von Willebrand Factor and Angiopoietin-2 are Sensitive Biomarkers of Pulsatility in Continuous-Flow Ventricular Assist Device Patients.

Nonsurgical bleeding occurs in a significant proportion of patients implanted with continuous-flow ventricular assist devices (CF-VADs) and is associated with nonphysiologic flow with diminished pulsatility. An in vitro vascular pulse perfusion model seeded with adult human aortic endothelial cells (HAECs) was used to identify biomarkers sensitive to changes in pulsatility. Diminished pulsatility resulted in an ~45% decrease in von Willebrand factor (vWF) levels from 9.80 to 5.32 ng/ml (n = 5, p < 0.05) and a threefold increase in angiopoietin-2 (ANGPT-2) levels from 775.29 to 2471.93 pg/ml (n = 5, p < 0.05) in cultured HAECs. These changes are in agreement with evaluation of patient blood samples obtained pre-CF-VAD implant and 30-day postimplant: a decrease in plasma vWF level by 50% from ~45.59 to ~22.49 µg/ml (n = 15, p < 0.01) and a 64% increase in plasma ANGPT-2 level from 7,073 to 11,615 pg/ml (n = 8, p < 0.05). This study identified vWF and ANGPT-2 as highly sensitive to changes in pulsatility, in addition to interleukin-6 (IL-6), IL-8, and tumor necrosis-α (TNF-α). These biomarkers may help determine the optimal level of pulsatility and help identify patients at high risk of nonsurgical bleeding.

Predicting Recurrence of Non-Muscle-Invasive Bladder Cancer: Current Techniques and Future Trends.

Bladder cancer (BC) is the 10th most common cancer globally and has a high mortality rate if not detected early and treated promptly. Non-muscle-invasive BC (NMIBC) is a subclassification of BC associated with high rates of recurrence and progression. Current tools for predicting recurrence and progression on NMIBC use scoring systems based on clinical and histopathological markers. These exclude other potentially useful biomarkers which could provide a more accurate personalized risk assessment. Future trends are likely to use artificial intelligence (AI) to enhance the prediction of recurrence in patients with NMIBC and decrease the use of standard clinical protocols such as cystoscopy and cytology. Here, we provide a comprehensive survey of the most recent studies from the last decade (N = 70 studies), focused on the prediction of patient outcomes in NMIBC, particularly recurrence, using biomarkers such as radiomics, histopathology, clinical, and genomics. The value of individual and combined biomarkers is discussed in detail with the goal of identifying future trends that will lead to the personalized management of NMIBC.

Acute Response of Human Aortic Endothelial Cells to Loss of Pulsatility as Seen during Cardiopulmonary Bypass.

Cardiopulmonary bypass (CPB) results in short-term (3-5 h) exposure to flow with diminished pulsatility often referred to as "continuous flow". It is unclear if short-term exposure to continuous flow influences endothelial function, particularly, changes in levels of pro-inflammatory and pro-angiogenic cytokines. In this study, we used the endothelial cell culture model (ECCM) to evaluate if short-term (≤5 h) reduction in pulsatility alters levels of pro-inflammatory/pro-angiogenic cytokine levels. Human aortic endothelial cells (HAECs) cultured within the ECCM provide a simple model to evaluate endothelial cell function in the absence of confounding factors. HAECs were maintained under normal pulsatile flow for 24 h and then subjected to continuous flow (diminished pulsatile pressure and flow) as observed during CPB for 5 h. The ECCM replicated pulsatility and flow morphologies associated with normal hemodynamic status and CPB as seen with clinically used roller pumps. Levels of angiopoietin-2 (ANG-2), vascular endothelial growth factor-A (VEGF-A), and hepatocyte growth factor were lower in the continuous flow group in comparison to the pulsatile flow group whereas the levels of endothelin-1 (ET-1), granulocyte colony stimulating factor, interleukin-8 (IL-8) and placental growth factor were higher in the continuous flow group in comparison to the pulsatile flow group. Immunolabelling of HAECs subjected to continuous flow showed a decrease in expression of ANG-2 and VEGF-A surface receptors, tyrosine protein kinase-2 and Fms-related receptor tyrosine kinase-1, respectively. Given that the 5 h exposure to continuous flow is insufficient for transcriptional regulation, it is likely that pro-inflammatory/pro-angiogenic signaling observed was due to signaling molecules stored in Weible-Palade bodies (ET-1, IL-8, ANG-2) and via HAEC binding/uptake of soluble factors in media. These results suggest that even short-term exposure to continuous flow can potentially activate pro-inflammatory/pro-angiogenic signaling in cultured HAECs and pulsatile flow may be a successful strategy in reducing the undesirable sequalae following continuous flow CPB.

