Development of in vitro microfluidic models to study endothelial responses to pulsatility with different mechanical circulatory support devices.

Continuous-flow ventricular assist devices (CFVAD) and counterpulsation devices (CPD) are used to treat heart failure (HF). CFVAD can diminish pulsatility, but pulsatile modes have been implemented to increase vascular pulsatility. The effects of CFVAD in a pulsatile mode and CPD support on the function of endothelial cells (ECs) are yet to be investigated. In this study, two in vitro microfluidic models for culturing ECs are proposed to reproduce blood pressure (BP) and wall shear stress (WSS) on the arterial endothelium while using these medical devices. The layout and parameters of the two microfluidic systems were optimized based on the principle of hemodynamic similarity to efficiently simulate physiological conditions. Moreover, the unique design of the double-pump and double afterload systems could successfully reproduce the working mode of CPDs in an in vitro microfluidic system. The performance of the two systems was verified by numerical simulations and in vitro experiments. BP and WSS under HF, CFVAD in pulsatile modes, and CPD were reproduced accurately in the systems, and these induced signals improved the expression of Ca2+, NO, and reactive oxygen species in ECs, proving that CPD may be effective in normalizing endothelial function and replacing CFVAD to a certain extent to treat non-severe HF. This method offers an important tool for the study of cell mechanobiology and a key experimental basis for exploring the potential value of mechanical circulatory support devices in reducing adverse events and improving outcomes in the treatment of HF in the future.

Improvement in Biventricular Cardiac Function After Ambulatory Counterpulsation.

BACKGROUND: The NupulseCV intravascular ventricular assist system (iVAS), which consists of a durable pump placed through the subclavian artery, provides extended-duration ambulatory counterpulsation. This study investigated the effect of iVAS on biventricular cardiac function. METHODS AND RESULTS: We reviewed all heart failure patients who received iVAS implantation as a bridge to transplantation or a bridge to candidacy since April 2016 as part of the iVAS first-in-humans and subsequent feasibility study. We compared data of transthoracic echocardiography performed just before implantation (without iVAS support) and again at 30 days or just before explantation (on iVAS support). Eighteen patients (58.8 ± 7.4 years old and 15 male) received iVAS support for 53 ± 43 days. Fourteen patients were bridged to cardiac replacement therapy after 35 ± 19 days and the remaining 4 patients had been supported for 118 ± 41 days. There were no deaths during iVAS support. At 30 days, there was a significant improvement in left ventricular ejection fraction (16.5% ± 11.9% vs 24.4% ± 12.8%; P = .007) and marked reduction in left atrial size (62.7 ± 35.7 mL/m2 vs 33.8 ± 17.2 mL/m2; P < .001). Right ventricular fractional area change improved dramatically (25.4% ± 12.9% vs 42.1% ± 12.4%; P < .001). All other right ventricular and right atrial parameters improved significantly as well (size, tricuspid annular plane systolic excursion, and velocity of tricuspid annular systolic motion). CONCLUSIONS: Improvement in biventricular cardiac function was observed after 30 days of iVAS support. Further studies should examine the use of this technology as a bridge to recovery.

Hemodynamic Impact of the C-Pulse Cardiac Support Device: A One-Dimensional Arterial Model Study.

The C-Pulse is a novel extra-aortic counter-pulsation device to unload the heart in patients with heart failure. Its impact on overall hemodynamics, however, is not fully understood. In this study, the function of the C-Pulse heart assist system is implemented in a one-dimensional (1-D) model of the arterial tree, and central and peripheral pressure and flow waveforms with the C-Pulse turned on and off were simulated. The results were studied using wave intensity analysis and compared with in vivo data measured non-invasively in three patients with heart failure and with invasive data measured in a large animal (pig). In all cases the activation of the C-Pulse was discernible by the presence of a diastolic augmentation in the pressure and flow waveforms. Activation of the device initiates a forward traveling compression wave, whereas a forward traveling expansion wave is associated to the device relaxation, with waves exerting an action in the coronary and the carotid vascular beds. We also found that the stiffness of the arterial tree is an important determinant of action of the device. In settings with reduced arterial compliance, the same level of aortic compression demands higher values of external pressure, leading to stronger hemodynamic effects and enhanced perfusion. We conclude that the 1-D model may be used as an efficient tool for predicting the hemodynamic impact of the C-Pulse system in the entire arterial tree, complementing in vivo observations.

