, whereas patients with glycosylated hemoglobin ≤7% had improved survival (hazard ratio 0.36, 95% confidence interval 0.15 to 0.86) equivalent to that of patients without diabetes. In conclusion, although the presence of diabetes, independent of other variables, increases the hazard of worse outcomes after CRT, there is additional risk conferred by insulin use and suboptimal peri-implantation glycemic control.