PhD Candidate, MIT
Using mechanical artificial support device function to determine organic natural organ state
Organ transplantation is a valuable treatment for patients suffering from organ failure, however it is limited by increasing shortage of donor organs. Because of this shortage, mechanical support has emerged as an effective therapy to promote recovery of native organ function, especially in the setting of acute heart failure. Acute heart failure caused by ischemic cardiogenic shock is increasingly common and is not being adequately treated via traditional medical therapy with mortality rates exceeding 40%. Mechanical circulatory support (MCS) devices that act as a pump to unload the heart have been shown to decrease mortality and promote recovery of native heart function in these patients, but only when correctly used. Despite decades of improvement, MCS devices remain nascent and difficult to operate with heavy reliance on qualitative clinician evaluation due to naiveté and poor insight into how these unique physiological situations behave. To propel our understanding, we hypothesize that well integrated support devices are coupled with residual native organ function and that their performance is inherently interconnected. Moreover, we propose that this understanding will lead to novel insights into physiology and determination of new ways to define organ state. Thus, the goals of this work are to leverage the interaction between a support device and failing organ to fully assess the state of the organ, and then utilize this information towards improved control of the device and understanding of the failing organ’s pathophysiology. To accomplish this, our research program uses a highly-integrated approach of benchtop testing, animal disease models, and retrospective patient data to determine clinically relevant markers of organ function using the Abiomed Impella as a paradigmatic device. We develop and utilize a novel mock circulatory loop (MCL) to identify and differentiate how a MCS device operates due to variation from the cardiac cycle and changing cardiac state through parametric analysis of device operation (motor current) and physiologic signals (pressures and flows). We then use this model to establish algorithms to predict existing parameters of cardiac state that are easily validated, as well as advanced metrics of cardiac dynamics and contractility. This is done through MCL testing for characterization, acute animal models for validation, and finally retrospective patient data to demonstrate clinical utility.
Abstract: Extracorporeal membrane oxygenation following cardiac surgery safeguards end-organ oxygenation but unfavorably alters cardiac hemodynamics. Along with the detrimental effects of cardiac surgery to the right heart, this might impact outcome, particularly in patients with preexisting right ventricular (RV) dysfunction. We sought to determine the prognostic impact of RV function and to improve established risk-prediction models in this vulnerable patient cohort.Of 240 patients undergoing extracorporeal membrane oxygenation support following cardiac surgery, 111 had echocardiographic examinations at our institution before implantation of extracorporeal membrane oxygenation and were thus included. Median age was 67 years (interquartile range 60-74), and 74 patients were male. During a median follow-up of 27 months (interquartile range 16-63), 75 patients died. Fifty-one patients died within 30 days, 75 during long-term follow-up (median follow-up 27 months, minimum 5 months, maximum 125 months). Metrics of RV function were the strongest predictors of outcome, even stronger than left ventricular function (P<0.001 for receiver operating characteristics comparisons). Specifically, RV free-wall strain was a powerful predictor univariately and after adjustment for clinical variables, Simplified Acute Physiology Score-3, tricuspid regurgitation, surgery type and duration with adjusted hazard ratios of 0.41 (95%CI 0.24-0.68; P=0.001) for 30-day mortality and 0.48 (95%CI 0.33-0.71; P<0.001) for long-term mortality for a 1-SD (SD=-6%) change in RV free-wall strain. Combined assessment of the additive EuroSCORE and RV free-wall strain improved risk classification by a net reclassification improvement of 57% for 30-day mortality (P=0.01) and 56% for long-term mortality (P=0.02) compared with the additive EuroSCORE alone.RV function is strongly linked to mortality, even after adjustment for baseline variables and clinical risk scores. RV performance improves established risk prediction models for short- and long-term mortality.
Pub.: 30 Jul '17, Pinned: 07 Sep '17
Abstract: The medical burden of heart failure (HF) has spurred interest in clinicians and scientists to develop therapies to restore the function of a failing heart. To advance this agenda, the National Heart Lung Blood Institute (NHLBI) convened a Working Group of experts on June 2-3, 2016 in Bethesda Maryland to develop recommendations for the NHLBI aimed at advancing the science of cardiac recovery in the setting of mechanical circulatory support (MCS). MSC devices effectively reduce volume and pressure overload that drives the cycle of progressive myocardial dysfunction, thereby triggering structural and functional reverse remodeling. Research in this field could be innovative in many ways and the Working Group specifically discussed opportunities associated with genome-phenome systems biology approaches, genetic epidemiology, bioinformatics and precision medicine at the population level, advanced imaging modalities including molecular and metabolic imaging, and developing minimally invasive surgical and percutaneous bioengineering approaches. These new avenues of investigations could lead to new treatments that target phylogenetically conserved pathways involved in cardiac reparative mechanisms. A central point that emerged from the NHLBI Working Group meeting was that the lessons learned from the MCS investigational setting can be extrapolated to the broader HF population. With the precedents set by the significant impact of studies of other well-controlled and tractable subsets on larger populations, such as the genetic work in both cancer and cardiovascular disease, the work to improve our understanding of cardiac recovery and resilience in MCS patients could be transformational for the greater HF population.