RheoStim: Development of an Adaptive Multi-Sensor to Prevent Venous Stasis.

Chronic venous insufficiency of the lower limbs is often underestimated and, in the absence of therapy, results in increasingly severe complications, including therapy-resistant tissue defects. Therefore, early diagnosis and adequate therapy is of particular importance. External counter pulsation (ECP) therapy is a method used to assist the venous system. The main principle of ECP is to squeeze the inner leg vessels by muscle contractions, which are evoked by functional electrical stimulation. A new adaptive trigger method is proposed, which improves and supplements the current therapeutic options by means of pulse synchronous electro-stimulation of the muscle pump. For this purpose, blood flow is determined by multi-sensor plethysmography. The hardware design and signal processing of this novel multi-sensor plethysmography device are introduced. The merged signal is used to determine the phase of the cardiac cycle, to ensure stimulation of the muscle pump during the filling phase of the heart. The pulse detection of the system is validated against a gold standard and provides a sensitivity of 98% and a false-negative rate of 2% after physical exertion. Furthermore, flow enhancement of the system has been validated by duplex ultrasonography. The results show a highly increased blood flow in the popliteal vein at the knee.

Novel external counterpulsation system, compact counterpulsation, was effective to treat severe ischemic heart failure: a case report.

Compact counterpulsation (CP) is a novel external counterpulsation system. The preoperative clinical utility of compact CP therapy in patients has not been established. In the present report, we describe a case wherein compact CP therapy was successfully used to treat severe ischemic heart failure. A 70-year-old man was diagnosed with ischemic heart disease and mitral valve regurgitation at 61 years of age. Therefore, he underwent coronary artery bypass and mitral valve plasty. The patient's condition started to gradually deteriorate at 68 years of age, and he became progressively dependent on catecholamine support. Mitral valve regurgitation recurred, which caused worsening of heart function. Before a mitral valve replacement, the patient had been treated with compact CP therapy to improve heart function and general condition. The patient's clinical condition improved with compact CP therapy after only ten sessions; in addition, he could be weaned off catecholamine support. No adverse effects were observed, and therefore, he could complete the CP therapy as an outpatient. Mitral valve replacement was performed after a total of 44 sessions. The patient had an uneventful postoperative course and was discharged on the 18th postoperative day. Compact CP therapy was thus performed on our patient without any discomfort and appears to be an effective treatment for patients with severe ischemic heart failure.

Novel control system to prevent right ventricular failure induced by rotary blood pump.

Right ventricular (RV) failure is a potentially fatal complication after treatment with a left ventricular assist device (LVAD). Ventricular septal shift caused by such devices is an important factor in the progress of RV dysfunction. We developed a control system for a rotary blood pump that can change rotational speed (RS) in synchrony with the cardiac cycle. We postulated that decreasing systolic RS using this system would alter ventricular septal movement and thus prevent RV failure. We implanted the EVAHEART ventricular assist device into seven adult goats weighing 54.1 ± 2.1 kg and induced acute bi-ventricular dysfunction by coronary embolization. Left and RV pressure was monitored, and ventricular septal movement was echocardiographically determined. We evaluated circuit-clamp mode as the control condition, as well as continuous and counter-pulse modes, both with full bypass. As a result, a leftward ventricular septal shift occurred in continuous and counter-pulse modes. The septal shift was corrected as a result of decreased RS during the systolic phase in counter-pulse mode. RV fractional area change improved in counter-pulse (59.0 ± 4.6%) compared with continuous (44.7 ± 4.0%) mode. In conclusion, decreased RS delivered during the systolic phase using the counter-pulse mode of our new system holds promise for the clinical correction of ventricular septal shift resulting from a LVAD and might confer a benefit upon RV function.

Overview of the 2012 Food and Drug Administration circulatory system devices panel meeting on the reclassification of external counterpulsation, intra-aortic balloon pump, and non-roller-type cardiopulmonary bypass blood pump devices.

