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Donor and Recipient Size Matching in Heart Transplantation with Predicted Heart and Lean Body Mass. Seminars in thoracic and cardiovascular surgery Miller, R. J., Hedman, K., Amsallem, M., Tulu, Z., Kent, W., Fatehi, A., Clarke, B., Heidenreich, P., Hiesinger, W., Khush, K. K., Teuteberg, J., Haddad, F. 2021
Abstract

Donor and recipient size matching during heart transplant can be assessed using weight or predicted heart mass (PHM) ratios. We developed sex-specific allomteric equations for PHM and predicted lean body mass (PLBM) using the United Kingdom Biobank (UKB) and evaluated their predictive value in the United Network of Organ Sharing (UNOS) database. Donor and recipient size matching was based on weight, PHM and PLBM ratios. PHM was calculated using the Multi-ethnic Study of Atherosclerosis and UKB equations. PLBM was calculated using the UKB and National Health and Nutrition Examination Survey (NHANES) equations. Relative prognostic utility was compared using multivariable Cox analysis, adjusted for predictors of one-year survival in the Scientific Registry of Transplant Recipients (SRTR) model. Of 53,648 adult patients in the UNOS database between 1996 and 2016, 6528 (12.2%) died within the first year. In multivariable analysis, undersized matches by any metric were associated with increased one-year mortality (all p<0.01). Oversized matches were at increased risk using PHM or PLBM (all p<0.01), but not weight ratio. There were significant differences in classification of size matching by weight or PHM in sex-mismatched donor-recipient pairs. A significant interaction was observed between pulmonary hypertension and donor undersizing (hazard ratio 1.15, p=0.026) suggesting increased risk of undersizing in pulmonary hypertension. Donor and recipient size matching with simplified PHM and PLBM offered an advantage over total body weight and may be more important for sex-mismatched donor-recipient pairs. Donor undersizing is associated with worse outcomes in patients with pulmonary hypertension.

View details for DOI 10.1053/j.semtcvs.2021.01.001

View details for PubMedID 33444763
Assessment of right ventricular function following left ventricular assist device (LVAD) implantation-The role of speckle-tracking echocardiography: A meta-analysis. Echocardiography (Mount Kisco, N.Y.) Barssoum, K., Altibi, A. M., Rai, D., Kharsa, A., Kumar, A., Chowdhury, M., Elkaryoni, A., Abuzaid, A. S., Baibhav, B., Parikh, V., Masri, A., Amsallem, M., Nanda, N. C. 2020
Abstract

BACKGROUND: Right ventricular failure (RVF) following left ventricular assist device (LVAD) implantation is associated with worse outcomes. Prediction of RVF is difficult with routine transthoracic echocardiography (TTE), while speckle-tracking echocardiography (STE) showed promising results. We performed systematic review and meta-analysis of published literature.METHODS: We queried multiple databases to compile articles reporting preoperative or intraoperative right ventricle global longitudinal strain (RVGLS) or right ventricle free wall strain (RVFWS) in LVAD recipients. The standard mean difference (SMD) in RVGLS and RVFWS in patients with and without RVF postoperatively was pooled using random-effects model.RESULTS: Seventeen studies were included. Patients with RVF had significantly lower RVGLS and RVFWS as compared to non-RVF patients; SMD: 2.79 (95% CI: -4.07 to -1.50; P: <.001) and -3.05 (95% CI: -4.11 to -1.99; P: <.001), respectively. The pooled odds ratio (OR) for RVF per percentage increase of RVGLS and RVFWS were 1.10 (95 CI: 0.98-1.25) and 1.63 (95% CI 1.07-2.47), respectively. In a subgroup analysis, TTE-derived GLS and FWS were significantly lower in RVF patients as compared to non-RVF patients; SMD of -3.97 (95% CI: -5.40 to -2.54; P: <.001) and -3.05 (95% CI: -4.11 to -1.99; P: <.001), respectively. There was no significant difference between RVF and non-RVF groups in TEE-derived RVGLS and RVFWS.CONCLUSION: RVGLS and RVFWS were lower in patients who developed RVF as compared to non-RVF patients. In a subgroup analysis, TTE-derived RVGLS and RVFWS were reduced in RVF patients as compared to non-RVF patients. This difference was not reported with TEE.

View details for DOI 10.1111/echo.14884

View details for PubMedID 33084128
Speckle tracking echocardiography can predict subclinical myocardial involvement in patients with sarcoidosis: A meta-analysis. Echocardiography (Mount Kisco, N.Y.) Barssoum, K., Altibi, A. M., Rai, D., Kumar, A., Kharsa, A., Chowdhury, M., Thakkar, S., Shahid, S., Abdelazeem, M., Abuzaid, A. S., Baibhav, B., Parikh, V., Feitell, S. C., Balmer-Swain, M., Rao, M., Amsallem, M., Nanda, N. C. 2020
Abstract

BACKGROUND: This meta-analysis aims to evaluate the utility of speckle tracking echocardiography (STE) as a tool to evaluate for cardiac sarcoidosis (CS) early in its course. Electrocardiography and echocardiography have limited sensitivity in this role, while advanced imaging modalities such as cardiac magnetic resonance (CMR) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) are limited by cost and availability.METHODS: We compiled English language articles that reported left ventricular global longitudinal strain (LVGLS) or global circumferential strain (GCS) in patients with confirmed extra-cardiac sarcoidosis versus healthy controls. Studies that exclusively included patients with probable or definite CS were excluded. Continuous data were pooled as a standard mean difference (SMD), comparing sarcoidosis group with healthy controls. A random-effect model was adopted in all analyses. Heterogeneity was assessed using Q and I2 statistics.RESULTS: Nine studies were included in our final analysis with an aggregate of 967 patients. LVGLS was significantly lower in the extra-cardiac sarcoidosis group as compared with controls, SMD -3.98, 95% confidence interval (CI): -5.32, -2.64, P<.001, also was significantly lower in patients who suffered major cardiac events (MCE), -3.89, 95% CI -6.14, -1.64, P<.001. GCS was significantly lower in the extra-cardiac sarcoidosis group as compared with controls, SMD: -3.33, 95% CI -4.71, -1.95, P<.001.CONCLUSION: LVGLS and GCS were significantly lower in extra-cardiac sarcoidosis patients despite not exhibiting any cardiac symptoms. LVGLS correlates with MCEs in CS. Further studies are required to investigate the role of STE in the early screening of CS.

View details for DOI 10.1111/echo.14886

View details for PubMedID 33058271
VO2/WR Slope And HR/VO2 Slope Predict Major Adverse Events In Patients With Severe Heart Failure Mueller, S., Christle, J. W., Moneghetti, K. J., Amsallem, M., Halle, M., Haddad, F., Myers, J. LIPPINCOTT WILLIAMS & WILKINS. 2020: 168
View details for Web of Science ID 000590026300477
Quantifying the Influence of Wedge Pressure, Age, and Heart Rate on the Systolic Thresholds for Detection of Pulmonary Hypertension. Journal of the American Heart Association Amsallem, M., Tedford, R. J., Denault, A., Sweatt, A. J., Guihaire, J., Hedman, K., Peighambari, S., Kim, J. B., Li, X., Miller, R. J., Mercier, O., Fadel, E., Zamanian, R., Haddad, F. 2020: e016265
Abstract

Background The strong linear relation between mean (MPAP) and systolic (SPAP) pulmonary arterial pressure (eg, SPAP=1.62*MPAP) has been mainly reported in precapillary pulmonary hypertension. This study sought to quantify the influence of pulmonary arterial wedge pressure (PAWP), heart rate, and age on the MPAP-SPAP relation. Methods and Results An allometric equation relating invasive MPAP and SPAP was developed in 1135 patients with pulmonary arterial hypertension, advanced lung disease, chronic thromboembolic pulmonary hypertension, or left heart failure. The equation was validated in 60885 patients from the United Network for Organ Sharing (UNOS) database referred for heart and/or lung transplant. The MPAP/SPAP longitudinal stability was assessed in pulmonary arterial hypertension with repeated right heart catheterization. The equation obtained was SPAP=1.39*MPAP*PAWP-0.07*(60/heart rate)0.12*age0.08 (P<0.001). It was validated in the UNOS cohort (R2=0.93, P<0.001), regardless of the type of organ(s) patients were listed for (mean bias [-1.96SD; 1.96SD] was 0.94 [-8.00; 9.88] for heart, 1.34 [-7.81; 10.49] for lung and 0.25 [-16.74; 17.24] mmHg for heart-lung recipients). Thresholds of SPAP for MPAP=25 and 20mmHg were lower in patients with higher PAWP (37.2 and 29.8mmHg) than in those with pulmonary arterial hypertension (40.1 and 32.0mmHg). In 186 patients with pulmonary arterial hypertension, the predicted MPAP/SPAP was stable over time (0.63�0.03 at baseline and follow-up catheterization, P=0.43). Conclusions This study quantifies the impact of PAWP, and to a lesser extent heart rate and age, on the MPAP-SPAP relation, supporting lower SPAP thresholds for pulmonary hypertension diagnosis in patients with higher PAWP for echocardiography-based epidemiological studies.

View details for DOI 10.1161/JAHA.119.016265

View details for PubMedID 32419583
PROGNOSTIC VALUE OF THE RELATIVE PULMONARY PRESSURE RATIO AND ITS TRAJECTORY IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION Bagherzadeh, S. P., Amsallem, M., Denault, A., Sweatt, A., Kudelko, K., Sung, Y., Haddad, F., Zamanian, R. ELSEVIER SCIENCE INC. 2020: 2096
View details for Web of Science ID 000522979102081
Physiology of the Assisted Circulation in Cardiogenic Shock: A State-of-the-Art Perspective. The Canadian journal of cardiology Guihaire, J., Haddad, F., Hoppenfeld, M., Amsallem, M., Christle, J. W., Owyang, C., Shaikh, K., Hsu, J. L. 2020; 36 (2): 170?83
Abstract

Mechanical circulatory support (MCS) has made rapid progress over the last 3 decades. This was driven by the need to develop acute and chronic circulatory support as well as by the limited organ availability for heart transplantation. The growth of MCS was also driven by the use of extracorporeal membrane oxygenation (ECMO) after the worldwide H1N1 influenza outbreak of 2009. The majority of mechanical pumps (ECMO and left ventricular assist devices) are currently based on continuous flow pump design. It is interesting to note that in the current era, we have reverted from the mammalian pulsatile heart back to the continuous flow pumps seen in our simple multicellular ancestors. This review will highlight key physiological concepts of the assisted circulation from its effects on cardiac dynamic to principles of cardiopulmonary fitness. We will also examine the physiological principles of the ECMO-assisted circulation, anticoagulation, and the haemocompatibility challenges that arise when the blood is exposed to a foreign mechanical circuit. Finally, we conclude with a perspective on smart design for future development of devices used for MCS.

View details for DOI 10.1016/j.cjca.2019.11.002

View details for PubMedID 32036862
Cardiogenic Shock: Reflections at the Crossroad Between Perfusion, Tissue Hypoxia, and Mitochondrial Function. The Canadian journal of cardiology O'Brien, C., Beaubien-Souligny, W., Amsallem, M., Denault, A., Haddad, F. 2020; 36 (2): 184?96
Abstract

Cardiogenic shock is classically defined by systemic hypotension with evidence of hypoperfusion and end organ dysfunction. In modern practice, however, these metrics often incompletely describe cardiogenic shock because patients present with more advanced cardiovascular disease and greater degrees of multiorgan dysfunction. Understanding how perfusion, congestion, and end organ dysfunction contribute to hypoxia at the cellular level are central to the diagnosis and management of cardiogenic shock. Although, in clinical practice, increased lactate level is often equated with hypoxia, several other factors might contribute to an elevated lactate level including mitochondrial dysfunction, impaired hepatic and renal clearance, as well as epinephrine use. To this end, we present the evidence underlying the value of lactate to pyruvate ratio as a potential discriminator of cellular hypoxia. We will then discuss the physiological implications of hypoxia and congestion on hepatic, intestinal, and renal physiology. Organ-specific susceptibility to hypoxia is presented in the context of their functional architecture. We discuss how the concepts of contractile reserve, fluid responsiveness, tissue oxygenation, and cardiopulmonary interactions can help personalize the management of cardiogenic shock. Finally, we highlight the limitations of using lactate for tailoring therapy in cardiogenic shock.

