Person: Picard, Michael
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Picard
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Michael
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Picard, Michael
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Publication Characteristics of Responders to Cardiac Resynchronization Therapy: The Impact of Echocardiographic Left Ventricular Volume(Wiley-Blackwell, 2012) Park, Mi Young; Altman, Robert K.; Orencole, Mary; Kumar, Prabhat; Parks, Kimberly; Heist, Kevin E.; Singh, Jagmeet; Picard, MichaelBackground: 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.Publication Assessment of Echocardiography and Biomarkers for the Extended Prediction of Cardiotoxicity in Patients Treated With Anthracyclines, Taxanes, and Trastuzumab(Ovid Technologies (Wolters Kluwer Health), 2012) Sawaya, H.; Sebag, I. A.; Plana, J. C.; Januzzi, James; Ky, B.; Tan, T. C.; Cohen, V.; Banchs, J.; Carver, J. R.; Wiegers, S. E.; Martin, R. P.; Picard, Michael; Gerszten, Robert; Halpern, Elkan F.; Passeri, Jonathan; Kuter, Irene; Scherrer-Crosbie, MarielleBackground: 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.Publication Validation of Noninvasive Measurements of Cardiac Output in Mice Using Echocardiography(Elsevier BV, 2011) Tournoux, François; Petersen, Bodil; Thibault, Hélène; Zou, Lin; Raher, Michael J.; Kurtz, Baptiste; Halpern, Elkan F.; Chaput, Miguel; Chao, Wei; Picard, Michael; Scherrer-Crosbie, MarielleAlthough 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.Publication Regulation of cardiac hypertrophy in vivo by the stress-activated protein kinases/c-Jun NH2-terminal kinases(American Society for Clinical Investigation, 1999) Choukroun, Gabriel; Hajjar, Roger; Fry, Stefanie; Del Monte, Federica; Haq, Syed; Guerrero, J. Luis; Picard, Michael; Rosenzweig, Anthony; Force, ThomasCardiac hypertrophy often presages the development of heart failure. Numerous cytosolic signaling pathways have been implicated in the hypertrophic response in cardiomyocytes in culture, but their roles in the hypertrophic response to physiologically relevant stimuli in vivo is unclear. We previously reported that adenovirus-mediated gene transfer of SEK-1(KR), a dominant inhibitory mutant of the immediate upstream activator of the stress-activated protein kinases (SAPKs), abrogates the hypertrophic response of neonatal rat cardiomyocytes to endothelin-1 in culture. We now report that gene transfer of SEK-1(KR) to the adult rat heart blocks SAPK activation by pressure overload, demonstrating that the activity of cytosolic signaling pathways can be inhibited by gene transfer of loss-of-function mutants in vivo. Furthermore, gene transfer of SEK-1(KR) inhibited pressure overload–induced cardiac hypertrophy, as determined by echocardiography and several postmortem measures including left ventricular (LV) wall thickness, the ratio of LV weight to body weight, cardiomyocyte diameter, and inhibition of atrial natriuretic factor expression. Our data suggest that the SAPKs are critical regulators of cardiac hypertrophy in vivo, and therefore may serve as novel drug targets in the treatment of hypertrophy and heart failure.Publication Phenotypic Spectrum Caused by Transgenic Overexpression of Activated Akt in the Heart(American Society for Biochemistry & Molecular Biology (ASBMB), 2002) Matsui, Takashi; Li, Ling; Wu, Justina; Cook, Stuart; Nagoshi, Tomohisa; Picard, Michael; Liao, Ronglih; Rosenzweig, AnthonyThe serine-threonine kinase, Akt, inhibits cardiomyocyte apoptosis acutely both in vitro and in vivo. However, the effects of chronic Akt activation in the heart are unknown. To address this issue, we generated transgenic mice (TG ) with cardiac-specific expression of a constitutively active mutant of Akt (myr-Akt) driven by the myosin heavy chain- promoter. Three TG founders (9–19 weeks) died suddenly with massive cardiac dilatation. Two viable TG lines (TG564 and TG20) derived from independent founders demonstrated cardiac-specific transgene