The Food and Drug Administration held a Circulatory System Devices Advisory Panel meeting, December 5 and 6, 2012, to review the classification or potential reclassification of the following device types: external counterpulsation, intra-aortic balloon pump (IABP), and non-roller-type cardiopulmonary bypass blood pumps. These 3 devices are preamendment (Medical Device Amendments of 1976) class III devices. The advisory panel discussed the data and provided recommendations for reclassification of these devices. The panel recommended reclassification of ECP to class II for stable angina pectoris and to retain a class III for all other indications. For IABP, the recommendation was to reclassify IABP to class II for several indications (acute coronary syndrome, cardiac and noncardiac surgery, and heart failure complications) and remain class III for all other indications. As for non-roller type, the panel recommended that for cardiopulmonary bypass and temporary circulatory bypass, these devices should be reclassified to class II while retaining a class III device status for all other indications, including ventricular support both for hemodynamically unstable patients and for prophylactic support in high-risk percutaneous interventions.

The role of enhanced external counter pulsation therapy in clinical practice.

Enhanced external counterpulsation (EECP) has been approved by the United States Food and Drug Administration (FDA) for management of refractory angina (Class IIb). EECP uses three sets of pneumatic cuffs that sequentially contract during diastole, increasing aortic diastolic pressure, augmenting coronary blood flow and central venous return. EECP improves anginal symptoms and exercise tolerance, and reduces nitroglycerin use in patients with chronic, stable angina. EECP has also been shown to be safe and beneficial in patients with symptomatic stable congestive heart failure. It has been postulated that cardiac benefits of EECP are mediated though vascular endothelial growth factor (VEGF) and nitric oxide mediated vasodilatation and angiogenesis. In June 2002, the FDA also approved EECP therapy for heart failure patients.

Counterpulsation with symphony prevents retrograde carotid, aortic, and coronary flows observed with intra-aortic balloon pump support.

A counterpulsation device (Symphony) is being developed to provide long-term circulatory support for advanced heart failure (HF) patients. In acute animal experiments, flow waveform patterns in the aortic, carotid, and coronary arteries were compared during Symphony and intra-aortic balloon pump (IABP) support. Human data were examined for similarities. The 30-mL Symphony was compared to a 40-mL IABP in calves with cardiac dysfunction (80-100 kg, n = 8). Aortic pressures and aortic, carotid, and coronary artery flows were simultaneously recorded at baseline (devices off) and during 1:1 and 1:2 support. Forward, retrograde, and mean flows were calculated and compared for each test condition. Findings were also compared to aortic flow measurements recorded in HF patients (n = 21) supported by 40-mL IABP. IABP caused significant retrograde flows in the aorta, coronary (IABP: -24 ± 8 mL/min, Symphony: -6 ± 2 mL/min, baseline: -2 ± 1 mL/min, P < 0.05), and carotid arteries (IABP: -30 ± 5 mL/min, Symphony: -0 ± 0 mL/min, baseline: -0 ± 0 L/min, P < 0.05) during ventricular systole compared to the Symphony. IABP support produced higher diastolic pressure and flow augmentation compared to Symphony. Due to retrograde flows during IABP support, Symphony provided higher overall coronary, carotid, and aortic flows. Similar reduction in total aortic flows due to retrograde flow was observed in HF patients during IABP support. Counterpulsation with an IABP via aortic volume displacement produces retrograde flows during rapid balloon deflation that reduces total flow. Counterpulsation with Symphony via volume removal eliminates retrograde flow and improves total flow more than that achieved with IABP. The Symphony may provide long-term hemodynamic benefits in HF patients.

Percutaneous aortic valve replacement. Part 3: Balloon counterpulsation of a novel temporary aortic valve.