View details for DOI 10.1016/j.cjca.2019.11.020

View details for PubMedID 32036863
Preliminary Experience Using Diastolic Right Ventricular Pressure Gradient Monitoring in Cardiac Surgery. Journal of cardiothoracic and vascular anesthesia Gronlykke, L., Couture, E. J., Haddad, F., Amsallem, M., Ravn, H. B., Raymond, M., Beaubien-Souligny, W., Demers, P., Rochon, A., Sarabi, M. E., Lamarche, Y., Desjardins, G., Denault, A. Y. 2020
Abstract

OBJECTIVES: Right ventricular (RV) dysfunction in cardiac surgery is associated with increased mortality and morbidity and difficult separation from cardiopulmonary bypass (DSB). The primary objective of the present study was to describe the prevalence and characteristics of patients with abnormal RV diastolic pressure gradient (PG). The secondary objective was to explore the association among abnormal diastolic PG and DSB, postoperative complications, high central venous pressure (CVP), and high RV end-diastolic pressure (RVEDP).DESIGN: Retrospective and prospective validation study.SETTING: Tertiary care cardiac institute.PARTICIPANTS: Cardiac surgical patients (n=374) from a retrospective analysis (n=259) and a prospective validation group (n=115).INTERVENTION: RV pressure waveforms were obtained using a pulmonary artery catheter with a pacing port opened at 19 cm distal to the tip of the catheter. Abnormal RV diastolic PG was defined as >4 mmHg. Both elevated RVEDP and high CVP were defined as >16 mmHg.MEASUREMENTS AND MAIN RESULTS: From the retrospective and validation cohorts, 42.5% and 48% of the patients had abnormal RV diastolic PG before cardiac surgery, respectively. Abnormal RV diastolic PG before cardiac surgery was associated with higher EuroSCORE II (odds ratio 2.29 [1.10-4.80] v 1.62 [1.10-3.04]; p?=?0.041), abnormal hepatic venous flow (45% v 29%; p?=?0.038), higher body mass index (28.9 [25.5-32.5] v 27.0 [24.9-30.5]; p?=?0.022), pulmonary hypertension (48% v 37%; p?=?0.005), and more frequent DSB (32% v 19%; p?=?0.023). However, RV diastolic PG was not an independent predictor of DSB, whereas RVEDP (odds ratio 1.67 [1.09-2.55]; p?=?0.018) was independently associated with DSB. In addition, RV pressure monitoring indices were superior to CVP in predicting DSB.CONCLUSION: Abnormal RV diastolic PG is common before cardiac surgery and is associated with a higher proportion of known preoperative risk factors. However, an abnormal RV diastolic PG gradient is not an independent predictor of DSB in contrast to RVEDP.

View details for DOI 10.1053/j.jvca.2019.12.042

View details for PubMedID 32037274
Preoperative C-reactive protein predicts early postoperative outcomes after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension. The Journal of thoracic and cardiovascular surgery Arthur Ataam, J., Amsallem, M., Guihaire, J., Haddad, F., Lamrani, L., Stephan, F., Jais, X., Humbert, M., Mercier, O., Fadel, E. 2020
Abstract

OBJECTIVE: To determine whether preoperative systemic inflammation (defined by C-reactive protein [CRP] levels ?10mg/L) is associated with worse functional and hemodynamic status and poor early outcomes postendarterectomy in patients with chronic thromboembolic pulmonary hypertension (CTEPH).METHODS: This study included 159 patients who underwent pulmonary endarterectomy from 2009 to 2013 (derivation cohort) and 238 patients from 2015 to 2016 (validation cohort) with CRP data from the national CTEPH registry. The correlations between proinflammatory markers (CRP, interleukins 1 and 6, fibrinogen, and leukocytes) and hemodynamics were assessed in the derivation cohort. Pre-, perioperative characteristics, and 30-day outcomes (ie, death or lung transplant or extracorporeal membrane oxygenation need or inotropic or vasopressor need ?3days) of patients with CRP levels?or <10mg/L were compared.RESULTS: Median age of the derivation cohort was 63 [52-73] years with 48% female, 80% in New York Heart Association class III/IV. The validation cohort had similar demographics and disease severity. Patients with CRP ?10mg/L had greater resistance levels and lower cardiac index than those with CRP <10mg/L in both cohorts. The primary endpoint was reached in 38% (derivation) and 42% (validation) of patients. In multivariable logistic regression analysis, CRP ?10mg/L was associated with the primary endpoint in both the derivation cohort (odd ratio, 2.49 [1.11-5.61], independently of New York Heart class class IV and aortic clamping duration) and the validation cohort (odd ratio, 1.89 [1.09-3.61], independently of age and aortic clamping duration).CONCLUSIONS: Preoperative CRP ?10mg/L is independently associated with adverse early outcomes postendarterectomy.

View details for DOI 10.1016/j.jtcvs.2019.11.133

View details for PubMedID 32007254
Circulating whole genome miRNA expression corresponds to progressive right ventricle enlargement and systolic dysfunction in adults with tetralogy of Fallot. PloS one Weldy, C. S., Syed, S. A., Amsallem, M., Hu, D., Ji, X., Punn, R., Taylor, A., Navarre, B., Reddy, S. 2020; 15 (11): e0241476
Abstract

INTRODUCTION: The adult congenital heart disease population with repaired tetralogy of Fallot (TOF) is subject to chronic volume and pressure loading leading to a 40% probability of right ventricular (RV) failure by the 3rd decade of life. We sought to identify a non-invasive signature of adverse RV remodeling using peripheral blood microRNA (miRNA) profiling to better understand the mechanisms of RV failure.METHODS: Demographic, clinical data, and blood samples were collected from adults with repaired TOF (N = 20). RNA was isolated from the buffy coat of peripheral blood and whole genome miRNA expression was profiled using Agilent's global miRNA microarray platform. Fold change, pathway analysis, and unbiased hierarchical clustering of miRNA expression was performed and correlated to RV size and function assessed by echocardiography performed at or near the time of blood collection.RESULTS: MiRNA expression was profiled in the following groups: 1. normal RV size (N = 4), 2. mild/moderate RV enlargement (N = 11) and 3. severe RV enlargement (N = 5). 267 miRNAs were downregulated, and 66 were upregulated across the three groups (fold change >2.0, FDR corrected p<0.05) as RV enlargement increased and systolic function decreased. qPCR validation of a subset of these miRNAs identified increasing expression of miRNA 28-3p, 433-3p, and 371b-3p to be associated with increasing RV size and decreasing RV systolic function. Unbiased hierarchical clustering of all patients based on miRNA expression demonstrates three distinct patient clusters that largely coincide with progressive RV enlargement. Pathway analysis of dysregulated miRNAs demonstrates up and downregulation of cell cycle pathways, extracellular matrix proteins and fatty acid synthesis. HIF 1alpha signaling was downregulated while p53 signaling was predicted to be upregulated.CONCLUSION: Adults with TOF have a distinct miRNA profile with progressive RV enlargement and dysfunction implicating cell cycle dysregulation and upregulation in extracellular matrix and fatty acid metabolism. These data suggest peripheral blood miRNA can provide insight into the mechanisms of RV failure and can potentially be used for monitoring disease progression and to develop RV specific therapeutics to prevent RV failure in TOF.

View details for DOI 10.1371/journal.pone.0241476

View details for PubMedID 33175850
Incremental value of diastolic stress test in identifying subclinical heart failure in patients with diabetes mellitus. European heart journal cardiovascular Imaging Nishi, T., Kobayashi, Y., Christle, J. W., Cauwenberghs, N., Boralkar, K., Moneghetti, K., Amsallem, M., Hedman, K., Contrepois, K., Myers, J., Mahaffey, K. W., Schnittger, I., Kuznetsova, T., Palaniappan, L., Haddad, F. 2020
Abstract

Resting echocardiography is a valuable method for detecting subclinical heart failure (HF) in patients with diabetes mellitus (DM). However, few studies have assessed the incremental value of diastolic stress for detecting subclinical HF in this population.Asymptomatic patients with Type 2 DM were prospectively enrolled. Subclinical HF was assessed using systolic dysfunction (left ventricular longitudinal strain <16% at rest and <19% after exercise in absolute value), abnormal cardiac morphology, or diastolic dysfunction (E/e' > 10). Metabolic equivalents (METs) were calculated using treadmill speed and grade, and functional capacity was assessed by percent-predicted METs (ppMETs). Among 161 patients studied (mean age of 59?�?11?years and 57% male sex), subclinical HF was observed in 68% at rest and in 79% with exercise. Among characteristics, diastolic stress had the highest yield in improving detection of HF with 57% of abnormal cases after exercise and 45% at rest. Patients with revealed diastolic dysfunction during stress had significantly lower exercise capacity than patients with normal diastolic stress (7.3?�?2.1 vs. 8.8?�?2.5, P?10 (beta = -0.17) were independently associated with peak METs (combined R2 = 0.46). A network correlation map revealed the connectivity of peak METs and diastolic properties as central features in patients with DM.Diastolic stress test improves the detection of subclinical HF in patients with diabetes mellitus.

View details for DOI 10.1093/ehjci/jeaa070

View details for PubMedID 32386203
Limitations of right ventricular annular parameters in the early postoperative period following pulmonary endarterectomy: an observational study. Interactive cardiovascular and thoracic surgery R�zaiguia-Delclaux, S., Haddad, F., Pilorge, C., Amsallem, M., Fadel, E., St�phan, F. 2020
Abstract

Echocardiographic right ventricular (RV) annular parameters are probably not as reliable to evaluate the surgical success in the postoperative period after pulmonary endarterectomy (PEA), whereas RV end-diastolic/left ventricular end-diastolic area ratio (RVEDA/LVEDA ratio) could be more useful. This study examined the relationship between RV annular parameters or RVEDA/LVEDA ratio and ideal cardiac index (ICI), before and after PEA.Among 80 patients who underwent PEA, the relationships between RVEDA/LVEDA ratio (21 patients), or tricuspid annular plane systolic excursion (32 patients), or systolic tricuspid annular velocity (55 patients) and ICI were modelled.Forty-eight hours following PEA, mean pulmonary artery pressure decreased (26?�?6 vs 46?�?12?mmHg, P?
View details for DOI 10.1093/icvts/ivaa088

View details for PubMedID 32577738
Mechanics of right ventricular dysfunction in pulmonary arterial hypertension and heart failure with preserved ejection fraction. Cardiovascular diagnosis and therapy Bernardo, R. J., Haddad, F., Couture, E. J., Hansmann, G., de Jesus Perez, V. A., Denault, A. Y., de Man, F. S., Amsallem, M. 2020; 10 (5): 1580?1603
Abstract

Right ventricular (RV) dysfunction is the most important determinant of survival in patients with pulmonary hypertension (PH). The manifestations of RV dysfunction not only include changes in global RV systolic function but also abnormalities in the pattern of contraction and synchrony. The effects of PH on the right ventricle have been mainly studied in patients with pulmonary arterial hypertension (PAH). However, with the demographic shift towards an aging population, heart failure with preserved ejection fraction (HFpEF) has become an important etiology of PH in recent years. There are significant differences in RV mechanics, function and adaptation between patients with PAH and HFpEF (with or without PH), which are related to different patterns of remodeling and dysfunction. Due to the unique features of the RV chamber, its connection with the main pulmonary artery and the pulmonary circulation, an understanding of the mechanics of RV function and its clinical significance is mandatory for both entities. In this review, we describe the mechanics of the pressure overloaded right ventricle. We review the different mechanical components of RV dysfunction and ventricular dyssynchrony, followed by insights via analysis of pressure-volume loop, energetics and novel blood flow patterns, such as vortex imaging. We conduct an in-depth comparison of prevalence and characteristics of RV dysfunction in HFpEF and PAH, and summarize key outcome studies. Finally, we provide a perspective on needed and expected future work in the field of RV mechanics.