expression as well as activation of Akt and p70S6 kinase. TG564 (n 19) showed cardiac hypertrophy with a heart/body weight ratio 2.3-fold greater than littermates (n 17, p < 0.005). TG20 (n 18) had less marked cardiac hypertrophy with a heart/body weight ratio 1.6-fold greater than littermates (n 17, p < 0.005). Isolated TG564 myocytes were also hypertrophic with surface areas 1.7-fold greater than littermates (p < 0.000001). Echocardiograms in both lines demonstrated concentric hypertrophy and preserved systolic function. After ischemia-reperfusion, TG had a 50% reduction in infarct size versus TG (17 3% versus 34 4%, p < 0.001). Thus, chronic Akt activation is sufficient to cause a spectrum of phenotypes from moderate cardiac hypertrophy with preserved systolic function and cardioprotection to massive cardiac dilatation and sudden death.Publication Heart of Darkness: The Downside of Trastuzumab(American Society of Clinical Oncology (ASCO), 2006) Hayes, D. F.; Picard, MichaelTrastuzumab has been shown to be quite effective in reducing suffering and mortality from breast cancer in both the metastatic and adjuvant settings. With short follow-up, remarkably consistent results across five adjuvant, prospective, randomized clinical trials suggest that trastuzumab may decrease the odds of distant recurrence and mortality by approximately one half and one third, respectively. Dr George Sledge, who discussed the first presentations of the adjuvant trials at the 2005 Annual Meeting of the American Society of Clinical Oncology, proclaimed these results “astonishing,” and we agree (oral communication, May 2005).Publication In Vivo Noninvasive Characterization of Brown Adipose Tissue Blood Flow by Contrast Ultrasound in Mice(Ovid Technologies (Wolters Kluwer Health), 2012) Baron, David M.; Clerte, Maeva; Brouckaert, Peter; Raher, Michael J.; Flynn, Aidan W.; Zhang, Haihua; Carter, Edward; Picard, Michael; Bloch, Kenneth; Buys, Emmanuel; Scherrer-Crosbie, MarielleBackground—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.Publication Mutant Mouse Models Reveal the Relative Roles of E2F1 and E2F3 In Vivo(American Society for Microbiology, 2002) Cloud, J. E.; Rogers, Catherine; Reza, Tammi; Ziebold, U.; Stone, James; Picard, Michael; Caron, A. M.; Bronson, Roderick; Lees, J. A.The E2F1, -2, and -3 transcription factors are key downstream targets of the retinoblastoma protein (pRB) tumor suppressor that drive expression of proliferation-associated genes. Here we use mutant mouse strains to investigate E2F3's role in vivo. We show that E2F3 is essential for embryonic viability in the pure 129/Sv background but the presence of C57BL/6 alleles yields some adult survivors. Although growth retarded, surviving E2f3−/− animals are initially healthy. However, they die prematurely, exhibiting no obvious tumor phenotype but with the typical signs of congestive heart failure. The defects are completely distinct from those arising in E2f1 mutant mice (S. J. Field et al., Cell 85:549-561; 1996; L. Yamasaki et al., Cell 85:537-548, 1996), supporting the prevailing view that these E2Fs must have some unique biological functions in vivo. To test this model, we examined the phenotypes of E2f1 E2f3 compound mutant mice. Almost all of the developmental and age-related defects arising in the individual E2f1 or E2f3 mice were exacerbated by the mutation of the other E2f. Thus, E2F1 and E2F3 appear to play critical, overlapping roles in the development and maintenance of a variety of tissues. Importantly, this study did identify one major difference in the properties of E2F1 and E2F3: either alone or in combination with E2F1 loss, E2f3 mutation did not increase the incidence of tumor formation. These data strongly suggest that tumor suppression is a specific property of E2F1 and not E2F3.Publication Brown Adipose Tissue Blood Flow and Mass in Obesity: A Contrast Ultrasound Study in Mice(Elsevier BV, 2013) Clerte, Maëva; Baron, David; Brouckaert, Peter; Ernande, Laura; Raher, Michael J.; Flynn, Aidan