A previously published two-part study described an engineering design of a percutaneous aortic valve (PAV) replacement system, which utilizes a novel temporary aortic valve (TAV) support to improve procedural outcomes and safety. Conceptually, this investigational approach can promote accurate PAV placement, procedural hemodynamic stability, smaller catheter delivery system, reduction in PAV regurgitation, reduction in conduction and vascular complications. The balloon TAV can potentially facilitate the PAV replacement procedure by serving as the patient's surrogate aortic valve while the native valve is pretreated and replaced. The original TAV is designed to function with an effective aortic stenosis and insufficiency in moderate ranges, which lessens from the patient's more critical valve condition, should be well tolerated when the native valve becomes nonfunctional during the replacement process. Further optimization of the TAV's hemodynamic profile could further improve the system's overall performance and enhance the realization of a truly minimally invasive, cath lab-based PAV replacement procedure comparable to that of percutaneous coronary intervention. This study explores design permutations from the original published TAV, including varying the number of balloons and adding balloon counterpulsations, to improve upon its hemodynamic profile to better serve as the patient's surrogate valve and the overall PAV replacement procedure.

A novel subcutaneous counterpulsation device: acute hemodynamic efficacy during pharmacologically induced hypertension, hypotension, and heart failure.

The miniaturization of mechanical assist devices and less invasive implantation techniques may lead to earlier intervention in patients with heart failure. As such, we evaluated the effectiveness of a novel, minimally invasive, implantable counterpulsation device (CPD) in augmenting cardiac function during impaired hemodynamics. We compared the efficacy of a 32-mL stroke volume CPD with a standard 40-mL intra-aortic balloon pump (IABP) over a range of clinically relevant pathophysiological conditions. Male calves were instrumented via thoracotomy, the CPD was anastomosed to the left carotid artery, and the IABP was positioned in the descending aorta. Hemodynamic conditions of hypertension, hypotension, and heart failure were pharmacologically simulated and data were recorded during CPD and IABP support (off, 1:2, 1:1 modes) for each condition. In all three pathophysiological conditions, the CPD and IABP produced similar and statistically significant (P < 0.05) increases in coronary artery blood flow normalized to the left ventricular (LV) workload. During hypotension and heart failure conditions, however, the CPD produced significantly greater reductions in LV workload and myocardial oxygen consumption as compared with the IABP. A novel 32-mL CPD connected to a peripheral artery produced equivalent or greater hemodynamic benefits than a standard 40-mL IABP during pharmacologically induced hypertension, hypotension, and heart failure conditions.

A novel external counterpulsation system for coronary artery disease and heart failure: pilot studies and initial clinical experiences.

External counterpulsation (ECP) is a beneficial and noninvasive treatment for coronary artery disease or heart failure; however, it still has a lot of limitations. We used a novel ECP system, Compact CP, the main feature of which is the double-lumen cuff that reduces the impact of cuff inflation and the size of the air compressor. The first lumen was a contact cuff that was attached to the legs with a constant pressure (8 kPa). The second lumen was a main cuff that was inflated and deflated with a driving pressure and synchronized to the cardiac cycle. In this report, we describe the results of four pilot studies in a total number of 39 healthy volunteers and initial clinical experiences of this system in three patients. The pilot studies demonstrated that the ECP system provided significant diastolic augmentation and systolic unloading. It also achieved a satisfactory diastolic/systolic pressure ratio (1.00 ± 0.06) with a high comfort level at a driving pressure of 40 kPa. Higher pressure (50-70 kPa) increased the assist performance but decreased the comfort level. ECP was also applied with a patient with chronic refractory angina and two patients with postoperative heart failure following cardiac surgery. The clinical conditions improved. No adverse effect was observed. Our novel ECP system is safe, effective, and promising in the treatment of coronary artery disease or heart failure. Further clinical investigations are needed to support the significance of this system.

Enhanced external counterpulsation: mechanisms of action and clinical applications.

Symptomatic coronary artery disease (CAD) and heart failure (HF), either of ischaemic or nonischaemic aetiology, are common medical problems. Despite optimal medical treatment and improved revascularisation techniques, a significant number of patients are not successfully managed.Among the non-pharmacological, alternative, non-invasive treatments suggested for these patients, enhanced external counterpulsation (EECP) is considered the most effective one. EECP, administered in an outpatient setting, consists of three pneumatic cuffs applied to each of the patient's legs that are sequentially inflated and deflated synchronised with the cardiac cycle. Numerous clinical trials have shown that EECP is safe and effective in patients with ischaemic heart disease, with or without left ventricular dysfunction, improving their quality of life. EECP appears to be beneficial as an adjunctive therapy in patients with HF of any aetiology. Cardiac syndrome X has been shown to be effectively treated with EECP. Research in EECP expanded in its potential use for entities other than heart disease. More trials are necessary, including sham-controlled trials, to further establish EECP among medical society.