View details for DOI 10.21037/cdt-20-479

View details for PubMedID 33224775

View details for PubMedCentralID PMC7666917
Targeted Proteomics of Right Heart Adaptation to Pulmonary Arterial Hypertension. The European respiratory journal Amsallem, M., Sweatt, A. J., Arthur Ataam, J., Guihaire, J., Lecerf, F., Lambert, M., Ghigna, M. R., Ali, M. K., Mao, Y., Fadel, E., Rabinovitch, M., de Jesus Perez, V., Spiekerkoetter, E., Mercier, O., Haddad, F., Zamanian, R. T. 2020
Abstract

No prior proteomic screening study has centered on the right ventricle (RV) in pulmonary arterial hypertension (PAH). This study investigates the circulating proteomic profile associated with right heart maladaptive phenotype (RHMP) in PAH.Plasma proteomic profiling was performed using multiplex immunoassay in 121 PAH patients (discovery cohort) and 76 patients (validation cohort). The association between proteomic markers and RHMP (defined by the Mayo right heart score [combining RV strain, New York Heart Association NYHA class and NT-proBNP] and Stanford score [RV end-systolic remodelling index, NYHA and NT-proBNP]) was assessed by partial least squares regression. Biomarkers expressions were measured in RV samples from PAH patients and controls, and pulmonary artery banding (PAB) mice.High levels of hepatic growth factor (HGF), stem cell growth factor beta, nerve growth factor and stromal derived factor-1 were associated with worse Mayo and Stanford scores independently from pulmonary resistance or pressure in both cohorts (the validation cohort had more severe disease features: lower cardiac index and higher NT-proBNP). In both cohorts, HGF added value to the REVEAL score in the prediction of death, transplant, or hospitalisation at 3?years. RV expression levels of HGF and its receptor c-Met were higher in end-stage PAH patients than controls, and in PAB mice than shams.High plasma HGF levels are associated with RHMP and predictive of 3-year clinical worsening. Both HGF and c-Met RV expression levels are increased in PAH. Assessing plasma HGF levels might identify patients at risk for heart failure who warrant closer follow-up and intensified therapy.

View details for DOI 10.1183/13993003.02428-2020

View details for PubMedID 33334941
Subclinical left atrial dysfunction profiles for prediction of cardiac outcome in the general population. Journal of hypertension Cauwenberghs, N., Haddad, F., Sabov?ik, F., Kobayashi, Y., Amsallem, M., Morris, D. A., Voigt, J. U., Kuznetsova, T. 2020
Abstract

Echocardiographic definitions of subclinical left atrial dysfunction based on epidemiological data remain scarce. In this population study, we derived outcome-driven thresholds for echocardiographic left atrial function parameters discriminating between normal and abnormal values.In 1306 individuals (mean age, 50.7 years; 51.6% women), we echocardiographically assessed left atrial function and LV global longitudinal strain. We derived cut-off values for left atrial emptying fraction (LAEF), left atrial function index (LAFI) and left atrial reservoir strain (LARS) to define left atrial dysfunction using receiver-operating curve threshold analysis. Main outcome was the incidence of cardiac events and atrial fibrillation (AFib) on average 8.5 years later.For prediction of new-onset AFib, left atrial cut-offs yielding the best balance between sensitivity and specificity (highest Youden index) were: LAEF less than 55%, LAFI less than 40.5 and LARS less than 23%. Applying these cut-offs, abnormal LAEF, LAFI and LARS were, respectively, present in 27, 37.1 and 18.1% of the cohort. Abnormal LARS (<23%) was independently associated with higher risk for cardiac events and new-onset AFib (P???0.012). Participants with both abnormal LAEF and LARS presented a significantly higher risk to develop cardiac events (hazard ratio: 2.10; P?=?0.014) and AFib (hazard ratio: 6.45; P?=?0.0036) than normal counterparts. The concomitant presence of an impaired LARS and LV global longitudinal strain improved prognostic accuracy beyond a clinical risk model for cardiac events and the CHARGE-AF Risk Score for AFib.Left atrial dysfunction based on outcome-driven thresholds predicted cardiac events and AFib independent of conventional risk factors. Screening for subclinical left atrial and LV systolic dysfunction may enhance cardiac disease prediction in the community.

View details for DOI 10.1097/HJH.0000000000002572

View details for PubMedID 32649644
Molecular Choreography of Acute Exercise. Cell Contrepois, K., Wu, S., Moneghetti, K. J., Hornburg, D., Ahadi, S., Tsai, M. S., Metwally, A. A., Wei, E., Lee-McMullen, B., Quijada, J. V., Chen, S., Christle, J. W., Ellenberger, M., Balliu, B., Taylor, S., Durrant, M. G., Knowles, D. A., Choudhry, H., Ashland, M., Bahmani, A., Enslen, B., Amsallem, M., Kobayashi, Y., Avina, M., Perelman, D., Sch�ssler-Fiorenza Rose, S. M., Zhou, W., Ashley, E. A., Montgomery, S. B., Chaib, H., Haddad, F., Snyder, M. P. 2020; 181 (5): 1112?30.e16
Abstract

Acute physical activity leads to several changes in metabolic, cardiovascular, and immune pathways. Although studies have examined selected changes in these pathways, the system-wide molecular response to an acute bout of exercise has not been fully characterized. We performed longitudinal multi-omic profiling of plasma and peripheral blood mononuclear cells including metabolome, lipidome, immunome, proteome, and transcriptome from 36 well-characterized volunteers, before and after a controlled bout of symptom-limited exercise. Time-series analysis revealed thousands of molecular changes and an orchestrated choreography of biological processes involving energy metabolism, oxidative stress, inflammation, tissue repair, and growth factor response, as well as regulatory pathways. Most of these processes were dampened and some were reversed in insulin-resistant participants. Finally, we discovered biological pathways involved in cardiopulmonary exercise response and developed prediction models revealing potential resting blood-based biomarkers of peak oxygen consumption.

View details for DOI 10.1016/j.cell.2020.04.043

View details for PubMedID 32470399
Hemodynamic trajectories and outcomes in patients with pulmonary arterial hypertension. Pulmonary circulation Amsallem, M., Bagherzadeh, S. P., Boulate, D., Sweatt, A. J., Kudelko, K. T., Sung, Y. K., Feinstein, J. A., Fadel, E., Mercier, O., Denault, A., Haddad, F., Zamanian, R. 2020; 10 (4): 2045894020941343
Abstract

The relative pulmonary to systemic pressure ratio (mean pulmonary arterial pressure/mean arterial pressure) has been proven to be valuable in cardiac surgery. Little is known on the prognostic value of baseline and trajectory of mean pulmonary arterial pressure/mean arterial pressure in pulmonary arterial hypertension. Patients with confirmed idiopathic, familial, drug and toxins, or connective tissue disease-related pulmonary arterial hypertension and at least one complete right heart catheterization were included and prospectively followed-up for 5.9?�?4.03 years. Correlates of the primary end point (i.e. death or lung transplant need) during follow-up were determined using Cox regression modeling. Results showed that among the 308 patients included, 187 had at least one follow-up catheterization (median time between catheterizations: 2.16 (1.16-3.19) years). In the total cohort (mean age 47.3?�?14.9 years, 82.8% of female and 58.1% in New York Heart Association class 3 or 4), mean pulmonary arterial pressure/mean arterial pressure (1.38 (1.07-1.77)) was associated with outcome (p?=?0.01). Mean pulmonary arterial pressure/mean arterial pressure was incremental to a basic model (including right atrial pressure, systolic blood pressure, New York Heart Association class 3 or 4, and connective tissue disease) for outcome prediction, while mean pulmonary arterial pressure was not. In the 187 patients with a follow-up catheterization, both delta mean pulmonary arterial pressure and delta mean pulmonary arterial pressure/mean arterial pressure were associated with outcome (1.32 (1.11-1.58) and 1.31 (1.1-1.57) respectively, p?
View details for DOI 10.1177/2045894020941343

View details for PubMedID 33335708

View details for PubMedCentralID PMC7724418
Echocardiographic Assessment of Left Ventricular Remodeling in American Style Footballers. International journal of sports medicine Moneghetti, K. J., Singh, T., Hedman, K., Christle, J. W., Kooreman, Z., Kobayashi, Y., Bouajila, S., Amsallem, M., Wheeler, M., Gerche, A. L., Ashley, E., Haddad, F. 2019
Abstract

Several athletic programs incorporate echocardiography during pre-participation screening of American Style Football (ASF) players with great variability in reported echocardiographic values. Pre-participation screening was performed in National Collegiate Athletic Association Division I ASF players from 2008 to 2016 at the Division of Sports Cardiology. The echocardiographic protocol focused on left ventricular (LV) mass, mass-to-volume ratio, sphericity, ejection fraction, and longitudinal Lagrangian strain. LV mass was calculated using the area-length method in end-diastole and end-systole. A total of two hundred and thirty players were included (18�1 years, 57% were Caucasian, body mass index 29�4kg/m2) after four players (2%) were excluded for pathological findings. Although there was no difference in indexed LV mass by race (Caucasian 78�11 vs. African American 81�10g/m2, p=0.089) or sphericity (Caucasian 1.81�0.13 vs. African American 1.78�0.14, p=0.130), the mass-to-volume ratio was higher in African Americans (0.91�0.09 vs. 0.83�0.08, p<0.001). No race-specific differences were noted in LV longitudinal Lagrangian strain. Player position appeared to have a limited role in defining LV remodeling. In conclusion, significant echocardiographic differences were observed in mass-to-volume ratio between African American and Caucasian players. These demographics should be considered as part of pre-participation screening.

View details for DOI 10.1055/a-1014-2994

View details for PubMedID 31791086
Blood pressure in athletic preparticipation evaluation and the implication for cardiac remodelling. Heart (British Cardiac Society) Hedman, K., Moneghetti, K. J., Christle, J. W., Bagherzadeh, S. P., Amsallem, M., Ashley, E., Froelicher, V., Haddad, F. 2019
Abstract

OBJECTIVES: To explore blood pressure (BP) in athletes at preparticipation evaluation (PPE) in the context of recently updated US and European hypertension guidelines, and to determine the relationship between BP and left ventricular (LV) remodelling.METHODS: In this retrospective study, athletes aged 13-35 years who underwent PPE facilitated by the Stanford Sports Cardiology programme were considered. Resting BP was measured in both arms; repeated once if ?140/90mm Hg. Athletes with abnormal ECGs or known hypertension were excluded. BP was categorised per US/European hypertension guidelines. In a separate cohort of athletes undergoing routine PPE echocardiography, we explored the relationship between BP and LV remodelling (LV mass, mass/volume ratio, sphericity index) and LV function.RESULTS: In cohort 1 (n=2733, 65.5% male), 34.3% of athletes exceeded US hypertension thresholds. Male sex (B=3.17, p<0.001), body mass index (BMI) (B=0.80, p<0.001) and height (B=0.25, p<0.001) were the strongest independent correlates of systolic BP. In the second cohort (n=304, ages 17-26), systolic BP was an independent correlate of LV mass/volume ratio (B=0.002, p=0.001). LV longitudinal strain was similar across BP categories, while higher BP was associated with slower early diastolic relaxation.CONCLUSION: In a large contemporary cohort of athletes, one-third presented with BP levels above the current US guidelines' thresholds for hypertension, highlighting that lowering the BP thresholds at PPE warrants careful consideration as well as efforts to standardise measurements. Higher systolic BP was associated with male sex, BMI and height and with LV remodelling and diastolic function, suggesting elevated BP in athletes during PPE may signify a clinically relevant condition.