W.; Picard, Michael; Bloch, Kenneth; Buys, Emmanuel; Scherrer-Crosbie, MarielleBackground: When activated by the sympathetic nervous system, brown adipose tissue (BAT) increases energy expenditure to produce heat. Augmenting BAT mass or increasing BAT activation could potentially be used to decrease obesity. Noninvasive methods to detect and monitor BAT mass are needed. Contrast ultrasound can estimate BAT blood flow and is able to measure the perfused volume of an organ and thus its mass. The objective of this study was to evaluate whether contrast ultrasound could characterize BAT mass in two mouse models of obesity: wild-type mice fed a high-fat diet and mutant db/db mice. Methods: Contrast ultrasound of BAT (Definity 2 μL/min; 14-MHz linear probe) was performed before and after stimulation of BAT with norepinephrine (NE). BAT replenishment curves were obtained, and blood flow was estimated by the product of the curve’s plateau and slope. Additionally, consecutive two-dimensional images of perfused BAT were acquired at 1-mm intervals after stimulation with NE and used to assess BAT volume and mass. Results: BAT blood flow increased after NE infusion in all mice studied. Blood flow response to NE was similar in wild-type mice fed either a low-fat diet or a high-fat diet. BAT blood flow was lower in db/db mice than in wild-type mice (P = .02). Contrast ultrasound–derived BAT mass was correlated with BAT mass obtained at necropsy (R2 = 0.83, P < .001). BAT mass was higher in mice fed a high-fat diet than in those fed a low-fat diet. Conclusions: Contrast ultrasound can be used to estimate BAT mass in mice when BAT vascularization is not significantly impaired. This noninvasive technique may potentially allow the serial evaluation of therapies designed to augment BAT mass.Publication Early Detection and Prediction of Cardiotoxicity in Chemotherapy-Treated Patients(Elsevier BV, 2011) Sawaya, Heloisa; Sebag, Igal A.; Plana, Juan Carlos; Januzzi, James; Ky, Bonnie; Cohen, Victor; Gosavi, Sucheta; Carver, Joseph R.; Wiegers, Susan E.; Martin, Randolph P.; Picard, Michael; Gerszten, Robert; Halpern, Elkan F.; Passeri, Jonathan; Kuter, Irene; Scherrer-Crosbie, MarielleAs breast cancer survival increases, cardiotoxicity associated with chemotherapeutic regimens such as anthracyclines and trastuzumab becomes a more significant issue. Assessment of the left ventricular (LV) ejection fraction fails to detect subtle alterations in LV function. The objective of this study was to evaluate whether more sensitive echocardiographic measurements and biomarkers could predict future cardiac dysfunction in chemotherapy-treated patients. Forty-three patients diagnosed with breast cancer who received anthracyclines and trastuzumab therapy underwent echocardiography and blood sampling at 3 time points (baseline and 3 and 6 months during the course of chemotherapy). The LV ejection fraction; peak systolic myocardial longitudinal, radial, and circumferential strain; echocardiographic markers of diastolic function; N-terminal pro–B-type natriuretic peptide; and high-sensitivity cardiac troponin I were measured. Nine patients (21%) developed cardiotoxicity (1 at 3 months and 8 at 6 months) as defined by the Cardiac Review and Evaluation Committee reviewing trastuzumab. A decrease in longitudinal strain from baseline to 3 months and detectable high-sensitivity cardiac troponin I at 3 months were independent predictors of the development of cardiotoxicity at 6 months. The LV ejection fraction, parameters of diastolic function, and N-terminal pro–B-type natriuretic peptide did not predict cardiotoxicity. In conclusion, cardiac troponin plasma concentrations and longitudinal strain predict the development of cardiotoxicity in patients treated with anthracyclines and trastuzumab. The 2 parameters may be useful to detect chemotherapy-treated patients who may benefit from alternative therapies, potentially decreasing the incidence of cardiotoxicity and its associated morbidity and mortality.