Clinical Outcomes and Quality of Life With an Ambulatory Counterpulsation Pump in Advanced Heart Failure Patients: Results of the Multicenter Feasibility Trial.

BACKGROUND: The NuPulseCV intravascular ventricular assist system (iVAS) provides extended duration ambulatory counterpulsation via a durable pump placed through the distal subclavian artery. METHODS: We performed a prospective, single-arm, multicenter, US Food and Drug Administration-approved feasibility trial of iVAS therapy as a bridge to transplant or decision following the FIH (First-In-Human) trial. RESULTS: Forty-seven patients were enrolled, and 45 patients (median 61 years old, 37 males, and 30 listed on United Network of Organ Sharing) received iVAS support for median 44 (25-87) days. There were no intraoperative complications. Success was defined as survival or transplant on iVAS therapy free from disabling stroke. Outcome success at 30 days (the primary end point of this study) and at 6 months was 89% and 80%, respectively. During 6 months of iVAS support, 2 patients died and 2 patients experienced disabling neurological dysfunction. Six-minute walk distance, 2-minute step test, and Kansas City Cardiomyopathy Questionnaire score improved during 4-week iVAS support. CONCLUSIONS: This feasibility trial demonstrated promising short-term outcomes of iVAS therapy with improved functional capacity and quality of life during the therapy. Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02645539.

Intermittent pneumatic compression and pharmacologic thrombosis prophylaxis.

PURPOSE OF REVIEW: Deep vein thrombosis and pulmonary embolism, together referred to as venous thromboembolism, represent a common, very serious healthcare concern. The Surgeon General recently issued a 'call to action' for venous thromboembolism, and the Joint Commission for Accreditation of Healthcare Organizations and the Surgical Care Improvement Project developed and implemented measures regarding thrombosis prophylaxis. Despite these measures, only about 50% of the 'at-risk' patients worldwide receive appropriate thrombosis prophylaxis. RECENT FINDINGS: New data are available regarding intermittent pneumatic compression. Several novel laboratory-synthesized anticoagulants have demonstrated both efficacy and safety in orthopedic surgery patients and are in various stages of approval. These drugs are pills and have a similar or improved efficacy/safety profile as traditional anticoagulants, including vitamin K antagonists. SUMMARY: Intermittent pneumatic compression in conjunction with currently available parenteral anticoagulants has shown the greatest efficacy in very-high-risk surgical patients. The new oral anticoagulants have similar efficacy and safety profiles as existing parenteral anticoagulants and allow easy and cost-effective outpatient administration without the need for monitoring. Since it has been shown that most venous thromboembolism events occur following hospital discharge, these new anticoagulants may result in very significant reduction in the overall incidence of venous thromboembolism events.

Salutary Effects of the PULVAD, a Novel Implantable Counterpulsation Assist Device, on Cardiac Mechanoenergetics.

The Pressure Unloading Left Ventricular Assist Vevice (PULVAD) is a novel implantable counterpulsation LVAD, designed to provide ventricular unloading with augmentation of LV performance and retention of pulsatility. We assessed the effects of the PULVAD on hemodynamics and LV mechanoenergetics in seven farm pigs with acute ischemic heart failure. The PULVAD was implanted in the thorax and was connected to the ascending aorta. The PULVAD was pneumatically driven by a standard intra-aortic balloon pump console and was electrocardiogram-synchronized to provide LV pressure unloading along with diastolic aortic pressure augmentation. Hemodynamics, indices of LV mechanoenergetics, and coronary blood flow were measured without and after brief PULVAD support. PULVAD support decreased LV afterload and improved LV mechanical performance (increased ejection fraction, stroke volume, cardiac output and maximum elastance). The PULVAD concurrently reduced LV energy consumption (decreased stroke work and pressure-volume area) and optimized LV energetic performance (improved the ratio of stroke work to pressure-volume area). PULVAD support increased mean coronary blood flow, through dramatic augmentation of diastolic blood flow. In conclusion, the PULVAD unloads the failing LV, optimizes LV mechanoenergetics, and augments coronary blood flow. These salutary effects of short-term PULVAD support provide the foundation for long-term testing.