View details for DOI 10.1136/heartjnl-2019-314815

View details for PubMedID 31142598
INDEPENDENT PROGNOSTIC VALUES OF CLINICAL RISK SCORES, RIGHT VENTRICULAR SYSTOLIC PRESSURE, AND N-TERMINAL PRO-B-TYPE PEPTIDE IN HEART FAILURE WITH PRESERVED EJECTION FRACTION: INSIGHTS FROM SUPERVISED AND UNSUPERVISED MODELS Tremblay-Gravel, M., Kobayashi, Y., Boralkar, K., Li, X., Bouajila, S., Nishi, T., Amsallem, M., Moneghetti, K., Selej, M., Ozen, M., Demirci, U., Ashley, E. A., Wheeler, M., Knowlton, K., Kouznetsova, T., Haddad, F. ELSEVIER SCIENCE INC. 2019: 718
View details for Web of Science ID 000460565900718
REPLY: Increasingly Recognized Role of Right Ventricle Assessment in Cardiac Amyloidosis JACC-HEART FAILURE Amsallem, M., Witteles, R., Haddad, F. 2019; 7 (3): 279?80
View details for DOI 10.1016/j.jchf.2018.12.010

View details for Web of Science ID 000460037600017

View details for PubMedID 30819389
Autologous endothelial progenitor cell therapy improves right ventricular function in a model of chronic thromboembolic pulmonary hypertension. The Journal of thoracic and cardiovascular surgery Loisel, F., Provost, B., Guihaire, J., Boulate, D., Arouche, N., Amsallem, M., Arthur-Ataam, J., Decante, B., Dorfm�ller, P., Fadel, E., Uzan, G., Mercier, O. 2019; 157 (2): 655?66.e7
Abstract

Right ventricular (RV) failure is the main prognostic factor in pulmonary hypertension, and ventricular capillary density (CD) has been reported to be a marker of RV maladaptive remodeling and failure. Our aim was to determine whether right intracoronary endothelial progenitor cell (EPC) infusion can improve RV function and CD in a piglet model of chronic thromboembolic pulmonary hypertension (CTEPH).We compared 3 groups: sham (n�=�5), CTEPH (n�=�6), and CTEPH with EPC infusion (CTEPH+EPC; n�=�5). After EPC isolation from CTEPH+EPC piglet peripheral blood samples at 3�weeks, the CTEPH and sham groups underwent right intracoronary infusion of saline, and the CTEPH+EPC group received EPCs at 6�weeks. RV function, pulmonary hemodynamics, and myocardial morphometry were investigated in the animals at 10�weeks.After EPC administration, the RV fractional area change increased from 32.75% (interquartile range [IQR], 29.5%-36.5%) to 39% (IQR, 37.25%-46.50%; P�=�.030). The CTEPH+EPC piglets had reduced cardiomyocyte surface areas (from 298.3 ?m2 [IQR, 277.4-335.3 ?m2] to 234.6 ?m2 (IQR, 211.1-264.7 ?m2; P�=�.017), and increased CD31 expression (from 3.12 [IQR, 1.27-5.09] to 7.14 [IQR, 5.56-8.41; P�=�.017). EPCs were found in the RV free wall at 4 and 24�hours after injection but not 4�weeks later.Intracoronary infusion of EPC improved RV function and CD in a piglet model of CTEPH. This novel cell-based therapy might represent a promising RV-targeted treatment in patients with pulmonary hypertension.

View details for DOI 10.1016/j.jtcvs.2018.08.083

View details for PubMedID 30669226
Echocardiographic evaluations of right ventriculo-arterial coupling in experimental and clinical pulmonary hypertension. Physiological reports Boulate, D., Amsallem, M., Kuznetsova, T., Zamanian, R. T., Fadel, E., Mercier, O., Haddad, F. 2019; 7 (24): e14322
Abstract

Tricuspid annular systolic excursion (TAPSE) or velocities (s') and right ventricular (RV) end-systolic dimensions are predictors of outcome in patients with pulmonary hypertension (PH). We explored the value of combining peak s' and RV end-systolic area index (RVESAi) as a surrogate of RV-pulmonary artery (RV-PA) coupling in a large animal of precapillary PH as well as clinically.The first experimental group included four control and four piglets with thromboembolic disease. RV-PA coupling was assessed by ventricular to arterial elastance ratio (Ees/Ea) at baseline, after esmolol and dobutamine administration. Echocardiographic metrics included s', TAPSE, fractional area change (RVFAC), and RVESAi. The findings were validated in six piglets with severe PH. Clinical cohorts were stable outpatients (n�=�141) and acutely decompensated pulmonary arterial hypertension (n�=�48).In the first experimental group, the best linear correlates of Ees/Ea were s' (R2 �=�.51, p�<�.001) and RVESAi (R2 �=�.50, p�<�.001), while RVFAC (R2 �=�.17, p�=�.01) and TAPSE showed weaker association (R2 �=�.21, p�=�.39). The ratio s'/RVESAi showed nominally but not significantly (higher) association with Ees/Ea (R2 �=�.58, p�<�.01). The association between changes in s'/RVESAi and Ees/Ea was strong (R2 �=�.56, p�<�.001). In more severe PH, Ees/Ea and changes in Ees/Ea correlated significantly with s'/RVESAi and changes in s'/RVESAi (R2 �=�.69; p�<�.001 and R2 �=�.64, p�<�.001, respectively). In the two clinical cohorts, the s'/RVESAi did not emerge as a stronger predictor of outcome than RVESAi.RV s'/RVESAi index represents a reasonable bedside-usable surrogate of RV-PA coupling and of its acute variations in PH. Its incremental prognostic value over end-systolic dimension alone remains to be proven.

View details for DOI 10.14814/phy2.14322

View details for PubMedID 31876125
Value of Neutrophil to Lymphocyte Ratio and Its Trajectory in Patients Hospitalized With Acute Heart Failure and Preserved Ejection Fraction. The American journal of cardiology Boralkar, K. A., Kobayashi, Y., Amsallem, M., Ataam, J. A., Moneghetti, K. J., Cauwenberghs, N., Horne, B. D., Knowlton, K. U., Maecker, H., Kuznetsova, T., Heidenreich, P. A., Haddad, F. 2019
Abstract

The neutrophil to lymphocyte ratio (NLR) has been proposed as a simple and routinely obtained marker of inflammation. This study sought to determine whether the NLR on admission as well as NLR trajectory would be complementary to the Get with the Guidelines Heart Failure (GWTG-HF) risk score in patients hospitalized with acute heart failure with preserved ejection fraction (HFpEF).Using the Stanford Translational Research Database, we identified 443 patients between January 2002 and December 2013 hospitalized with acute HFpEF and with complete data of NLR both on admission and at discharge. The primary endpoint was all-cause mortality. Mean age was 77?�?16 years, 58% were female, with a high prevalence of diabetes mellitus (35.4%), coronary artery disease (58.2%), systemic hypertension (96.6%) and history of atrial fibrillation (57.5%). Over a median follow-up of 2.2 years, 121 (27.3%) patients died. The median NLR on admission was 6.5 (IQR 3.6?-?11.1); a majority of patients decreased their NLR during the course of hospitalization. On multivariable Cox modeling, both NLR on admission (HR 1.18 95% CI (1.00?-?.38), p?=?0.04) and absolute NLR trajectory (HR 1.26 95% CI (1.10?-?1.45), p?=?0.001) were shown to be incremental to GWTG-HF risk score (p?
View details for DOI 10.1016/j.amjcard.2019.10.020

View details for PubMedID 31753313
ICAM-1 promotes the abnormal endothelial cell phenotype in chronic thromboembolic pulmonary hypertension. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Arthur Ataam, J., Mercier, O., Lamrani, L., Amsallem, M., Arthur Ataam, J., Arthur Ataam, S., Guihaire, J., Lecerf, F., Capuano, V., Ghigna, M. R., Haddad, F., Fadel, E., Eddahibi, S. 2019
Abstract

Pulmonary endothelial cells play a key role in the pathogenesis of Chronic Thromboembolic Pulmonary Hypertension (CTEPH). Increased synthesis and/or the release of intercellular adhesion molecule-1 (ICAM-1) by pulmonary endothelial cells of patients with CTEPH has been recently reported, suggesting a potential role for ICAM-1 in CTEPH.We studied pulmonary endarterectomy specimens from 172 patients with CTEPH and pulmonary artery specimens from 97 controls undergoing lobectomy for low-stage cancer without metastasis.ICAM-1 was overexpressed in vitro in isolated and cultured endothelial cells from endarterectomy specimens. Endothelial cell growth and apoptosis resistance were significantly higher in CTEPH specimens than in the controls (p < 0.001). Both abnormalities were abolished by pharmacological inhibition of ICAM-1 synthesis or activity. The overexpression of ICAM-1 contributed to the acquisition and maintenance of abnormal EC growth and apoptosis resistance via the phosphorylation of SRC, p38 and ERK1/2 and the overproduction of survivin. Regarding the ICAM-1 E469K polymorphism, the KE heterozygote genotype was significantly more frequent in CTEPH than in the controls, but it was not associated with disease severity among patients with CTEPH.ICAM-1 contributes to maintaining the abnormal endothelial cell phenotype in CTEPH.

View details for DOI 10.1016/j.healun.2019.06.010

View details for PubMedID 31324443
Approaching Higher Dimension Imaging Data Using Cluster-Based Hierarchical Modeling in Patients with Heart Failure Preserved Ejection Fraction. Scientific reports Kobayashi, Y., Tremblay-Gravel, M., Boralkar, K. A., Li, X., Nishi, T., Amsallem, M., Moneghetti, K. J., Bouajila, S., Selej, M., Ozen, M. O., Demirci, U., Ashley, E., Wheeler, M., Knowlton, K. U., Kouznetsova, T., Haddad, F. 2019; 9 (1): 10431
Abstract

Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality, accounting for the majority of heart failure (HF) hospitalization. To identify the most complementary predictors of mortality among clinical, laboratory and echocardiographic data, we used cluster based hierarchical modeling. Using Stanford Translational Research Database, we identified patients hospitalized with HFpEF between 2005 and 2016 in whom echocardiogram and NT-proBNP were both available at the time of admission. Comprehensive echocardiographic assessment including left ventricular longitudinal strain (LVLS), right ventricular function and right ventricular systolic pressure (RVSP) was performed. The outcome was defined as all-cause mortality. Among patients identified, 186 patients with complete echocardiographic assessment were included in the analysis. The cohort included 58% female, with a mean age of 78.7?�?13.5 years, LVLS of -13.3?�?2.5%, an estimated RVSP of 38?�?13?mmHg. Unsupervised cluster analyses identified six clusters including ventricular systolic-function cluster, diastolic-hemodynamic cluster, end-organ function cluster, vital-sign cluster, complete blood count and sodium clusters. Using a stepwise hierarchical selection from each cluster, we identified NT-proBNP (standard hazard ratio [95%CI]?=?1.56 [1.17-2.08]) and RVSP (1.37 [1.09-1.78]) as independent correlates of outcome. When adding these parameters to the well validated Get with the Guideline Heart Failure risk score, the Chi-square was significantly improved (p?=?0.01). In conclusion, NT-proBNP and RVSP were independently predictive in HFpEF among clinical, imaging, and biomarker parameters. Cluster-based hierarchical modeling may help identify the complementally predictive parameters in small cohorts with higher dimensional clinical data.

View details for DOI 10.1038/s41598-019-46873-7

View details for PubMedID 31320698
Assessment of Left Ventricular Diastolic Function by Transesophageal Echocardiography Before Cardiopulmonary Bypass: Clinical Implications of a Restrictive Profile. Journal of cardiothoracic and vascular anesthesia Beaubien-Souligny, W., Brand, F. Z., Lenoir, M., Amsallem, M., Haddad, F., Denault, A. Y. 2019; 33 (9): 2394?2401
Abstract

Left ventricular (LV) diastolic function can be assessed by transesophageal echocardiography before cardiopulmonary bypass in the setting of cardiac surgery. The objective of this study was to determine whether the assessment of LV diastolic dysfunction (LVDD) improves mortality risk prediction.Retrospective single-center cohort study.Single tertiary cardiac surgery center.Data from patients undergoing cardiac surgery using cardiopulmonary bypass (CPB) and for which an evaluation for LVDD was performed before CPB between February 1999 and November 2015.Cases were reviewed retrospectively from a transesophageal echocardiography hemodynamic database. LV diastolic function was graded as normal, impaired relaxation (grade 1), pseudo-normalization (grade 2), or restrictive (grade 3) determined by mitral inflow waves, tissue Doppler imaging of the mitral annulus, and pulmonary venous flow. The main outcome was in-hospital mortality.A total of 760 patients were included, 144 (18.9%) patients with normal diastolic function, 331 (43.6%) patients with grade 1 LVDD, 218 (28.7%) patients with grade 2 LVDD, and 67 (8.8%) patients with grade 3 LVDD. In-hospital mortality occurred in 31 patients (4.1%). The presence of grade 3 LVDD was associated with an increased likelihood of in-hospital mortality (odds ratio [OR]: 19.39, confidence interval [CI]: 2.37-158.48, p?=?0.006). In contrast, LV systolic dysfunction was not independently associated with increased mortality. When added to the Parsonnet score, the addition of diastolic function resulted in a net reclassification improvement of in-hospital mortality (NRI: 0.419 CI: 0.049-0.759, p?=?0.02), and in integrated discrimination improvement (IDI: 0.0179 CI: 0.0049-0.031, p?=?0.007). Difficult separation from CPB was observed more frequently in patients with grade 3 LVDD (62.9% v 36.1%, p?=?0.01).In contrast to LV systolic dysfunction, restrictive LVDD is associated with an increased risk of in-hospital mortality in cardiac surgical patients. Further studies should explore how this information may be used by the attending anesthesiologist to tailor perioperative management.