A novel computer-aided diagnostic system for accurate detection and grading of liver tumors.

Liver cancer is a major cause of morbidity and mortality in the world. The primary goals of this manuscript are the identification of novel imaging markers (morphological, functional, and anatomical/textural), and development of a computer-aided diagnostic (CAD) system to accurately detect and grade liver tumors non-invasively. A total of 95 patients with liver tumors (M = 65, F = 30, age range = 34-82 years) were enrolled in the study after consents were obtained. 38 patients had benign tumors (LR1 = 19 and LR2 = 19), 19 patients had intermediate tumors (LR3), and 38 patients had hepatocellular carcinoma (HCC) malignant tumors (LR4 = 19 and LR5 = 19). A multi-phase contrast-enhanced magnetic resonance imaging (CE-MRI) was collected to extract the imaging markers. A comprehensive CAD system was developed, which includes the following main steps: i) estimation of morphological markers using a new parametric spherical harmonic model, ii) estimation of textural markers using a novel rotation invariant gray-level co-occurrence matrix (GLCM) and gray-level run-length matrix (GLRLM) models, and iii) calculation of the functional markers by estimating the wash-in/wash-out slopes, which enable quantification of the enhancement characteristics across different CE-MR phases. These markers were subsequently processed using a two-stages random forest-based classifier to classify the liver tumor as benign, intermediate, or malignant and determine the corresponding grade (LR1, LR2, LR3, LR4, or LR5). The overall CAD system using all the identified imaging markers achieved a sensitivity of 91.8%±0.9%, specificity of 91.2%±1.9%, and F[Formula: see text] score of 0.91±0.01, using the leave-one-subject-out (LOSO) cross-validation approach. Importantly, the CAD system achieved overall accuracies of [Formula: see text], 85%±2%, 78%±3%, 83%±4%, and 79%±3% in grading liver tumors into LR1, LR2, LR3, LR4, and LR5, respectively. In addition to LOSO, the developed CAD system was tested using randomly stratified 10-fold and 5-fold cross-validation approaches. Alternative classification algorithms, including support vector machine, naive Bayes classifier, k-nearest neighbors, and linear discriminant analysis all produced inferior results compared to the proposed two stage random forest classification model. These experiments demonstrate the feasibility of the proposed CAD system as a novel tool to objectively assess liver tumors based on the new comprehensive imaging markers. The identified imaging markers and CAD system can be used as a non-invasive diagnostic tool for early and accurate detection and grading of liver cancer.

Heart slice culture system reliably demonstrates clinical drug-related cardiotoxicity.

The limited availability of human heart tissue and its complex cell composition are major limiting factors for the reliable testing of drug efficacy and toxicity. Recently, we developed functional human and pig heart slice biomimetic culture systems that preserve the viability and functionality of 300 µm heart slices for up to 6 days. Here, we tested the reliability of this culture system for testing the cardiotoxicity of anti-cancer drugs. We tested three anti-cancer drugs (doxorubicin, trastuzumab, and sunitinib) with known different mechanisms of cardiotoxicity at three concentrations and assessed the effect of these drugs on heart slice viability, structure, function and gene expression. Slices incubated with any of these drugs for 48 h showed diminished in viability as well as loss of cardiomyocyte structure and function. Mechanistically, RNA sequencing of doxorubicin-treated tissues demonstrated a significant downregulation of cardiac genes and upregulation of oxidative stress responses. Trastuzumab treatment downregulated cardiac muscle contraction-related genes consistent with its clinically known effect on cardiomyocytes. Interestingly, sunitinib treatment resulted in significant downregulation of angiogenesis-related genes, in line with its mechanism of action. Similar to hiPS-derived-cardiomyocytes, heart slices recapitulated the expected toxicity of doxorubicin and trastuzumab, however, slices were superior in detecting sunitinib cardiotoxicity and mechanism in the clinically relevant concentration range of 0.1-1 µM. These results indicate that heart slice culture models have the potential to become a reliable platform for testing and elucidating mechanisms of drug cardiotoxicity.