Pub.: 25 Jul '17, Pinned: 07 Sep '17
Abstract: Patients with a Ventricular Assist Device (VAD) are hemodynamically stable but show an impaired exercise capacity. Aim of this work is to identify and to describe the limiting factors of exercise physiology with a VAD. We searched for data concerning exercise in heart failure condition and after VAD implantation from the literature. Data were analyzed by using a cardiorespiratory simulator that worked as a collector of inputs coming from different papers. As a preliminary step the simulator was used to reproduce the evolution of hemodynamics from rest to peak exercise (ergometer cycling) in heart failure condition. Results evidence an increase of cardiac output of +2.8 l/min and a heart rate increase to 67% of the expected value. Then, we simulated the effect of a continuous-flow VAD at both rest and exercise. Total cardiac output increases of +3.0 l/min (+0.9 l/min due to the VAD and +2.1 l/min to the native ventricle). Since the left ventricle works in a non-linear portion of the diastolic stiffness line, we observed a consistent increase of pulmonary capillary wedge pressure (from 14 to 20 mmHg) for a relatively small increase of end-diastolic volume (from 182 to 189 cm3). We finally increased VAD speed during exercise to the maximum possible value and we observed a reduction of wedge pressure (-4.5 mmHg), a slight improvement of cardiac output (8.0 l/min) and a complete unloading of the native ventricle. The VAD can assure a proper hemodynamics at rest, but provides an insufficient unloading of the left ventricle and does not prevent wedge pressure from rising during exercise. Neither the VAD provides major benefits during exercise in terms of total cardiac output, which increases to a similar extend to an unassisted heart failure condition. VAD speed modulation can contribute to better unload the ventricle but the maximal flow reachable with the current devices is below the cardiac output observed in a healthy heart.
Pub.: 25 Jul '17, Pinned: 07 Sep '17
Abstract: Despite major advances, ischemic cardiomyopathy (ICM) remains a significant cause of death and disability worldwide, with coronary artery disease (CAD) the leading cause of left ventricular (LV) systolic dysfunction. Coronary revascularization may improve LV function, heart failure symptoms and cardiovascular outcomes in high-risk patients with myocardial viability. Multiple imaging modalities have been utilized to detect viable myocardium and predict functional recovery following revascularization. Dobutamine stress echocardiography (DSE), nuclear imaging and cardiac MRI (CMR) are frequently used to assess viability. This review will summarize the extant literature on this topic, describe the role and methods for viability imaging in modern clinical practice, provide a patient-centered perspective regarding the controversies surrounding the current utility of viability imaging, as well as discuss future directions.
Pub.: 25 Jul '17, Pinned: 07 Sep '17
Abstract: Mechanical circulatory support (MCS) devices have become a standard therapy for heart failure (HF) patients. MCS device designs may differ by level of support, inflow and/or outflow cannulation sites, and mechanism(s) of cardiac unloading and blood flow delivery. Investigation and direct comparison of hemodynamic parameters that help characterize performance of MCS devices has been limited. We quantified cardiac and vascular hemodynamic responses for different types of MCS devices. Continuous flow (CF) left ventricular (LV) assist devices (LVAD) with LV or left atrial (LA) inlet, counterpulsation devices, percutaneous CF LVAD, and intra-aortic rotary blood pumps (IARBP) were quantified using established computer simulation and mock flow loop models. Hemodynamic data were analyzed on a beat-to-beat basis at baseline HF and over a range of MCS support. Results demonstrated that all LVAD greatly diminished vascular pulsatility (P) and LV external work (LVEW). LVAD with LA inflow provided a greater reduction in LVEW compared to LVAD with LV inflow, but at the potential risk for blood stasis/thrombosis in the LV at high support. Counterpulsation provided greater coronary flow (CoF) augmentation, but had a lower reduction in LVEW compared to partial percutaneous LVAD support. IARBP diminished LVEW, but at the expense of diminished CoF due to coronary steal. The hemodynamic benefits for each type of mechanical circulatory support system are unique and clinical decisions on device selection to maximize end organ perfusion and minimize invasiveness needs to be considered for an individual patients' presentation.