View details for DOI 10.1053/j.jvca.2019.05.014

View details for PubMedID 31235379
The Incremental Value of Right Ventricular Size and Strain in the Risk Assessment of Right Heart Failure Post - Left Ventricular Assist Device Implantation. Journal of cardiac failure Aymami, M., Amsallem, M., Adams, J., Sallam, K., Moneghetti, K., Wheeler, M., Hiesinger, W., Teuteberg, J., Weisshaar, D., Verhoye, J., Woo, Y. J., Ha, R., Haddad, F., Banerjee, D. 2018; 24 (12): 823?32
Abstract

BACKGROUND: Right heart failure (RHF) after left ventricular assist device (LVAD) implantation is associated with high morbidity and mortality. Existing risk scores include semiquantitative evaluation of right ventricular (RV) dysfunction. This study aimed to determine whether quantitative evaluation of both RV size and function improve risk stratification for RHF after LVAD implantation beyond validated scores.METHODS AND RESULTS: From 2009 to 2015, 158 patients who underwent implantation of continuous-flow devices who had complete echocardiographic and hemodynamic data were included. Quantitative RV parameters included RV end-diastolic (RVEDAI) and end-systolic area index, RV free-wall longitudinal strain (RVLS), fractional area change, tricuspid annular plane systolic excursion, and right atrial area and pressure. Independent correlates of early RHF (<30 days) were determined with the use of logistic regression analysis. Mean age was 56 � 13 years, with 79% male; 49% had INTERMACS profiles ?2. RHF occurred in 60 patients (38%), with 20 (13%) requiring right ventricular assist device. On multivariate analysis, INTERMACS profiles (adjusted odds ratio 2.38 [95% confidence interval [CI] 1.47-3.85]), RVEDAI (1.61 [1.08-2.32]), and RVLS (2.72 [1.65-4.51]) were independent correlates of RHF (all P < .05). Both RVLS and RVEDAI were incremental to validated risk scores (including the EUROMACS score) for early RHF after LVAD (all P < .01).CONCLUSIONS: RV end-diastolic and strain are complementary prognostic markers of RHF after LVAD implantation.

View details for PubMedID 30539717
Forgotten No More: A Focused Update on the Right Ventricle in CardiovascularDisease. JACC. Heart failure Amsallem, M., Mercier, O., Kobayashi, Y., Moneghetti, K., Haddad, F. 2018
Abstract

In the last decade, there has been renewed interest in the study of the right ventricle. It is now well established that right ventricular function is a strong predictor of mortality, not only in heart failure but also in pulmonary hypertension, congenital heart disease, and cardiothoracic surgery. The right ventricle is part of a cardiopulmonary unit with connections to the pulmonary circulation, venous return, atria, and left ventricle. In this context, ventriculoarterial coupling, interventricular interactions, and pericardial constraint become important to understand right ventricular adaptation to injury or abnormal loading conditions. This state-of-the-art review summarizes major advances that occurred in the field of right ventricular research over the last decade. The first section focuses on right ventricular physiology and pulmonary circulation. The second section discusses the emerging data on right ventricular phenotyping, highlighting the importance of myocardial deformation (strain) imaging and assessment of end-systolic dimensions. The third section reviews recent clinical trials involving patients at risk for or with established right ventricular failure, focusing on beta blockade, phosphodiesterase inhibition, and mechanical support of the failing right heart. The final section presents a perspective on active areas of research that are most likely to translate in clinical practice in the next decade.

View details for PubMedID 30316939
Right ventricular load adaptability metrics in patients undergoing left ventricular assist device implantation. The Journal of thoracic and cardiovascular surgery Amsallem, M., Aymami, M., Hiesinger, W., Zeigler, S., Moneghetti, K., Marques, M., Teuteberg, J., Ha, R., Banerjee, D., Haddad, F. 2018
Abstract

OBJECTIVE: Several right load adaptability metrics have been proposed as predictors of right heart failure (RHF) following left ventricular assist device implantation. This study sought to validate and compare the prognostic value of these indices.METHODS: This retrospective study included 194 patients undergoing continuous-flow left ventricular assist device implantation. The primary end point was unplanned right atrial assist device (RVAD) need within 30days after left ventricular assist device implantation; the secondary end points included clinical RHF syndrome without RVAD need and the composite of RHF or RVAD need. Load adaptability indices or interventricular ratios were divided into surrogates of ventriculoarterial coupling (RV area change:end-systolic area), indices reflecting adaptation proportionality (Dandel's index=tricuspid regurgitation velocity-time integral normalized for average RV radius in diastole or systole), and simple ratios (eg, pulse pressure:right atrial pressure or right arterial pressure:pulmonary arterial wedge pressure).RESULTS: Mean age was 55�13years with 77% of men. RHF occurred in 75 patients with 30 patients requiring RVAD implantation. Among right heart metrics, right arterial pressure (normalized odd ratio, 1.62; 95% confidence interval, 1.15-2.38), right arterial pressure:pulmonary arterial wedge pressure (normalized odds ratio, 1.59; 95% confidence interval, 1.08-2.32) and pulse pressure:right arterial pressure<2.0 (normalized odds ratio, 2.56; 95% confidence interval, 1.16-5.56) were associated with RVAD need (all P values<.02). These 3 metrics significantly added incremental prognostic value to the Interagency Registry for Mechanically Assisted Circulatory Support classification score in a similar range, whereas only RAP was incremental to the Michigan score. Correlates of RHF not requiring RVAD included RV end-systolic area index and the Dandel indices, which provided similar incremental value to the Interagency Registry for Mechanically Assisted Circulatory Support, Michigan, and European Registry for Patients with Mechanical Circulatory Support scores.CONCLUSIONS: Although associated with outcome, right load adaptability indices do not appear to provide strong incremental value when compared with simple metrics.

View details for PubMedID 30482529
Impact of the initiation of balloon pulmonary angioplasty program on referral of patients with chronic thromboembolic pulmonary hypertension to surgery. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Amsallem, M., Guihaire, J., Arthur Ataam, J., Lamrani, L., Boulate, D., Mussot, S., Fabre, D., Taniguchi, Y., Haddad, F., Sitbon, O., Jais, X., Humbert, M., Simonneau, G., Mercier, O., Brenot, P., Fadel, E. 2018
Abstract

BACKGROUND: Balloon pulmonary angioplasty (BPA) is a technique proposed for inoperable patients with chronic thromboembolic pulmonary hypertension (CTEPH). In this study we aimed to determine whether initiation of the BPA program has modified the characteristics and outcome of patients undergoing pulmonary endarterectomy (PEA), and compared the characteristics of patients undergoing one or the other procedure.METHODS: This prospective registry study included all patients with CTEPH who underwent PEA in the French National Reference Center before (2012 to 2013) and after (2015 to 2016) BPA program initiation (February 2014). Pre-operative clinical and hemodynamics profiles, peri-operative (Jamieson classification, surgery duration, need of assistance) characteristics of both groups, and all-cause mortality were compared using the t-test or chi-square test. Characteristics of patients subjected to surgery or BPA since February 2014 were also compared.RESULTS: The total number of patients referred to the CTEPH team increased in the BPA era (n?=?291vs n?=?484). The pre-operative characteristics of patients from the pre-BPA era (n?=?240) were similar to those from the BPA era (n?=?246). Despite more Jamieson Type 3 cases (29%) in the second period, 30- and 90-day mortality remained stable (both p > 0.30). Patients subjected to BPA (n?=?177) were older than those subjected to PEA (n?=?364) (64 � 14vs 60 � 14years, respectively), and had higher rates of splenectomy (10% vs 1%) or implantable port (9% vs 3%), lower total pulmonary resistance, better cardiac index, and better renal function (all p < 0.01).CONCLUSIONS: This study shows the influence of the initiation of the BPA program on the profile of patients with CTEPH undergoing PEA.

View details for PubMedID 30037729
Optimizing right ventricular focused four-chamber views using three-dimensional imaging, a comparative magnetic resonance based study. The international journal of cardiovascular imaging Amsallem, M., Lu, H., Tang, X., Do Couto Francisco, N. L., Kobayashi, Y., Moneghetti, K., Shiran, H., Rogers, I., Schnittger, I., Liang, D., Haddad, F. 2018
Abstract

Obtaining focused right ventricular (RV) apical view remains challenging using conventional two-dimensional (2D) echocardiography. This study main objective was to determine whether measurements from RV focused views derived from three-dimensional (3D) echocardiography (3D-RV-focused) are closely related to measurements from magnetic resonance (CMR). A first cohort of 47 patients underwent 3D echocardiography and CMR imaging within 2h of each other. A second cohort of 25 patients had repeat 3D echocardiography to determine the test-retest characteristics; and evaluate the bias associated with unfocused RV views. Tomographic views were extracted from the 3D dataset: RV focused views were obtained using the maximal RV diameter in the transverse plane, and unfocused views from a smaller transverse diameter enabling visualization of the tricuspid valve opening. Measures derived using the 3D-RV-focused view were strongly associated with CMR measurements. Among functional metrics, the strongest association was between RV fractional area change (RVFAC) and ejection fraction (RVEF) (r=0.92) while tricuspid annular plane systolic excursion moderately correlated with RVEF (r=0.47), all p<0.001. Among RV size measures, the strongest association was found between RV end-systolic area (RVESA) and volume (r=0.87, p<0.001). RV unfocused views led on average to 10% underestimation of RVESA. The 3D-RV-focused method had acceptable test-retest characteristics with a coefficient of variation of 10% for RVESA and 11% for RVFAC. Deriving standardized RV focused views using 3D echocardiography strongly relates to CMR-derived measures and may improve reproducibility in RV 2D measurements.

View details for PubMedID 29654480
RIGHT VENTRICULAR LOAD ADAPTABILITY IN PATIENTS UNDERGOING CONTINUOUS-FLOW LEFT VENTRICULAR ASSIST DEVICE IMPLANTATION Amsallem, M., Aymami, M., Hiesinger, W., Zeigler, S., Moneghetti, K., Marques, M., Wheeler, M., Teuteberg, J., Ha, R., Banerjee, D., Haddad, F. ELSEVIER SCIENCE INC. 2018: 1624
View details for DOI 10.1016/S0735-1097(18)32165-X

View details for Web of Science ID 000429659703274
THE COMPLEMENTARY VALUE OF THE GET WITH THE GUIDELINES: HEART FAILURE RISK SCORE AND LABORATORY MARKERS AT DISCHARGE IN PREDICTING MORTALITY IN PATIENTS HOSPITALIZED WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION Boralkar, K., Kobayashi, Y., Pargaonkar, V., Moneghetti, K., Tuzovic, M., Krishnan, G., Amsallem, M., Kouznetsova, T., Horne, B., Knowlton, K., Heidenreich, P., Haddad, F. ELSEVIER SCIENCE INC. 2018: 839
View details for DOI 10.1016/S0735-1097(18)31380-9

View details for Web of Science ID 000429659702089
Stem cell therapy targeting the right ventricle in pulmonary arterial hypertension: is it a potential avenue of therapy? PULMONARY CIRCULATION Loisel, F., Provost, B., Haddad, F., Guihaire, J., Amsallem, M., Vrtovec, B., Fadel, E., Uzan, G., Mercier, O. 2018; 8 (2): 2045893218755979
Abstract

Pulmonary arterial hypertension (PAH) is an incurable disease characterized by an increase in pulmonary arterial pressure due to pathological changes to the pulmonary vascular bed. As a result, the right ventricle (RV) is subject to an increased afterload and undergoes multiple changes, including a decrease in capillary density. All of these dysfunctions lead to RV failure. A number of studies have shown that RV function is one of the main prognostic factors for PAH patients. Many stem cell therapies targeting the left ventricle are currently undergoing development. The promising results observed in animal models have led to clinical trials that have shown an improvement of cardiac function. In contrast to left heart disease, stem cell therapy applied to the RV has remained poorly studied, even though it too may provide a therapeutic benefit. In this review, we discuss stem cell therapy as a treatment for RV failure in PAH. We provide an overview of the results of preclinical and clinical studies for RV cell therapies. Although a large number of studies have targeted the pulmonary circulation rather than the RV directly, there are nonetheless encouraging results in the literature that indicate that cell therapies may have a direct beneficial effect on RV function. This cell therapy strategy may therefore hold great promise and warrants further studies in PAH patients.