Cavopulmonary assist: Long-term reversal of the Fontan paradox.

OBJECTIVE: Fontan circulatory inefficiency can be addressed by replacing the missing subpulmonary power source to reverse the Fontan paradox. An implantable cavopulmonary assist device is described that will simultaneously reduce systemic venous pressure and increase pulmonary arterial pressure, improving preload and cardiac output, in a univentricular Fontan circulation on a long-term basis. METHODS: A rotary blood pump that was based on the von Karman viscous pump was designed for implantation into the total cavopulmonary connection (TCPC). It will impart modest pressure energy to augment Fontan flow without risk of obstruction. In the event of rotational failure, it is designed to default to a passive flow diverter. Pressure-flow performance was characterized in vitro in a Fontan mock circulatory loop with blood analog. RESULTS: The pump performed through the fully specified operating range, augmenting flow in all 4 directions of the TCPC. Pressure rise of 6 to 8 mm Hg was readily achieved, ranging to 14 mm Hg at highest speed (5600 rpm). Performance was consistent across a wide range of cardiac outputs. In stalled condition (0 rpm), there was no discernible pressure loss across the TCPC. CONCLUSIONS: A blood pump technology is described that can reverse the Fontan paradox and may permit a surgical strategy of long-term biventricular maintenance of a univentricular Fontan circulation. The technology is intended for Fontan failure in which right-sided circulatory inefficiencies predominate and ventricular systolic function is preserved. It may also apply before clinical Fontan failure as health maintenance to preempt the progression of Fontan disease.

Feasibility Study of Pulsatile Left Ventricular Assist Device for Prolonged Ex Vivo Lung Perfusion.

BACKGROUND: Ex vivo lung perfusion (EVLP) has the potential to increase the donor pool for lung transplantation by facilitating resuscitation and extended evaluation of marginal organs. Current EVLP methodology employs continuous flow (CF) pumps that produce non-pulsatile EVLP hemodynamics. In this feasibility study, we tested the hypothesis that a pulsatile flow (PF) pump will provide better EVLP support than a CF pump through delivery of physiologic hemodynamics. METHODS: Porcine lungs were supported in an EVLP model by centrifugal CF (n = 3) or PF (n = 4) left ventricular assist devices. Lungs were ventilated at 4 to 5 mL/kg, 0.21 fraction of inspired oxygen (FiO2), and perfused with an acellular, albumin-based solution corrected for osmolarity, acid-base balance, and carbon dioxide pressure (≤20 hours at 30°C) for a minimum of 12 hours support. Prostaglandin E1 and 30% albumin were infused continuously. Hemodynamic, respiratory, and blood gas parameters were continuously monitored and digitally recorded hourly. Parenchymal biopsies were used for quantification of wet to dry weight ratio. RESULTS: All lungs maintained function in the EVLP circuit for a minimum of 12 hours (mean 14.7 ± 1 hours) and demonstrated minimal edema formation. The PF EVLP produced higher pulsatility as demonstrated by greater energy equivalent pressure and surplus hemodynamic energy compared with CF EVLP (p < 0.05). There were no statistically significant differences in pulmonary impedance, arterial partial pressure of oxygen/fraction of inspired oxygen, wet to dry weight ratio, and peak airway pressure between CF and PF EVLP. CONCLUSIONS: The CF and PF EVLP systems successfully maintained lungs 12+ hours using a modified Steen perfusate (XVIVO Perfusion, Inc, Goteborg, Sweden); however, there were no statistically significant differences between CF and PF groups despite higher pulsatility, suggesting that PF may not offer immediate benefits over CF for prolonged ex vivo lung preservation.

