Mean Aortic Pressure Research Articles

Abstract 4120749: GPR39 Orchestrates the Myogenic Response in Coronary Autoregulation

Background: Coronary autoregulation is the ability of a normal heart to maintain constant coronary blood flow (CBF) over a wide range of coronary driving pressures (CDPs) provided cardiac work remains constant. It is based on the myogenic response, the molecular mechanism of which is unknown. We recently described the presence of a G-protein coupled receptor (GPR39) in the vascular smooth muscle cells (VSMCs) of coronary arterioles in the mouse heart. We showed that endogenous eicosanoids, the vasoconstrictor 15-hydroxyeicosatetraenoic acid (15-HETE) and the vasodilator 14,15-epoxyeicosatrienoic acid (14,15 EET). act through this receptor to maintain coronary vascular tone. Hypothesis: We, therefore, hypothesized that GPR39 is the molecular switch responsible for the coronary myogenic response and autoregulation. Methods: We studied 6 anesthetized dogs at baseline and after administration of VC-108, a specific, potent GPR39 antagonist. Both during baseline and drug administration multiple coronary stenoses were created on the left anterior descending coronary artery (LAD). At each stage, heart rate, mean aortic pressure, distal LAD pressure, and right atrial pressure (RAP) were measured, as was CBF. Stenosis severity was defined by the CDP (LAD pressure minus RAP). Results: Mean basal coronary hyperemic response was 3.0 in all anesthetized animals indicating normal vasomotor function. Systemic hemodynamics did not differ between baseline and drug stages. Figure 1 is an example from a single dog where, at baseline, CBF remained constant over a CDP of 40-90 mm Hg indicating intact autoregulation. As expected, CBF declined when CDP fell below the autoregulatory range. After VC-108 administration CBF correlated linearly with CDP, indicating abolishment of the myogenic response. Baseline CDP vs. CBF data from all 6 animals within the autoregulatory range is depicted in Figure 2. No relation is noted between the two indicating intact autoregulation. In contrast, CDP vs. CBF relation is linear in all animals after VC108 is administered over the entire range of CDP’s measured, indicating abolishment of autoregulation (Figure 3). Conclusions: Our results indicate that GPR39 is a potential molecular switch for the regulation of the myogenic response underlying coronary autoregulation. Pharmacological blockage of GPR39 abolishes the myogenic tone. These novel findings set the stage for development of novel pharmacological agents for treatment of coronary artery disease.

Aortic valve tract dynamics in normal-flow low-gradient and normal-flow high-gradient severe aortic stenosis

Abstract Introduction Aortic stenosis (AS) is the most common valvular heart disease in developed countries. Severe AS is defined as a mean pressure gradient (MG) ≥ 40 mmHg, a maximum aortic jet velocity≥4 m/s and an aortic valve area (AVA)≤1 cm2. However, classification of AS severity may be challenging due to discordant results on echocardiography. The normal-flow low-gradient severe AS (NFLG-AS) is defined as AVA≤1 cm2, MG<40 mmHg, left ventricular ejection fraction ≥ 50%, and stroke volume index (SVi) ≥ 35 ml/m2, whereas in the presence of MG > 40mmHg the condition is described as normal-flow high-gradient AS (NFHG-AS). Purpose The purpose of this study was to seek differences in the dynamic changes of the aortic valve tract throughout the cardiac cycle between the two clinical entities: NFHG-AS (Group 1) and NFLG-AS (Group 2). Methods In total, 130 patients with normal flow severe AS who underwent TAVI and had 3D transoesophageal echocardiographic data sets were screened. 38 patients with NFHG-severe AS and 40 patients with NFLG-severe AS with matching clinical characteristics and aortic valve area were identified. A custom-made semi-automated application developed by SQ was used. The application allows tracking of the aortic valve tract surface throughout the cardiac cycle in 3D transoesophageal echocardiograms and provides measurements of the geometrical planes at 4 levels: left ventricular outflow tract (LVOT), aortic annulus (AoA), sinuses of Valsalva (SoV) and sinotubular junction (STJ). Results The echocardiographic characteristics and the dynamic changes of the aortic valve tract between the two groups are shown in Tables 1 and 2. Both groups had comparable echocardiographic characteristic apart from the mean aortic valve pressure gradient as expected. With regards to the aortic valve tract geometrical dynamic changes, the relative LVOT and AoA area changes were bigger in Group 1 (36.8±15.9% vs 29.1±11.9%; p=0.017 and 21.0±8.39% vs 17.1±6.6%; p=0.028). The SoV and STJ relative changes were similar between the two groups. The same applies to aortic stiffness parameters, namely compliance and distensibility of the ascending aorta, systemic arterial compliance, and valvulo-arterial impedance. Conclusion The LVOT and aortic annulus area demonstrate more prominent dynamic changes in patients with normal-flow high-gradient severe AS compared to individuals with normal-flow low-gradient severe AS. While the SoV and the STJ geometry does not change significantly through the cardiac cycle, a more elastic outflow tract allows larger expansion in systole and higher pressure gradients across the aortic valve, whereas a stiffer outflow tract and annulus result in lower pressure gradients, despite the presence of severe aortic stenosis (AVA<1.0cm2). These differences in dynamic LVOT and aortic annulus changes may explain the discrepancy between aortic valve area and pressure gradients in patients with normal-flow low-gradient AS.