View details for PubMedID 29480154

View details for PubMedCentralID PMC5844533
EXPRESS: Non-invasive Right Ventricular Load Adaptability Indices in Patients with Scleroderma-Associated Pulmonary Arterial Hypertension. Pulmonary circulation French, S., Amsallem, M., Ouazani, N., Li, S., Kudelko, K., Zamanian, R., Haddad, F., Chung, L. 2018: 2045894018788268
View details for PubMedID 29938590
In Situ Antegrade Laser Fenestrations During Endovascular Aortic Repair European journal of vascular and endovascular surgery : the official journal of the European Society for Vascular Surgery Le Houerou, T., Fabre, D., Alonso, C., Bourkaib, R., Angel, C., Amsallem, M., Haulon, S. 2018; 56 (3): 356?62
View details for DOI 10.1016/j.ejvs.2018.05.014
Current Knowledge and Recent Advances of Right Ventricular Molecular Biology and Metabolism from Congenital Heart Disease to Chronic Pulmonary Hypertension BIOMED RESEARCH INTERNATIONAL Guimaron, S., Guihaire, J., Amsallem, M., Haddad, F., Fadel, E., Mercier, O. 2018: 1981568
Abstract

Studies about pulmonary hypertension and congenital heart diseases have introduced the concept of right ventricular remodeling leading these pathologies to a similar outcome: right ventricular failure. However right ventricular remodeling is also a physiological process that enables the normal fetal right ventricle to adapt at birth and gain its adult phenotype. The healthy mature right ventricle is exposed to low pulmonary vascular resistances and is compliant. However, in the setting of chronic pressure overload, as in pulmonary hypertension, or volume overload, as in congenital heart diseases, the right ventricle reverts back to a fetal phenotype to sustain its function. Mechanisms include angiogenic changes and concomitant increased metabolic activity to maintain energy production. Eventually, the remodeled right ventricle cannot resist the increased afterload, leading to right ventricular failure. After comparing the fetal and adult healthy right ventricles, we sought to review the main metabolic and cellular changes occurring in the setting of PH and CHD. Their association with RV function and potential impact on clinical practice will also be discussed.

View details for PubMedID 29581963

View details for PubMedCentralID PMC5822779
Right Heart End-Systolic Remodeling Index Strongly Predicts Outcomes in Pulmonary Arterial Hypertension: Comparison With Validated Models. Circulation. Cardiovascular imaging Amsallem, M., Sweatt, A. J., Aymami, M. C., Kuznetsova, T., Selej, M., Lu, H., Mercier, O., Fadel, E., Schnittger, I., McConnell, M. V., Rabinovitch, M., Zamanian, R. T., Haddad, F. 2017; 10 (6)
Abstract

Right ventricular (RV) end-systolic dimensions provide information on both size and function. We investigated whether an internally scaled index of end-systolic dimension is incremental to well-validated prognostic scores in pulmonary arterial hypertension.From 2005 to 2014, 228 patients with pulmonary arterial hypertension were prospectively enrolled. RV end-systolic remodeling index (RVESRI) was defined by lateral length divided by septal height. The incremental values of RV free wall longitudinal strain and RVESRI to risk scores were determined. Mean age was 49�14 years, 78% were female, 33% had connective tissue disease, 52% were in New York Heart Association class ?III, and mean pulmonary vascular resistance was 11.2�6.4 WU. RVESRI and right atrial area were strongly connected to the other right heart metrics. Three zones of adaptation (adapted, maladapted, and severely maladapted) were identified based on the RVESRI to RV systolic pressure relationship. During a mean follow-up of 3.9�2.4 years, the primary end point of death, transplant, or admission for heart failure was reached in 88 patients. RVESRI was incremental to risk prediction scores in pulmonary arterial hypertension, including the Registry to Evaluate Early and Long-Term PAH Disease Management score, the Pulmonary Hypertension Connection equation, and the Mayo Clinic model. Using multivariable analysis, New York Heart Association class III/IV, RVESRI, and log NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) were retained (?(2), 62.2; P<0.0001). Changes in RVESRI at 1 year (n=203) were predictive of outcome; patients initiated on prostanoid therapy showed the greatest improvement in RVESRI. Among right heart metrics, RVESRI demonstrated the best test-retest characteristics.RVESRI is a simple reproducible prognostic marker in patients with pulmonary arterial hypertension.

View details for DOI 10.1161/CIRCIMAGING.116.005771

View details for PubMedID 28592589
Editor's Choice-Medically managed patients with non-ST-elevation acute myocardial infarction have heterogeneous outcomes, based on performance of angiography and extent of coronary artery disease. European heart journal. Acute cardiovascular care Feldman, L., Steg, P. G., Amsallem, M., Puymirat, E., Sorbets, E., Elbaz, M., Ritz, B., Hueber, A., Cattan, S., Piot, C., Ferri�res, J., Simon, T., Danchin, N. 2017; 6 (3): 262-271
Abstract

Medically managed individuals represent a high-risk group among patients with non-ST-elevation acute myocardial infarction (NSTE-AMI). We hypothesized that prognosis in this group is heterogeneous, depending on whether medical management was decided with or without coronary angiography (CAG).Using data from the French Registry of Acute ST-Elevation or Non-ST-Elevation Myocardial Infarction (FAST-MI), we analysed data from 798 patients with NSTE-AMI who were medically managed (i.e. without revascularization during the index hospitalization). Patients were categorized according to the performance of CAG and, if performed, to the extent of coronary artery disease (CAD).There were marked differences in baseline demographics, according to whether CAG was performed and to the extent of CAD. While the overall mortality rate at five years was high (56.2%), it differed greatly between groups, with patients who did not undergo CAG having a higher mortality rate (77.4%) than patients who underwent CAG (36.7%, p<0.001), and a higher mortality rate even than patients with multivessel CAD (54.2%, p<0.001). By multivariable analysis, non-performance of CAG was an independent predictor of all-cause mortality among medically managed NSTE-AMI patients (adjusted hazard ratios (95% confidence intervals) 3.19 (1.79-5.67) at 30 days, 2.28 (1.60-3.26) at one year, and 1.63 (1.28-2.07) at five years; all p<0.001).Medically managed patients with NSTE-AMI are a heterogeneous group in terms of baseline characteristics and outcomes. The highest risk patients are those who do not undergo CAG. Non-performance of CAG is a strong predictor of death. (FAST-MI, NCT00673036).

View details for DOI 10.1177/2048872615626354

View details for PubMedID 26758543
Investigating the value of right heart echocardiographic metrics for detection of pulmonary hypertension in patients with advanced lung disease. The international journal of cardiovascular imaging Amsallem, M., Boulate, D., Kooreman, Z., Zamanian, R. T., Fadel, G., Schnittger, I., Fadel, E., McConnell, M. V., Dhillon, G., Mercier, O., Haddad, F. 2017
Abstract

This study determined whether novel right heart echocardiography metrics help to detect pulmonary hypertension (PH) in patients with advanced lung disease (ALD). We reviewed echocardiography and catheterization data of 192 patients from the Stanford ALD registry and echocardiograms of 50 healthy controls. Accuracy of echocardiographic right heart metrics to detect PH was assessed using logistic regression and area under the ROC curves (AUC) analysis. Patients were divided into a derivation (n?=?92) and validation cohort (n?=?100). Experimental validation was assessed in a piglet model of mild PH followed longitudinally. Tricuspid regurgitation�(TR) was not interpretable in 52% of patients. In the derivation cohort, right atrial maximal volume index (RAVI), ventricular end-systolic area index (RVESAI), free-wall longitudinal strain and tricuspid annular plane systolic excursion (TAPSE) differentiated patients with and without PH; 20% of patients without PH had moderate to severe RV enlargement by RVESAI. On multivariate analysis, RAVI and TAPSE were independently associated with PH (AUC?=?0.77, p??0.05) and provided moderate detection value in patients without TR. Only two patients with more severe PH (mean pulmonary pressure 35 and 36�mmHg) were missed. The animal model confirmed that right heart enlargement discriminated best pigs with PH from shams. This study highlights the frequency of right heart enlargement and dysfunction in ALD irrespectively from presence of PH, therefore limiting their use for detection of PH.

View details for DOI 10.1007/s10554-017-1069-3

View details for PubMedID 28120156
Full Circle on Pulmonary Flow Dynamics in�Pulmonary Arterial Hypertension. JACC. Cardiovascular imaging Haddad, F., Amsallem, M. 2017; 10 (10 Pt B): 1278?80
View details for PubMedID 29025578
Full Circle on Pulmonary Flow Dynamics in Pulmonary Arterial Hypertension. JACC Cardiovasc Imaging Haddad, F., Amsallem, M. 2017
View details for DOI 10.1016/j.jcmg.2016.12.022
Early Development of Right Ventricular Ischemic Lesions in a Novel Large Animal Model of Acute Right Heart Failure in Chronic Thromboembolic Pulmonary Hypertension. Journal of cardiac failure Boulate, D., Arthur Ataam, J., Connolly, A. J., Giraldeau, G., Amsallem, M., Decante, B., Lamrani, L., Fadel, E., Dorfmuller, P., Perros, F., Haddad, F., Mercier, O. 2017
Abstract

Our aim was to develop a model of acute right heart failure (ARHF) in the setting of pulmonary hypertension and to characterize acute right ventricular lesions that develop early after hemodynamic restoration.We used a described piglet model of chronic pulmonary hypertension (cPH) induced by pulmonary artery occlusions. We induced ARHF in animals with cPH (ARHF-cPH group, n?=?9) by volume loading and iterative acute pulmonary embolism until hemodynamic compromise followed by dobutamine infusion for hemodynamic restoration before sacrifice for right ventricular tissue evaluation. The median duration of ARHF before sacrifice was 162 (135-189) minutes. Although ventriculoarterial coupling (measured with multibeat pressure-volume loops) and stroke volume decreased after iterative pulmonary embolism and improved with dobutamine, relative pulmonary to systemic pressure increased by 2-fold and remained similarly increased with dobutamine. Circulating high-sensitivity troponin I increased after hemodynamic restoration. We found an increase in right ventricular subendocardial and subepicardial focal ischemic lesions and in expression of autophagy-related protein LC3-II (Western blot) in the ARHF-cPH group compared with the cPH (n?=?5) and control (n?=?5) groups.We developed and phenotyped a novel large animal model of ARHF on cPH in which right ventricular ischemic lesions were observed early after hemodynamic restoration.