Feasibility study of particulate extracellular matrix (P-ECM) and left ventricular assist device (HVAD) therapy in chronic ischemic heart failure bovine model.

Myocardial recovery with left ventricular assist device (LVAD) support is uncommon and unpredictable. We tested the hypothesis that injectable particulate extracellular matrix (P-ECM) with LVAD support promotes cell proliferation and improves cardiac function. LVAD, P-ECM, and P-ECM + LVAD therapies were investigated in chronic ischemic heart failure (IHF) calves induced using coronary embolization. Particulate extracellular matrix emulsion (CorMatrix, Roswell, GA) was injected intramyocardially using a 7 needle pneumatic delivery tool. Left ventricular assist devices (HVAD, HeartWare) were implanted in a left ventricle (LV) apex to proximal descending aorta configuration. Cell proliferation was identified using BrdU (5 mg/kg) injections over the last 45 treatment days. Echocardiography was performed weekly. End-organ regional blood flow (RBF) was quantified at study endpoints using fluorescently labeled microspheres. Before treatment, IHF calves had an ejection fraction (EF) of 33 ± 2% and left ventricular end-diastolic volume of 214 ± 18 ml with cardiac cachexia (0.69 ± 0.06 kg/day). Healthy weight gain was restored in all groups (0.89 ± 0.03 kg/day). EF increased with P-ECM + HVAD from 36 ± 5% to 75 ± 2%, HVAD 38 ± 4% to 58 ± 5%, and P-ECM 27 ± 1% to 66 ± 6%. P-ECM + HVAD demonstrated the largest increase in cell proliferation and end-organ RBF. This study demonstrates the feasibility of combined LVAD support with P-ECM injection to stimulate new cell proliferation and improve cardiac function, which warrants further investigation.

Hyperglycemic arterial disturbed flow niche as an in vitro model of atherosclerosis.

Type 2 diabetes significantly elevates the risk of cardiovascular disease. This can be largely attributed to the adverse effects of hyperglycemic conditions on normal endothelial cell (EC) function. ECs in both large and small vessels are influenced by hyperglycemic conditions, which increase susceptibility to EC dysfunction and atherosclerotic lesion formation. Fluid shear stress and flow patterns play an essential role in atherogenesis: lesions form only at locations where fluid flow behavior can be classified as "disturbed flow" (i.e., low shear stress recirculation and/or retrograde flow). Since regions of disturbed flow are the focal points of atherosclerotic cardiovascular disease, we hypothesized that the combinatorial effects of high glucose and disturbed flow conditions elicit significantly different responses from ECs than high glucose alone. To validate our hypothesis, we used our endothelial cell culture model (ECCM) to establish vascular niches associated with "normal" and "disturbed" flow conditions typically seen in vivo along with physiological pressure and stretch. We subjected human aortic endothelial cells (HAECs) to hyperglycemic conditions under both "normal" and "disturbed" flow. Our results confirm significant and quantifiable differences in phenotypic and functional markers between cells cultured under conditions of "normal" and "disturbed flow" under hyperglycemic conditions suggesting that elevated glucose in conjunction with "disturbed" flow conditions results in significantly higher level of EC dysfunction. The ECCM can therefore be used as a physiologically relevant model to study early stage hyperglycemia induced atherosclerosis for basic research, drug discovery, and screening and toxicity studies.

Early feasibility testing and engineering development of a sutureless beating heart connector for left ventricular assist devices.

APK Advanced Medical Technologies (Atlanta, GA) is developing a sutureless beating heart (SBH) left ventricular assist device (LVAD) connector system consisting of anchoring titanium coil, titanium cannula with integrated silicone hemostatic valve, coring and delivery tool, and LVAD locking mechanism to facilitate LVAD inflow surgical procedures. Feasibility testing was completed in human cadavers (n = 4) under simulated normal and hypertensive conditions using saline to observe seal quality in degraded human tissue and assess anatomic fit; acutely in ischemic heart failure bovine model (n = 2) to investigate short-term performance and ease of use; and chronically for 30 days in healthy calves (n = 2) implanted with HeartWare HVAD to evaluate performance and biocompatibility. Complete hemostasis was achieved in human cadavers and animals at LV pressures up to 170 mm Hg. In animals, off-pump (no cardiopulmonary bypass) anchoring of the connector was accomplished in less than 1 minute with no residual bleeding after full delivery and locking of the LVAD; and implant of connector and LVAD were successfully completed in under 10 minutes with total procedure blood loss less than 100 ml. In chronic animals before necropsy, no signs of leakage or disruption at the attachment site were observed at systolic LV pressures >200 mm Hg.