Impact of systolic coronary flow reversal in patients with aortic stenosis: assessment with transthoracic echocardiography

Abstract Background In patients with aortic stenosis (AS), increased systolic wall stress due to increased afterload reduces systolic coronary flow, often leading to systolic coronary flow reversal (SFR) in epicardial coronary arteries. Purpose We used transthoracic echocardiography (TTE) to evaluate severity of AS, left ventricular function, and coronary flow, and investigated echocardiographic indicators associated with SFR. Methods We prospectively evaluated consecutively presenting patients who visited our valvular heart disease outpatient clinic or were admitted to our hospital for investigation of AS (July 2023 to February 2024). Based on ESC guidelines, severity of AS and the left ventricular function were assessed with TTE. At the same time, TTE was used to measure distal left anterior descending coronary artery flow. SFR was defined as the presence of a reversal coronary flow component in systole. Based on the presence or absence of SFR in coronary flow measurements, patients were classified into SFR+ or SFR− groups. The inclusion criteria were AS of moderate or greater severity, and the exclusion criteria were known coronary stenosis and the inability to assess coronary flow. Results Enrolled 28 patients were classified into SFR+ (7 patients) and SFR − (21 patients) groups. Comparing baseline characteristics between the SFR+ and SFR− groups, although there were no significant differences in left ventricular indicators such as left ventricular mass index, left ventricular ejection fraction, stroke volume index, and E/e’ between the two groups, left ventricular global longitudinal strain was significantly lower in the SFR+ group (12.0±3.1%, 14.9±3.0%, p=0.026) (Table 1). Regarding indexes of AS assessment, aortic valve peak velocity and aortic valve mean pressure gradient values were significantly higher in the SFR+ group than in the SFR − group ([475±68 cm/s, 379±55 cm/s, p<0.001] and [56.2±16.5 mm Hg, 34.8±10.5 mm Hg, p<0.001], respectively) (Table 1). Representative cases show Figure 1. Conclusion The presence of SFR in patients with AS assessed using TTE may be a simple echocardiographic index that may be associated with potential decline in left ventricular function and progression of AS.