View details for PubMedID 28801076
Load Adaptability in Patients With Pulmonary Arterial Hypertension. The American journal of cardiology Amsallem, M., Boulate, D., Aymami, M., Guihaire, J., Selej, M., Huo, J., Denault, A. Y., McConnell, M. V., Schnittger, I., Fadel, E., Mercier, O., Zamanian, R. T., Haddad, F. 2017; 120 (5): 874?82
Abstract

Right ventricular (RV) adaptation to pressure overload is a major prognostic factor in patients with pulmonary arterial hypertension (PAH). The objectives were first to define the relation between RV adaptation and load using allometric modeling, then to compare the prognostic value of different indices of load adaptability in PAH. Both a derivation (n?=?85) and a validation cohort (n?=?200) were included. Load adaptability was assessed using 3 approaches: (1) surrogates of ventriculo-arterial coupling (e.g., RV area change/end-systolic area), (2) simple ratio of function and load (e.g., tricuspid annular plane systolic excursion/right ventricular systolic pressure), and (3) indices assessing the proportionality of adaptation using allometric pressure-function or size modeling. Proportional hazard modeling was used to compare the hazard ratio for the outcome of death or lung transplantation. The mean age of the derivation cohort was 44?�?11 years, with 80% female and 74% in New York Heart Association class III or IV. Mean pulmonary vascular resistance index (PVRI) was 24?�?11 with a wide distribution (1.6 to 57.5 WU/m2). Allometric relations were observed between PVRI and RV fractional area change (R2?=?0.53, p?
View details for PubMedID 28705377
Load Adaptability in Patients With Pulmonary Arterial Hypertension. Am J Cardiol Amsallem, M., et al 2017: 874?82
Abstract

Right ventricular (RV) adaptation to pressure overload is a major prognostic factor in patients with pulmonary arterial hypertension (PAH). The objectives were first to define the relation between RV adaptation and load using allometric modeling, then to compare the prognostic value of different indices of load adaptability in PAH. Both a derivation (n?=?85) and a validation cohort (n?=?200) were included. Load adaptability was assessed using 3 approaches: (1) surrogates of ventriculo-arterial coupling (e.g., RV area change/end-systolic area), (2) simple ratio of function and load (e.g., tricuspid annular plane systolic excursion/right ventricular systolic pressure), and (3) indices assessing the proportionality of adaptation using allometric pressure-function or size modeling. Proportional hazard modeling was used to compare the hazard ratio for the outcome of death or lung transplantation. The mean age of the derivation cohort was 44?�?11 years, with 80% female and 74% in New York Heart Association class III or IV. Mean pulmonary vascular resistance index (PVRI) was 24?�?11 with a wide distribution (1.6 to 57.5 WU/m2). Allometric relations were observed between PVRI and RV fractional area change (R2?=?0.53, p?
View details for DOI 10.1016/j.amjcard.2017.05.053
Dual-Modality Activity-Based Probes as Molecular Imaging Agents for Vascular Inflammation JOURNAL OF NUCLEAR MEDICINE Withana, N. P., Saito, T., Ma, X., Garland, M., Liu, C., Kosuge, H., Amsallem, M., Verdoes, M., Ofori, L. O., Fischbein, M., Arakawa, M., Cheng, Z., McConnell, M. V., Bogyo, M. 2016; 57 (10): 1583-1590
Abstract

Macrophages are cellular mediators of vascular inflammation and are involved in the formation of atherosclerotic plaques. These immune cells secrete proteases such as matrix metalloproteinases and cathepsins that contribute to disease formation and progression. Here, we demonstrate that activity-based probes (ABPs) targeting cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes can also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations.Macrophage-rich carotid lesions were induced in FVB mice fed on a high-fat diet by streptozotocin injection followed by ligation of the left common carotid artery. Mice with carotid atherosclerotic plaques were injected with the optical or dual-modality probes BMV109 and BMV101, respectively, via the tail vein and noninvasively imaged by optical and small-animal PET/CT at different time points. After noninvasive imaging, the murine carotid arteries were imaged in situ and ex vivo, followed by immunofluorescence staining to confirm target labeling. Additionally, human carotid plaques were topically labeled with the probe and analyzed by both sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunofluorescence staining to confirm the primary targets of the probe.Quantitative analysis of the signal intensity from both optical and PET/CT imaging showed significantly higher levels of accumulation of BMV109 and BMV101 (P < 0.005 and P < 0.05, respectively) in the ligated left carotid arteries than the right carotid or healthy arteries. Immunofluorescence staining for macrophages in cross-sectional slices of the murine artery demonstrated substantial infiltration of macrophages in the neointima and adventitia of the ligated left carotid arteries compared with the right. Analysis of the human plaque tissues by sodium dodecyl sulfate polyacrylamide gel electrophoresis confirmed that the primary targets of the probe were cathepsins X, B, S, and L. Immunofluorescence labeling of the human tissue with the probe demonstrated colocalization of the probe with CD68, elastin, and cathepsin S, similar to that observed in the experimental carotid inflammation murine model.We demonstrate that ABPs targeting the cysteine cathepsins can be used in murine models of atherosclerosis to noninvasively image activated macrophage populations using both optical and PET/CT methods. The probes could also be used to topically label human carotid plaques demonstrating similar specific labeling of activated macrophage populations. Therefore, ABPs targeting the cysteine cathepsins are potentially valuable new reagents for rapid and noninvasive imaging of atherosclerotic disease progression and plaque vulnerability.

View details for DOI 10.2967/jnumed.115.171553

View details for PubMedID 27199363
Challenging the complementarity of different metrics of left atrial function: insight from a cardiomyopathy-based study. European heart journal cardiovascular Imaging Kobayashi, Y., Moneghetti, K. J., Boralkar, K., Amsallem, M., Tuzovic, M., Liang, D., Yang, P. C., Narayan, S., Kuznetsova, T., Wu, J. C., Schnittger, I., Haddad, F. 2016
Abstract

Left ventricular (LV) strain provides incremental values to LV ejection fraction (LVEF) in predicting outcome. We sought to investigate if similar relationship is observed between left atrial (LA) emptying fraction and LA strain.In this study, we selected 50 healthy subjects, 50 patients with dilated, 50 hypertrophic, and 50 infiltrative (light-chain (AL) amyloidosis) cardiomyopathy (CMP). Echocardiographic measures included LVEF and LA emptying fraction as well as LV and LA longitudinal strain (LVLS and LALS). After regression analysis, comparison of least square means of LA strain among aetiologies was performed. Intraclass correlation coefficient (ICC) and coefficient of variation (COV) were used in the assessment of variability and reproducibility of LV and LA metrics. The mean LVLS and all LA metrics were impaired in patients with all CMP compared with healthy subjects. In contrast to the moderate relationship between LVEF and LVLS (r = -0.51, P < 0.001), there was a strong linear relationship between LA emptying fraction and LA strain (r = 0.87, P < 0.001). In multiple regression analysis, total LA strain was associated with LVLS (? = -0.48, P < 0.001), lateral E/e' (? = -0.24, P < 0.001), age (? = -0.21, P < 0.001), and heart rate (? = -0.14, P = 0.02). The least square mean of LA strain adjusted for the parameters was not different among aetiologies (ANOVA P = 0.82). The ICC (>0.77) and COV (<13) were acceptable.In contrast to LV measures, there is a strong linear relationship between volumetric and longitudinal deformation indices of left atrium irrespective of CMP aetiology. Either LA emptying fraction or LA strain could be used as an important parameter in predictive models.

View details for PubMedID 27638850
Right heart imaging in patients with heart failure: a tale of two ventricles. Current opinion in cardiology Amsallem, M., Kuznetsova, T., Hanneman, K., Denault, A., Haddad, F. 2016; 31 (5): 469-482
Abstract

The purpose is to describe the recent advances made in imaging of the right heart, including deformation imaging, tissue, and flow characterization by MRI, and molecular imaging.Recent developments have been made in the field of deformation imaging of the right heart, which may improve risk stratification of patients with heart failure and pulmonary hypertension. In addition, more attention has been given to load adaptability metrics of the right heart; these simplified indices, however, still face challenges from a conceptual point of view. The emergence of novel MRI sequences, such as native T1 mapping, allows better detection and quantification of myocardial fibrosis and could allow better prediction of postsurgical recovery of the right heart. Other advances in MRI include four-dimensional flow imaging, which may be particularly useful in congenital heart disease or for the detection of early stages of pulmonary vascular disease.The review will place the recent developments in right heart imaging in the context of clinical care and research.

View details for DOI 10.1097/HCO.0000000000000315

View details for PubMedID 27467173
Magnetic Resonance Imaging and Positron Emission Tomography Approaches to Imaging Vascular and Cardiac Inflammation CIRCULATION JOURNAL Amsallem, M., Saito, T., Tada, Y., Dash, R., McConnell, M. V. 2016; 80 (6): 1269-1277
Abstract

Inflammation plays a significant role in a wide range of cardiovascular diseases (CVDs). The numerous implications of inflammation in all steps of CVDs, including initiation, progression and complications, have prompted the emergence of noninvasive imaging modalities as diagnostic, prognostic and monitoring tools. In this review, we first synthesize the existing evidence on the role of inflammation in vascular and cardiac diseases, in order to identify the main targets used in noninvasive imaging. We chose to focus on positron emission tomographic (PET) and magnetic resonance imaging (MRI) studies, which offer the greatest potential of translation and clinical application. We detail the main preclinical and clinical studies in the following CVDs: coronary and vascular atherosclerosis, abdominal aortic aneurysms, myocardial infarction, myocarditis, and acute heart transplant rejection. We highlight the potential complementary roles of these imaging modalities, which are currently being studied in the emerging technology of PET/MRI. Finally, we provide a perspective on innovations and future applications of noninvasive imaging of cardiovascular inflammation. (Circ J 2016; 80: 1269-1277).

View details for DOI 10.1253/circj.CJ-16-0224

View details for PubMedID 27151335
Regional right ventricular dysfunction in acute pulmonary embolism: relationship with clot burden and biomarker profile INTERNATIONAL JOURNAL OF CARDIOVASCULAR IMAGING Tuzovic, M., Adigopula, S., Amsallem, M., Kobayashi, Y., Kadoch, M., Boulate, D., Krishnan, G., Liang, D., Schnittger, I., Fleischmann, D., McConnell, M. V., Haddad, F. 2016; 32 (3): 389-398
Abstract

Regional right ventricular (RV) dysfunction (RRVD) is an echocardiographic feature in acute pulmonary embolism (PE), primarily reported in patients with moderate-to-severe RV dysfunction. This study investigated the clinical importance of RRVD by assessing its relationship with clot burden and biomarkers. We identified consecutive patients admitted to the emergency department between 1999 and 2014 who underwent computed tomographic angiography, echocardiography, and biomarker testing (troponin and NT-proBNP) for suspected acute PE. RRVD was defined as normal excursion of the apex contrasting with hypokinesis of the mid-free wall segment. RV assessment included measurements of ventricular dimensions, fractional area change, free-wall longitudinal strain and tricuspid annular plane systolic excursion. Clot burden was assessed using the modified Miller score. Of 82 patients identified, 51 had acute PE (mean age 66��17�years, 43�% male). No patient had RV myocardial infarction. RRVD was present in 41�% of PEs and absent in all patients without PE. Among patients with PE, 86�% of patients with RRVD had central or multi-lobar PE. Patients with RRVD had higher prevalence of moderate-to-severe RV dilation (81 vs. 30�%, p�<�0.01) and dysfunction (86 vs. 23�%, p�<�0.01). There was a strong trend for higher troponin level in PE patients with RRVD (38 vs. 13�% in PE patients without RRVD, p�=�0.08), while there was no significant difference for NT-proBNP (67 vs. 73�%, p�=�0.88). RRVD showed good concordance between readers (87�%). RRVD is associated with an increased clot burden in acute PE and is more prevalent among patients with moderate-to-severe RV enlargement and dysfunction.

View details for DOI 10.1007/s10554-015-0780-1

View details for PubMedID 26428674
Addressing the Controversy of Estimating Pulmonary Arterial Pressure by Echocardiography JOURNAL OF THE AMERICAN SOCIETY OF ECHOCARDIOGRAPHY Amsallem, M., Sternbach, J. M., Adigopula, S., Kobayashi, Y., Vu, T. A., Zamanian, R., Liang, D., Dhillon, G., Schnittger, I., McConnell, M. V., Haddad, F. 2016; 29 (2): 93-102
Abstract

There is currently controversy over whether echocardiography provides reliable estimations of pulmonary pressures. The objective of this study was to determine the factors influencing the accuracy and reliability of estimating right ventricular systolic pressure (RVSP) using echocardiography in patients with advanced lung disease or pulmonary arterial hypertension.Between January 2001 and December 2012, 667 patients with advanced lung disease or pulmonary arterial hypertension underwent right heart catheterization and transthoracic echocardiography. Of those, 307 had both studies within 5�days of each other. The correlation and bias in estimating RVSP according to tricuspid regurgitation (TR) signal quality and reader expertise were retrospectively determined. Reasons for under- and overestimation were analyzed. The diagnostic performance of estimated RVSP, relative right ventricular size, eccentricity index, and tricuspid annular plane systolic excursion was compared for classifying patients with pulmonary hypertension (mean pulmonary artery pressure�?�25�mm�Hg).Invasive mean and systolic pulmonary artery pressures were strongly correlated (R(2)�=�0.95, P�<�.001), with mean pulmonary artery pressure�=�0.60�נsystolic pulmonary artery pressure�+�2.1�mm�Hg. Among patients undergoing right heart catheterization and transthoracic echocardiography within 5�days, level 3 readers considered only 61% of TR signals interpretable, compared with 72% in clinical reports. Overestimation in the clinical report was related mainly to not assigning peak TR velocity at the modal frequency and underestimation to overreading of uninterpretable signals. When the TR signal was interpretable, the areas under the curve for classifying pulmonary hypertension were 0.97 for RVSP and 0.98 for RVSP and eccentricity index (P�>�.05). When TR signals were uninterpretable, eccentricity index and right ventricular size were independently associated with pulmonary hypertension (area under the curve, 0.77).Echocardiography reliably estimates RVSP when attention is given to simple quality metrics.