Performance evaluation of a pediatric viscous impeller pump for Fontan cavopulmonary assist.

OBJECTIVE: The anatomic and physiologic constraints for pediatric cavopulmonary assist differ markedly from adult Fontan circulations owing to smaller vessel sizes and risk of elevated pulmonary resistance. In this study, hemodynamic and hemolysis performance of a catheter-based viscous impeller pump (VIP) to power the Fontan circulation is assessed at a pediatric scale (∼15 kg) and performance range (0-30 mm Hg). METHODS: Computer simulation and mock circulation studies were conducted to assess the hydraulic performance, acute hemodynamic response to different levels VIP support, and the potential for vena caval collapse. Computational fluid dynamics simulations were used to estimate VIP hydraulic performance, shear rates, and potential for hemolysis. Hemolysis was quantified in a mock loop with fresh bovine blood. RESULTS: A VIP augmented 4-way total cavopulmonary connection flow at pediatric scales and restored systemic pressures and flows to biventricular values, without causing flow obstruction or suction. VIP generated flows up to 4.1 L/min and pressure heads of up to 38 mm Hg at 11,000 rpm. Maximal shear rate was 160 Pa, predicting low hemolysis risk. Observed hemolysis was low with plasma free hemoglobin of 11.4 mg · dL(-1) · h(-1). CONCLUSIONS: A VIP will augment Fontan cavopulmonary flow in the proper pressure and flow ranges, with low hemolysis risk under more stringent pediatric scale and physiology compared with adult scale. This technology may be developed to simultaneously reduce systemic venous pressure and improve cardiac output after stage 2 or 3 Fontan repair. It may serve to compress surgical staging, lessening the pathophysiologic burden of repair.

Mechanism of myocardial ischemia with an anomalous left coronary artery from the right sinus of Valsalva.

OBJECTIVE: An ectopic coronary artery that courses between the aortic root and the pulmonary trunk may lead to sudden cardiac death, especially in athletes. It has been speculated that during exercise, compression of the coronary artery between the great vessels may impair coronary blood flow and produce myocardial ischemia and fatal arrhythmia. However, this hypothesis cannot be tested in humans, and little experimental data exist to explain this phenomenon. To this end, in a calf with an anomalous left coronary artery that coursed from the right sinus of Valsalva between the great vessels, we assessed for myocardial ischemia during pharmacologically induced tachycardia and hypertension. METHODS: We identified a juvenile male calf (103 kg) with an anomalous left coronary artery from the right sinus of Valsalva that coursed between the great vessels. Via thoracotomy, the animal was instrumented for hemodynamic measurements. Intravenous dobutamine increased heart rate and myocardial metabolic demands. Intravenous phenylephrine produced arterial hypertension and increased myocardial metabolic demands. Fluorescent-labeled microspheres were used to map regional myocardial blood flow, and hemodynamics were recorded during each condition. Masson's trichrome staining for fibrosis, wheat-germ agglutinin staining for myocyte size, terminal deoxynucleotidyl transferase dUTP nick end-label staining for apoptosis, and isolectin-B4 staining for capillary density were performed. RESULTS: For the first time, empiric data documented that an ectopic coronary artery produced myocardial ischemia during elevated myocardial metabolic demands. Left coronary artery resistance increased in a cardiac cycle-dependent pattern that was consistent with systolic compression between the great vessels. Increased cardiac fibrosis, myocyte hypertrophy, cardiac apoptosis, and capillary density indicated that regional ischemic, inflammatory-mediated myocardial remodeling was present. CONCLUSIONS: These findings confirm the proposed mechanism of sudden death and support early surgical repair of coronary arteries that course between the aortic root and the pulmonary trunk.