A propensity score matched analysis of transcatheter aortic valve replacement in failed bioprosthetic valves

Abstract Introduction While recently published data indicate similar long-term results of transcatheter aortic valve replacement (TAVR) compared to surgical procedures, surgical aortic valve replacement (SAVR) remains the standard of care in low-risk patients. However, since life expectancy increases, a non-negligible number of patients experience bioprosthetic valve dysfunction with the need for reintervention, but long-term data of TAVR in failed bioprosthetic valves is scarce. Purpose The aim of the study was to analyse long-term data of patients with TAVR in failed bioprosthetic valves compared to patients with native valve TAVR. The primary endpoint was 6-year all-cause mortality and the main secondary endpoint was echocardiographic valve function. Methods Patients undergoing TAVR for severe aortic valve disease between December 2012 and December 2020 were retrospectively analysed. Prior TAVR or aortic valve homografts led to exclusion from the study. A 2:1 propensity score matching by the optimal neighbor matching algorithm was performed to overcome differences in baseline characteristics. Results Between December 2012 and December 2020, 3,423 patients received TAVR for severe aortic valve disease and met inclusion criteria for the study. Of those, 3,287 patients underwent native valve TAVR, whereas 136 patients experienced bioprosthetic valve dysfunction and were treated with TAVR-in-SAV. After 2:1 propensity score matching, baseline characteristics without any relation to prior SAVR were similar between both groups. Concerning postprocedural echocardiographic function, a less pronounced gradient reduction (57.0 vs. 71.0 %, p < 0.01, Figure 1) and a higher number of patients with elevated mean pressure gradient > 20 mmHg could be found after prior SAVR (19.4 vs. 3.0 %, p < 0.01). However, there was no difference regarding 6-year all-cause mortality between both groups (log rank test p = 0.8, Figure 2). Conclusions Besides a less pronounced gradient reduction and higher mean aortic pressure gradients after TAVR-in-SAV compared to patients with native valve TAVR, no differences in 6-year all-cause mortality could be observed in a propensity score matched analysis.Reduction of mean pressure gradient6-year all-cause mortality

Early-stage Development of the CoRISMA Mechanical Circulatory Support (CMCS) System for Heart Failure Therapy.

CoRISMA MCS Systems Inc (Hamden CT) is developing an innovative mechanical circulatory support system (CMCS) as a durable therapeutic option for heart failure (HF) patients. The CMCS system is comprised of an axial flow pump, non-contacting hydrodynamic bearings, and integrated DC motor designed to be fully implantable in a left atrial (LA) to aortic (Ao) configuration; this unloading strategy may be particularly beneficial for HF patients with preserved ejection fraction (HFpEF). The small (5.5 cm3), lightweight (20g), and low power (5-7W) device design should allow for a less invasive off-pump implant. We present early-stage engineering development and testing of the prototype CoRISMA pumps. Computational fluid dynamics (CFD) modeling was performed to evaluate flow and shear in two impeller (3 blades, 0.5mm thickness, 8.9mm diameter, 0.15mm gap, polished titanium) and diffusor (5 blades, polished titanium) candidate designs. Test apparatuses were custom built to expedite development of the impeller/diffuser designs and iteratively refine the CFD models. Two candidate impeller/diffusor designs were fabricated and tested in each of the two test apparatuses (n = 4 impeller/diffuser + test fixture configurations) in static mock flow loops (hydrodynamic H-Q curves, 3.5 cP glycerol solution at 37°C), and in dynamic mock flow loops (hemodynamics, 3.5 cP glycerol solution at 37°C) tuned to HF conditions (mean aortic pressure 50 mmHg, central venous pressure 15 mmHg, aortic flow 3.0L/min, and heart rate 80bpm). CFD predicted flows of 4.56L/min and 4.82L/min at 100 mmHg for impellers/diffusers 1 and 2, respectively. Impeller 2 required less torque to generate a 6% increase in fluidic flow, and the diffuser had a larger area of high pressure, indicative of lower friction, which likely contributed to the increased efficiency. Experimental testing for all four configurations in the static and dynamic mock loops met performance metrics as evidenced by generating 4.0-4.5L/min flow against 70-76 mmHg pressure at 25,000rpm and restoring hemodynamics in the dynamic mock flow loop (MAP = 80 mmHg, CVP = 0 mmHg, total flow = 5.5L/min) from baseline simulated HF test conditions. These results demonstrate proof-of-concept of the early engineering design and performance of the prototype CoRISMA pumps. Engineering specifications, challenges observed, and proposed solutions for the next design iteration were identified for the continued development of an effective, reliable, and safe LA-to-Ao CMCS system for HF patients. Current design plans are underway for incorporating a wireless energy transfer system for communication and power, eliminating the need for and complications associated with an external driveline, to achieve a fully-implantable system.