View details for DOI 10.1016/j.echo.2015.11.001

View details for Web of Science ID 000369168700003
Early and late outcomes after trans-catheter aortic valve implantation in patients with previous chest radiation. Heart Bouleti, C., Amsallem, M., et al 2016
View details for DOI 10.1136/heartjnl-2015-309101
Exercise Strain Echocardiography in Patients With a Hemodynamically Significant Myocardial Bridge Assessed by Physiological Study JOURNAL OF THE AMERICAN HEART ASSOCIATION Kobayashi, Y., Tremmel, J. A., Kobayashi, Y., Amsallem, M., Tanaka, S., Yamada, R., Rogers, I. S., Haddad, F., Schnittger, I. 2015; 4 (11)
Abstract

Although a myocardial bridge (MB) is often regarded as a benign coronary variant, recent studies have associated MB with focal myocardial ischemia. The physiological consequences of MB on ventricular function during stress have not been well established.We enrolled 58 patients with MB of the left anterior descending artery, diagnosed by intravascular ultrasound. Patients underwent invasive physiological evaluation of the MB by diastolic fractional flow reserve during dobutamine challenge and exercise echocardiography. Septal and lateral longitudinal strain (LS) were assessed at rest and immediately after exercise and compared with strain of matched controls. Absolute and relative changes in strain were also calculated. The mean age was 42.5�16.0 years. Fifty-five patients had a diastolic fractional flow reserve ?0.76. At rest, there was no significant difference between the 2 groups in septal LS (19.0�1.8% for patients with MB versus 19.2�1.5% for control, P=0.53) and lateral LS (20.1�2.0% versus 20.0�1.6%, P=0.83). With stress, compared with controls, patients with MB had a lower peak septal LS (18.9�2.6% versus 21.7�1.6%, P<0.001) and lower absolute (-0.1�2.1% versus 2.5�1.3%, P<0.001) and relative change (-0.6�11.2% versus 13.1�7.8%, P<0.001) in septal LS, whereas there was no significant difference in lateral LS. In multivariate analysis, diastolic fractional flow reserve and length were independent determinants of lower changes in septal LS.Patients with a hemodynamically significant MB, determined by invasive diastolic fractional flow reserve, have significantly lower change in septal LS on exercise echocardiography, suggesting that septal LS may be useful for noninvasively assessing the hemodynamic significance of an MB.

View details for DOI 10.1161/JAHA.115.002496

View details for Web of Science ID 000366615600020

View details for PubMedID 26581225
Exercise Strain Echocardiography in Patients With a Hemodynamically Significant Myocardial Bridge Assessed by Physiological Study. Journal of the American Heart Association Kobayashi, Y., Tremmel, J. A., Kobayashi, Y., Amsallem, M., Tanaka, S., Yamada, R., Rogers, I. S., Haddad, F., Schnittger, I. 2015; 4 (11)
Abstract

Although a myocardial bridge (MB) is often regarded as a benign coronary variant, recent studies have associated MB with focal myocardial ischemia. The physiological consequences of MB on ventricular function during stress have not been well established.We enrolled 58 patients with MB of the left anterior descending artery, diagnosed by intravascular ultrasound. Patients underwent invasive physiological evaluation of the MB by diastolic fractional flow reserve during dobutamine challenge and exercise echocardiography. Septal and lateral longitudinal strain (LS) were assessed at rest and immediately after exercise and compared with strain of matched controls. Absolute and relative changes in strain were also calculated. The mean age was 42.5�16.0 years. Fifty-five patients had a diastolic fractional flow reserve ?0.76. At rest, there was no significant difference between the 2 groups in septal LS (19.0�1.8% for patients with MB versus 19.2�1.5% for control, P=0.53) and lateral LS (20.1�2.0% versus 20.0�1.6%, P=0.83). With stress, compared with controls, patients with MB had a lower peak septal LS (18.9�2.6% versus 21.7�1.6%, P<0.001) and lower absolute (-0.1�2.1% versus 2.5�1.3%, P<0.001) and relative change (-0.6�11.2% versus 13.1�7.8%, P<0.001) in septal LS, whereas there was no significant difference in lateral LS. In multivariate analysis, diastolic fractional flow reserve and length were independent determinants of lower changes in septal LS.Patients with a hemodynamically significant MB, determined by invasive diastolic fractional flow reserve, have significantly lower change in septal LS on exercise echocardiography, suggesting that septal LS may be useful for noninvasively assessing the hemodynamic significance of an MB.

View details for DOI 10.1161/JAHA.115.002496

View details for PubMedID 26581225
Predictors of high on-aspirin platelet reactivity in high-risk vascular patients treated with single or dual antiplatelet therapy. American journal of cardiology Amsallem, M., Manzo-Silberman, S., Dillinger, J., Sideris, G., Voicu, S., Bal dit Sollier, C., Drouet, L., Henry, P. 2015; 115 (9): 1305-1310
Abstract

Aspirin is the key treatment in the secondary prevention of atherothrombosis. Interindividual variability of response has been linked to a higher risk for ischemic events. The aim of this study was to identify clinical and biologic factors predicting high on-aspirin platelet reactivity (HPR) in a high-risk, "real-world" population of vascular patients. All platelet testing performed from 2011 to 2013 in consecutive patients receiving long-term treatment with aspirin for coronary or cerebrovascular disease was retrospectively analyzed. Indications for platelet testing were recurrent ischemic events or high-risk angioplasty. HPR was defined as aggregation intensity?20% using light-transmission aggregometry with arachidonic acid 0.5 mg/ml. Collagen-epinephrine platelet function analysis was also performed (threshold<165 seconds). Cardiovascular risk factors, usual biologic parameters, and antiplatelet treatment were recorded. A total of 1,508 patients were included (mean age 63 years, 71% men, 23% with diabetes). Antiplatelet treatment was aspirin alone in 333 patients and dual-antiplatelet therapy in 1,175 patients. HPR was found in 11.1% of patients. In multivariate analysis, independent predictive factors of HPR on light-transmission aggregometry with arachidonic acid were diabetes mellitus (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.39 to 3.16), age (OR 1.25, 95% CI 1.06 to 1.47), fibrinogen level (OR 1.20, 95% CI 1.02 to 1.42), and von Willebrand factor level (OR 1.06, 95% CI 1.03 to 1.09). On light-transmission aggregometry with arachidonic acid and collagen-epinephrine platelet function analysis, fibrinogen remained the main factor associated with HPR (OR 1.33, 95% CI 1.19 to 1.61). Similar results were found in patients treated with aspirin alone or dual-antiplatelet therapy. A fibrinogen level>4.0 g/L was associated with a 3.9-fold increased risk for HPR in patients aged <75 years. In conclusion, fibrinogen level was the major predictor of HPR on aspirin in this large population of high-risk vascular patients.

View details for DOI 10.1016/j.amjcard.2015.02.012

View details for PubMedID 25759104
Comparative assessment of ascending aortic aneurysms in Marfan patients using ECG-gated computerized tomographic angiography versus trans-thoracic echocardiography INTERNATIONAL JOURNAL OF CARDIOLOGY Amsallem, M., Ou, P., Milleron, O., Henry-Feugeas, M., Detaint, D., Arnoult, F., Vahanian, A., Jondeau, G. 2015; 184: 22-27
Abstract

Contrast-enhanced computed tomography (CT) is routinely used as a complementary technique to trans-thoracic echocardiography (TTE) for assessing thoracic aortic aneurysms (TAA). However different measures can be obtained on CT and there are no recommendations on which to use. The objective was to determine which CT measurements most closely match reference TTE measurements in Marfan patients with TAA.TTE measurements were obtained using the leading edge-to-leading edge technique in end-diastole on the parasternal longitudinal view. ECG-gated CT measurements were obtained, using the inner-to-inner technique in end-diastole by double oblique reconstruction: on three-cavity view (3C), left ventricle-aorta view (LVAo), and strict transverse plane passing through the maximal diameter "cusp to commissure" and "cusp to cusp" for each cusp. CT and TTE were performed within one month.44 Marfan patients (39 � 19 years, 48% men) were included. Dilatation of the ascending aorta was maximal at the level of the sinuses (TTE diameters: mean 47.5 � 5.3 mm). TTE diameters were similar to 3C, LVAo (mean differences: 2.2 and -0.1 mm, p=NS) and to the three "cusp to cusp" diameters (mean differences ranging from 0 to 1.1mm, p=NS), whereas "cusp to commissure" diameters were all statistically smaller than TTE (3.6 mm, 2.9 mm and 3.7 mm, p ? 0.01).Inner-to-inner "cusp to cusp" diameter measured on an ECG-gated CT should be used for comparison with 2D TTE aortic diameter at the level of the sinuses of Valsalva in patients with thoracic aortic aneurysms.

View details for DOI 10.1016/j.ijcard.2015.01.086

View details for Web of Science ID 000353763800006

View details for PubMedID 25705006
Addressing the Controversy of Estimating Pulmonary Arterial Pressure by Echocardiography. Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography Amsallem, M., Sternbach, J. M., Adigopula, S., Kobayashi, Y., Vu, T. A., Zamanian, R., Liang, D., Dhillon, G., Schnittger, I., McConnell, M. V., Haddad, F. 2015
Abstract

There is currently controversy over whether echocardiography provides reliable estimations of pulmonary pressures. The objective of this study was to determine the factors influencing the accuracy and reliability of estimating right ventricular systolic pressure (RVSP) using echocardiography in patients with advanced lung disease or pulmonary arterial hypertension.Between January 2001 and December 2012, 667 patients with advanced lung disease or pulmonary arterial hypertension underwent right heart catheterization and transthoracic echocardiography. Of those, 307 had both studies within 5�days of each other. The correlation and bias in estimating RVSP according to tricuspid regurgitation (TR) signal quality and reader expertise were retrospectively determined. Reasons for under- and overestimation were analyzed. The diagnostic performance of estimated RVSP, relative right ventricular size, eccentricity index, and tricuspid annular plane systolic excursion was compared for classifying patients with pulmonary hypertension (mean pulmonary artery pressure�?�25�mm�Hg).Invasive mean and systolic pulmonary artery pressures were strongly correlated (R(2)�=�0.95, P�<�.001), with mean pulmonary artery pressure�=�0.60�נsystolic pulmonary artery pressure�+�2.1�mm�Hg. Among patients undergoing right heart catheterization and transthoracic echocardiography within 5�days, level 3 readers considered only 61% of TR signals interpretable, compared with 72% in clinical reports. Overestimation in the clinical report was related mainly to not assigning peak TR velocity at the modal frequency and underestimation to overreading of uninterpretable signals. When the TR signal was interpretable, the areas under the curve for classifying pulmonary hypertension were 0.97 for RVSP and 0.98 for RVSP and eccentricity index (P�>�.05). When TR signals were uninterpretable, eccentricity index and right ventricular size were independently associated with pulmonary hypertension (area under the curve, 0.77).Echocardiography reliably estimates RVSP when attention is given to simple quality metrics.

View details for PubMedID 26691401
Ticagrelor effectiveness overestimated by VASP index Platelet inhibition by ticagrelor versus prasugrel in acute coronary syndrome patients according to platelet function tests INTERNATIONAL JOURNAL OF CARDIOLOGY Dillinger, J., Silberman, S. M., Sollier, C. B., Amsallem, M., Sideris, G., Voicu, S., Henry, P., Drouet, L. 2014; 176 (2): 557-559
View details for DOI 10.1016/j.ijcard.2014.07.019

View details for Web of Science ID 000341422200076

View details for PubMedID 25074556
Optical Coherence Tomography Imaging of Takayasu Coronary Arteritis CANADIAN JOURNAL OF CARDIOLOGY Amsallem, M., Henry, P., Silberman, S. M. 2014; 30 (4)
View details for DOI 10.1016/j.cjca.2013.12.019

View details for Web of Science ID 000333459100014

View details for PubMedID 24582722

Myriam Amsallem, MD PhD

Instructor, Medicine - Cardiovascular Medicine

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