Cavopulmonary assist: (em)powering the univentricular fontan circulation.

Since the Fontan/Kreutzer procedure was introduced, evolutionary clinical advances via a staged surgical reconstructive approach have markedly improved outcomes for patients with functional single ventricle. However, significant challenges remain. Early stage mortality risk seems impenetrable. Serious morbidities - construed as immutable consequences of palliation - have hardly been addressed. Late functional status is increasingly linked to pathophysiologic consequences of prior staged procedures. As more single-ventricle patients survive into adulthood, Fontan failure is emerging as an intractable problem for which there is no targeted therapy. Incremental solutions to address these ongoing problems have not had a measurable impact. Therefore, a fundamental reconsideration of the overall approach is reasonable and warranted. The ability to provide a modest pressure boost (2 to 6 mmHg) to existing blood flow at the total cavopulmonary connection can effectively restore more stable biventricular status. This would impact not only treatment of late Fontan failure, but also facilitate early surgical repair. A realistic means to provide such a pressure boost has never been apparent. Recent advances are beginning to unravel the unique challenges that must be addressed to realize this goal, with promise to open single-ventricle palliation to new therapeutic vistas.

Transapical miniaturized ventricular assist device: design and initial testing.

BACKGROUND: Left ventricular assist devices are increasingly used to treat patients with advanced and otherwise refractory heart failure as bridge to transplant or destination therapy. We evaluated a new miniaturized left ventricular assist device that requires minimal surgery for implantation, potentially allowing implantation in earlier stage heart failure. METHODS: HeartWare (Miami Lakes, Fla) developed transapical miniaturized ventricular assist device. Acute (n = 4), 1-week (n = 2), and 30-day (n = 4) bovine model experiments evaluated hemodynamic efficacy and biocompatibility of the device, which was implanted through small left thoracotomy with single insertion at apex of left ventricle without cardiopulmonary bypass. The device outflow cannula was positioned across the aortic valve. The international normalized ratio was maintained between 2.0 and 2.5 with warfarin. Hemodynamic, echocardiographic, fluoroscopic, hematologic, and blood chemistry measurements were evaluated. RESULTS: The device was successfully implanted through the left ventricular apex in all 10 animals. The device was operated at 15,000 ± 1000 rpm (power consumption, 3.5-6.0 W). The device maintained normal end-organ perfusion with no significant hemolysis (0-30 mg/dL). There were no pump failures or device-related complications. At autopsy, no abnormalities were seen in endocardium, aortic valve leaflets, or aortic root. There was no evidence of thromboembolism or abnormalities in any peripheral end organs. CONCLUSIONS: We successfully demonstrated feasibility of a novel intraventricular assist device that can be completely implanted through left ventricular apex. This transapical surgical approach eliminates needs for sternotomy, device pocket, cardiopulmonary bypass, ventricular coring, and construction of an outflow graft anastomosis.

Cavopulmonary assist for the univentricular Fontan circulation: von Kármán viscous impeller pump.

OBJECTIVE: In a univentricular Fontan circulation, modest augmentation of existing cavopulmonary pressure head (2-5 mm Hg) would reduce systemic venous pressure, increase ventricular filling, and thus substantially improve circulatory status. An ideal means of providing mechanical cavopulmonary support does not exist. We hypothesized that a viscous impeller pump, based on the von Kármán viscous pump principle, is optimal for this role. METHODS: A 3-dimensional computational model of the total cavopulmonary connection was created. The impeller was represented as a smooth 2-sided conical actuator disk with rotation in the vena caval axis. Flow was modeled under 3 conditions: (1) passive flow with no disc; (2) passive flow with a nonrotating disk, and (3) induced flow with disc rotation (0-5K rpm). Flow patterns and hydraulic performance were examined for each case. Hydraulic performance for a vaned impeller was assessed by measuring pressure increase and induced flow over 0 to 7K rpm in a laboratory mock loop. RESULTS: A nonrotating actuator disc stabilized cavopulmonary flow, reducing power loss by 88%. Disk rotation (from baseline dynamic flow of 4.4 L/min) resulted in a pressure increase of 0.03 mm Hg. A further increase in pressure of 5 to 20 mm Hg and 0 to 5 L/min flow was obtained with a vaned impeller at 0 to 7K rpm in a laboratory mock loop. CONCLUSIONS: A single viscous impeller pump stabilizes and augments cavopulmonary flow in 4 directions, in the desired pressure range, without venous pathway obstruction. A viscous impeller pump applies to the existing staged protocol as a temporary bridge-to-recovery or -transplant in established univentricular Fontan circulations and may enable compressed palliation of single ventricle without the need for intermediary surgical staging or use of a systemic-to-pulmonary arterial shunt.