Prognostic value of brachial-ankle pulse wave velocity changes post-transcatheter aortic valve replacement.

Transcatheter aortic valve replacement (TAVR) offers a solution, especially for high-risk aortic stenosis (AS) patients. However, patient outcomes post-TAVR show variability, highlighting the need for reliable prognostic indicators. Brachial-ankle pulse wave velocity (baPWV), a measure of arterial stiffness, may predict outcomes post-TAVR. This study aims to explore baPWV's prognostic value in relation to all-cause mortality post-TAVR. This study prospectively enrolled 212 severe AS patients undergoing TAVR between September 2015 and December 2021, focusing on pre- and post-TAVR baPWV measurements to explore associations with all-cause mortality. Of the 212 patients (119 females, 93 males, mean age 85years), post-TAVR baPWV increased significantly from 1589 ± 376 to 2010 ± 521cm/s (p < 0.001). Aortic valve (AV) peak velocity and mean pressure gradient decreased, while AV area increased, indicating procedural success. Despite this, 88% of patients experienced an increase in baPWV, with higher pre-procedure AV peak velocity and mean pressure gradient identified as predictors of increased baPWV post-TAVR. Over 23months, 29 patients (14%) reached the primary endpoint of all-cause mortality. Notably, changes in baPWV, rather than baseline values, were significantly associated with event-free survival (HR: 0.64 per 1SD increase, p = 0.009). The study highlights the prognostic value of baPWV changes post-TAVR in predicting patient outcomes. Elevated baPWV post-TAVR may reflect a beneficial adaptation to altered hemodynamics, suggesting the need for individualized patient evaluation and the integration of baPWV measurements into clinical practice for improved post-TAVR management.

Clinical Efficacy of Permanent Internal Mammary Artery Occlusion in Chronic Coronary Syndrome: A Double-Blind, Randomized, Sham-Controlled Trial

The CLIMACCS trial, a randomized, sham-controlled trial tested the CLinical efficacy of permanent internal mammary artery (IMA) device occlusion on symptoms in patients with chronic coronary syndrome (CCS), on coronary artery occlusive blood supply, and on myocardial ischemia. This was a prospective trial in 101 patients with CCS randomly allocated (1:1) to IMA device occlusion (verum group) or to IMA sham intervention (placebo group). The primary study endpoint was the change in treadmill exercise time (ΔET in seconds, s) at 6 weeks after trial intervention. Secondary study endpoints were the changes in collateral flow index (CFI), and angina pectoris during a simultaneous 1-minute proximal balloon occlusion of a coronary artery. CFI is the ratio between simultaneous mean coronary occlusive divided by mean aortic pressure both subtracted by central venous pressure. In the verum and placebo group, exercise time changed from 398±176s to 421±198s in the verum group (p=0.1745), and from 426±162s to 430±166s in the placebo group (p=0.55); DET amounted to +23±116s and +4±120s, respectively (p=0.44). CFI change during follow-up equalled +0.022±0.061 in the verum and-0.039±0.072 in the placebo group (p<0.0001). Angina pectoris at follow-up during the coronary balloon occlusion for CFI measurement had decreased or disappeared in 20/48 patients of the verum, and in 9/47 patients of the placebo group (p=0.0242). In conclusion, permanent IMA device occlusion tends to augment treadmill exercise time in response to heightened coronary artery occlusive blood supply, the fact of which is reflected by mitigated symptoms and signs of myocardial ischemia.

Twenty-four-hour Normothermic Ex Vivo Heart Perfusion With Low Flow Functional Assessment in an Adult Porcine Model.