Pub.: 15 Jul '17, Pinned: 07 Sep '17
Abstract: Few published studies have evaluated the power of the oxygen uptake efficiency slope (OUES) to predict outcomes in patients with idiopathic pulmonary arterial hypertension (IPAH), who typically die of right-sided heart failure. Our study sought to evaluate the power of OUES to predict clinical worsening and mortality in patients with IPAH.Patients with newly diagnosed IPAH who underwent symptom-limited cardiopulmonary exercise testing from November 11, 2010, to June 25, 2015, in our hospital were prospectively enrolled and followed for up to 66 months. Clinical worsening and mortality were recorded. A total of 210 patients with IPAH (159 women; mean age, 32±10 years) were studied with a median follow-up of 41 months. Thirty-one patients died, 1 patient underwent lung transplantation, and 85 patients presented with clinical worsening. The univariate analysis revealed that OUES, OUESI (OUESI=OUES/body surface area), peak oxygen uptake (V˙O2), peak V˙O2/kg, ventilation (V˙E)/carbon dioxide output (V˙CO2) slope, peak systolic blood pressure, heart rate recovery, pulmonary vascular resistance, cardiac index, N-terminal prohormone brain natriuretic peptide, and World Health Organization functional class were all predictive of clinical worsening and mortality (all P<0.05). Multivariate analysis demonstrated that OUESI and cardiac index were independently predictive of clinical worsening, and OUESI and N-terminal prohormone brain natriuretic peptide were independently predictive of mortality. Patients with OUESI ≤0.52 m(-2) had a worse 5-year survival rate than patients with OUESI >0.52 m(-2) (41.9% versus 89.8%, P<0.0001).The OUES, a submaximal parameter obtained from cardiopulmonary exercise testing, provides prognostic information for predicting clinical worsening and mortality in patients with IPAH.
Pub.: 02 Jul '17, Pinned: 07 Sep '17
Abstract: In an important number of heart failure (HF) patients substantial or complete myocardial recovery occurs. In the strictest sense, myocardial recovery is a return to both normal structure and function of the heart. HF patients with myocardial recovery or recovered ejection fraction (EF; HFrecEF) are a distinct population of HF patients with different underlying etiologies, demographics, comorbidities, response to therapies and outcomes compared to HF patients with persistent reduced (HFrEF) or preserved ejection fraction (HFpEF). Improvement of left ventricular EF has been systematically linked to improved quality of life, lower rehospitalization rates and mortality. However, mortality and morbidity in HFrecEF patients remain higher than in the normal population. Also, persistent abnormalities in biomarker and gene expression profiles in these patients lends weight to the hypothesis that pathological processes are ongoing. Currently, there remains a lack of data to guide the management of HFrecEF patients. This review will discuss specific characteristics, pathophysiology, clinical implications and future needs for HFrecEF.
Pub.: 30 May '17, Pinned: 07 Sep '17
Abstract: Mechanical circulatory support devices (MCSDs) have gained widespread clinical acceptance as an effective heart failure (HF) therapy. The concept of harnessing the kinetic energy (KE) available in the forward aortic flow (AOF) is proposed as a novel control strategy to further increase the cardiac output (CO) provided by MCSDs. A complete mathematical development of the proposed theory and its application to an example MCSDs (two-segment extra-aortic cuff) are presented. To achieve improved device performance and physiologic benefit, the example MCSD timing is regulated to maximize the forward AOF KE and minimize retrograde flow. The proof-of-concept was tested to provide support with and without KE control in a computational HF model over a wide range of HF test conditions. The simulation predicted increased stroke volume (SV) by 20% (9 mL), CO by 23% (0.50 L/min), left ventricle ejection fraction (LVEF) by 23%, and diastolic coronary artery flow (CAF) by 55% (3 mL) in severe HF at a heart rate (HR) of 60 beats per minute (BPM) during counterpulsation (CP) support with KE control. The proposed KE control concept may improve performance of other MCSDs to further enhance their potential clinical benefits, which warrants further investigation. The next step is to investigate various assist technologies and determine where this concept is best applied. Then bench-test the combination of kinetic energy optimization and its associated technology choice and finally test the combination in animals.
Pub.: 18 May '17, Pinned: 07 Sep '17