Preload Sensitivity with TORVAD Counterpulse Support Prevents Suction and Overpumping.

PURPOSE: This study compares preload sensitivity of continuous flow (CF) VAD support to counterpulsation using the Windmill toroidal VAD (TORVAD). The TORVAD is a two-piston rotary pump that ejects 30 mL in early diastole, which increases cardiac output while preserving aortic valve flow. METHODS: Preload sensitivity was compared for CF vs. TORVAD counterpulse support using two lumped parameter models of the cardiovascular system: (1) an open-loop model of the systemic circulation was used to obtain ventricular function curves by isolating the systemic circulation and prescribing preload and afterload boundary conditions, and (2) a closed-loop model was used to test the physiological response to changes in pulmonary vascular resistance, systemic vascular resistance, heart rate, inotropic state, and blood volume. In the open-loop model, ventricular function curves (cardiac output vs left ventricular preload) are used to assess preload sensitivity. In the closed-loop model, left ventricular end systolic volume is used to assess the risk of left ventricular suction. RESULTS: At low preloads of 5 mmHg, CF support overpumps the circulation compared to TORVAD counterpulse support (cardiac output of 3.3 L/min for the healthy heart, 4.7 with CF support, and 3.5 with TORVAD counterpulse support) and has much less sensitivity than counterpulse support (0.342 L/min/mmHg for the healthy heart, 0.092 with CF support, and 0.306 with TORVAD counterpulse support). In the closed-loop model, when PVR is increased beyond 0.035 mmHg s/mL, CF support overpumps the circulation and causes ventricular suction events, but TORVAD counterpulse support maintains sufficient ventricular volume and does not cause suction. CONCLUSIONS: Counterpulse support with the TORVAD preserves aortic valve flow and provides physiological sensitivity across all preload conditions. This should prevent overpumping and minimize the risk of suction.

Perfusion augmentation in acute stroke using mechanical counter-pulsation-phase IIa: effect of external counterpulsation on middle cerebral artery mean flow velocity in five healthy subjects.

BACKGROUND AND PURPOSE: External counterpulsation (ECP) improves coronary perfusion, increases left ventricular stroke volume similar to intraaortic balloon counterpulsation, and recruits arterial collaterals within ischemic territories. We sought to determine ECPs effect on middle cerebral artery (MCA) blood flow augmentation in normal controls as a first step to support future clinical trials in acute stroke. METHODS: Healthy volunteers were recruited and screened for exclusions. Bilateral 2-MHz pulsed wave transcranial Doppler (TCD) probes were mounted by head frame, and baseline M1 MCA TCD measurements were obtained. ECP was then initiated using standard procedures for 30 minutes, and TCD readings were repeated at 5 and 20 minutes. Physiological correlates associated with ECP-TCD waveform morphology were identified, and measurable criteria for TCD assessment of ECP arterial mean flow velocity (MFV) augmentation were constructed. RESULTS: Five subjects were enrolled in the study. Preprocedural M1 MCA TCD measurements were within normal limits. Onset of ECP counterpulsation produced an immediate change in TCD waveform configuration with the appearance of a second upstroke at the dicrotic notch, labeled peak diastolic augmented velocity (PDAV). Although end-diastolic velocities did not increase, both R-MCA and L-MCA PDAVs were significantly higher than baseline end-diastolic values (P<0.05 Wilcoxon rank-sum test) at 5 and 20 minutes. Augmented MFVs (aMFVs) were also significantly higher than baseline MFV in the R-MCA and L-MCA at both 5 and 20 minutes (P<0.05). CONCLUSIONS: ECP induces marked changes in cerebral arterial waveforms and augmented peak diastolic and mean MCA flow velocities on TCD in 5 healthy subjects.