Cold static storage and normothermic ex vivo heart perfusion are routinely limited to 6 h. This report describes intermittent left atrial (LA) perfusion that allows cardiac functional assessment in a working heart mode. Using our adult porcine model, general anesthesia was induced and a complete cardiectomy was performed following cardioplegic arrest. Back-table instrumentation was completed and normothermic ex vivo heart perfusion (NEHP) was initiated in a nonworking heart mode (Langendorff). After 1 h of resuscitation and recovery, LA perfusion was initiated and the heart was transitioned to a coronary flow-only working heart mode for 30 min. Baseline working heart parameters were documented and the heart was returned to nonworking mode. Working heart assessments were performed for 30 min every 6 h for 24 h. Twenty-four-hour NEHP on 9 consecutive hearts (280 ± 42.1 g) was successful and no significant differences were found between working heart parameters at baseline and after 24 h of perfusion. There was no difference between initial and final measurements of LA mean pressures (5.0 ± 3.1 versus 9.0 ± 6.5 mm Hg, P = 0.22), left ventricular systolic pressures (44.3 ± 7.2 versus 39.1 ± 9.0 mm Hg, P = 0.13), mean aortic pressures (30.9 ± 5.8 versus 28.1 ± 8.1 mm Hg, P = 0.37), and coronary resistance (0.174 ± 0.046 versus 0.173 ± 0.066 mL/min/g, P = 0.90). There were also no significant differences between lactate (2.4 ± 0.5 versus 2.6 ± 0.4 mmol/L, P = 0.17) and glucose (173 ± 75 versus 156 ± 70 mg/dL, P = 0.37). A novel model using intermittent LA perfusion to create a coronary flow-only working heart mode for assessment of ex vivo cardiac function has been successfully developed.

#1397 Predictive factors for bioprosthetic valve stenosis and prognostic factors for survival following TAVR in hemodialysis patients with severe AS

Abstract Background and Aims Transcatheter aortic valve replacement (TAVR) is a promising option for the treatment of severe aortic valve stenosis (AS) in patients undergoing hemodialysis. Although the incidence of bioprosthetic valve deterioration (SVD) after TAVR has been reported to be lower than after surgical aortic valve replacement (SAVR), hemodialysis itself is still associated with a high risk of SVD. Until now, the factors that determine the prognosis of TAVR in hemodialysis patients were unknown. We previously reported that preoperative hypomagnesemia was correlated with an increase in postoperative mean aortic valve pressure gradient (MPG), an index of bioprosthetic valve stenosis as one of the indicators of SVD, in hemodialysis patients (Ren Fail. 2022 Dec;44(1):1083-1089). However, the study had a limited sample size of 24 cases, which raised concerns about statistical power. Therefore, we re-evaluate predictors of SVD and life expectancy in a larger number of post-TAVR hemodialysis patients. Methods From April 2012 to November 2021, all 100 hemodialysis patients treated with TAVR at Osaka University Hospital were included in the analysis. Pre- and post-operative demographic and laboratory data were analyzed by linear mixed-effects model and cox proportional hazards model. Results During the follow-up period (maximum 7 years), 4 out of 100 patients required re-TAVR (valve-in-valve) due to valve stenosis. The MPG increased over time with the lower preoperative serum Mg concentration (linear mixed-effects mode; +1.40 mmHg/year per 1mg/dl lower in Mg, p=0.006). However, serum calcium, phosphate, and intact PTH levels had no significant effect on the increase in MPG. In addition, a higher preoperative left ventricular ejection fraction (LVEF) was associated with a lower risk of death in a multivariate Cox proportional hazards model (hazard ratio [HR] 0.97 per 1% increase in LVEF; P=0.02). Conclusions Consistent with our previous report, preoperative hypomagnesemia was associated with increased MPG after TAVR. In addition, preoperative low cardiac function (LVEF&amp;lt;40%) may be a risk factor for postoperative mortality in dialysis patients. This was a single-center observational study, and the number of patients was still small, so our data may not be necessarily applicable to every patient. Further research is needed to identify a prognostic predictor of SVD and mortality, that will lead to the prevention of adverse outcomes in hemodialysis patients.