Human, bovine and porcine systematic vascular input impedances are not equivalent: implications for device testing and xenotransplantation in heart failure.

BACKGROUND: Advanced therapies for heart failure (HF), such as mechanical circulatory support (MCS) devices and xenotransplantation, are usually tested in bovine and porcine models. This approach assumes a priori that animal (patho)physiology will closely match that of humans. Systemic aortic input impedance (Z(ART)) is an important physiologic determinant of left ventricular (LV) performance. We tested the hypothesis that Z(ART) is lower in bovine and porcine than in humans with normal or failing hearts. METHODS: High-fidelity aortic pressure and flow waveforms were recorded intra-operatively at native and paced heart rates of 100 beats per minute (bpm) in adult human patients with normal LV function (n = 13) or end-stage HF (n = 15), and normal calves (n = 10) and pigs (n = 18). Fast Fourier transformation was used to calculate Z(ART), and arterial resistance and compliance were estimated using a 4-element Windkessel model. RESULTS: Humans with HF had greater Z(ART) than those with normal LV function, characterized by higher resistance (1.16 +/- 0.12 vs 1.00 +/- 0.10 mm Hg x s/ml, p < 0.05) and lower compliance (1.53 +/- 0.21 vs 1.88 +/- 0.33 ml x mm Hg, p < 0.05). Healthy calves and pigs had significantly lower resistance (calf: 0.63 +/- 0.07 mm Hg x s/ml; pig: 0.90 +/- 0.07 mm Hg x s/ml) and higher compliance (calf: 2.79 +/- 0.37 ml x mm Hg; pig: 2.80 +/- 0.64 ml x mm Hg) when compared to humans (p < 0.05) with normal or failing hearts. CONCLUSIONS: Z(ART) is significantly lower in calves and pigs than in humans with or without HF. This finding has important implications for the pre-clinical testing of MCS devices and xenotransplants, which are usually examined in bovine and porcine models, respectively. Specifically, these therapies may respond differently in humans than animals due to non-equivalence of systemic after-load.

Vascular pulsatility in patients with a pulsatile- or continuous-flow ventricular assist device.

OBJECTIVE: We sought to investigate differences in indices of pulsatility between patients with normal ventricular function and patients with heart failure studied at the time of implantation with continuous-flow or pulsatile-flow left ventricular assist devices. METHODS: Eight patients with normal ventricular function and 22 patients with heart failure were studied. A high-fidelity aortic and left ventricular pressure catheter was inserted retrograde through the aortic valve into the left ventricle, and transit-time flow probes were placed on the aorta and device outflow graft. Hemodynamic waveforms were recorded at native heart rate before cardiopulmonary bypass and over a range of device flow rates controlled by adjusting beat rate or rpm. These data were used to calculate vascular input impedance and 2 indices of vascular pulsatility: energy-equivalent pressure and surplus hemodynamic energy. RESULTS: At low support levels, pulsatile support restored surplus hemodynamic energy to within 2.5% of normal values, whereas continuous support diminished surplus energy by more than 93%. At high support levels, pulsatile support augmented surplus energy by 49% over normal values, whereas continuous support further diminished surplus energy by 97%. Pulsatile support diminished vascular impedance from baseline failure values, whereas continuous support increased impedance. Vascular impedances at baseline for patients undergoing pulsatile and continuous support and during pulsatile support revealed normal vascular compliance, whereas impedance during continuous support indicated a loss of compliance (or "stiffening") of the vasculature. CONCLUSION: These results suggest that selection of device type and flow rate can influence vascular pulsatility and input impedance, which might affect clinical outcomes.