Prognostic Value of Microvascular Resistance Reserve Measured Immediately After PCI in Stable Coronary Artery Disease.

Microvascular resistance reserve (MRR) has been proposed as a specific metric to quantify coronary microvascular function. The long-term prognostic value of MRR measured in stable patients immediately after percutaneous coronary intervention (PCI) is unknown. This study sought to determine the prognostic value of MRR measured immediately after PCI in patients with stable coronary artery disease. This study included 502 patients with stable coronary artery disease who underwent elective PCI and coronary physiological measurements, including pressure and flow estimation using a bolus thermodilution method after PCI. MRR was calculated as coronary flow reserve divided by fractional flow reserve times the ratio of mean aortic pressure at rest to that at maximal hyperemia induced by hyperemic agents. An abnormal MRR was defined as ≤2.5. Major adverse cardiac events (MACEs) were defined as a composite of all-cause mortality, any myocardial infarction, and target-vessel revascularization. During a median follow-up of 3.4 years, the cumulative MACE rate was significantly higher in the abnormal MRR group (12.5 versus 8.3 per 100 patient-years; hazard ratio 1.53 [95% CI, 1.10-2.11]; P<0.001). A higher all-cause mortality rate primarily drove this difference. On multivariable analysis, a higher MRR value was independently associated with lower MACE and lower mortality. When comparing 4 subgroups according to MRR and the index of microcirculatory resistance, patients with both abnormal MRR and index of microcirculatory resistance (≥25) had the highest MACE rate. An abnormal MRR measured immediately after PCI in patients with stable coronary artery disease is an independent predictor of MACE, particularly all-cause mortality.

Patient-specific closed-loop model of the fontan circulation: Calibration and validation

The Fontan circulation, designed for managing patients with a single functional ventricle, presents challenges in long-term outcomes. Computational methods offer potential solutions, yet their application in cardiology practice remains largely unexplored. Our aim was to assess the ability of a patient-specific, closed-loop, reduced-order blood flow model to simulate pulsatile blood flow in the Fontan circulation. Using one-dimensional models, we simulated the aorta, superior and inferior venae cavae, and right and left pulmonary arteries, while lumping heart chambers and remaining vessels into zero-dimensional models. The model was calibrated with patient-specific haemodynamic data from combined cardiac catheterisation and magnetic resonance exams, using a novel physics-based stepwise methodology involving simpler open-loop models. Testing on a 10-year-old, anesthetised patient, demonstrated the model's capability to replicate pulsatile pressure and flow in the larger vessels and ventricular pressure. Average relative errors in mean pressure and flow were 2.9 % and 3.6 %, with average relative point-to-point errors (RPPE) in pressure and flow at 5.2 % and 16.0 %. Comparing simulation results to measurements, mean aortic pressure and flow values were 50.7 vs. 50.4 mmHg and 41.6 vs. 41.9 ml/s, respectively, while ventricular pressure values were 28.7 vs. 27.4 mmHg. The model accurately described time-varying ventricular volume with a RPPE of 2.9 %, with mean, minimum, and maximum ventricular volume values for simulation results vs. measurements at 59.2 vs. 58.2 ml, 38.0 vs. 37.6 ml, and 76.0 vs. 74.4 ml, respectively. It provided physiologically realistic predictions of haemodynamic changes from pulmonary vasodilation and atrial fenestration opening. The new model and calibration methodology are freely available, offering a platform to virtually investigate the Fontan circulation's response to clinical interventions and explore potential mechanisms of Fontan failure. Future efforts will concentrate on broadening the model's applicability to a wider range of patient populations and clinical scenarios, as well as testing its effectiveness.

The relative potential contribution of volume load and vascular mechanisms to hypertension in non-dialysis and dialysis chronic kidney disease patients.

Hypertension is highly prevalent and particularly difficult to treat adequately in patients with chronic kidney disease (CKD). The relative contribution of volume overload and vascular mechanisms to blood pressure measures in CKD and whether these effects differ in non-dialysis compared to dialysis patients is unknown. We determined the potential impact of volume load (stroke volume) and vascular mechanisms (inverse of total arterial compliance (inv TAC) and systemic vascular resistance (SVR)) on mean and brachial and aortic systolic blood pressures in 67 non-dialysis and 48 dialysis chronic kidney disease (CKD) patients. Relationships were determined in confounder adjusted regression models. Stroke volume (p value = 0.003) was more strongly associated with mean arterial pressure than SVR (p value = 0.9) (p value for difference = 0.03). When stroke volume and SVR were entered in the same regression model (model R2 = 0.324), they contributed equally to the variation in mean arterial pressure (p value for difference = 0.5). Stroke volume (p value ≤ 0.002) and inv TAC (p value ≤ 0.001) contributed equally to the variation in systolic pressures (p value for difference ≥ 0.9). When stroke volume and inv TAC were entered in the same regression model (model R2 = 0.752 to 0.765), they contributed equally to the variation in systolic blood pressures (p value for difference = 0.7). Stroke volume, TAC and SVR were similar (p value ≥ 0.5) and associated to the same extent with blood pressure measures in non-dialysis and dialysis CKD patients (p value for difference ≥ 0.1). In receiver operator characteristic curve analysis, elevated systolic blood pressure was determined by stroke volume (p value = 0.005) and inv TAC (p value = 0.03) but not SVR (p value = 0.8). The calculated power of the study was 0.999 based on α = 0.05. The present investigation suggests that both volume load and vascular mechanisms should be considered in the management of hypertension among patients with CKD. The extent and relative potential impact of volume load and vascular mechanisms on blood pressure measures are as large in non-dialysis compared to dialysis CKD patients.

One-year initial efficacy and safety outcomes of the premounted dry-pericardium Vienna self-expandable transcatheter aortic valve system: A first-in-human VIVA feasibility study.

The dry-pericardium Vienna transcatheter aortic valve system is repositionable and retrievable, already premounted on the delivery system, eliminating the need for assembly and crimping of the device before valve implantation. The VIVA first-in-human feasibility study, a prospective, nonrandomized, single-center trial, evaluated the Vienna aortic valve in 10 patients with severe symptomatic aortic stenosis, who were at intermediate or high surgical risk. This study, registered at ClinicalTrials.gov (NCT04861805), focused on the safety, feasibility, clinical and hemodynamic performance of the Vienna system up to 1-year follow-up. The mean patient age was 79 ± 5 years, 60% male. Valve sizes used: 26 mm (10%), 29 mm (30%), 31 mm (60%). Key hemodynamic improvements were significant: mean aortic valve pressure gradient (mmHg) decreased from 48.7 to 8.1, aortic valve area (cm2) increased from 0.75 to 1.91, and maximum jet velocity through the aortic valve (m/s) decreased from 4.41 to 1.95 (p < 0.0001). No moderate/severe paravalvular leakage was observed, and computed tomography scans revealed no evidence of hypo-attenuated leaflet thickening. The study recorded one life-threatening bleeding event, two cases requiring postprocedural pacemaker implantation, and three ischemic events, with only one causing lasting neurological impairment. Importantly, there were no cases of cardiovascular mortality and only one noncardiovascular death, which was confirmed as unrelated to the device. The study indicates the Vienna valve as a potential option for severe symptomatic aortic stenosis, designed to streamline the procedure and potentially lower healthcare costs by reducing resource and equipment needs, also procedural errors. Further research is essential to thoroughly evaluate its safety and efficacy.

Autotaxin inhibition attenuates the aortic valve calcification by suppressing inflammation-driven fibro-calcific remodeling of valvular interstitial cells

BackgroundPatients with fibro-calcific aortic valve disease (FCAVD) have lipid depositions in their aortic valve that engender a proinflammatory impetus toward fibrosis and calcification and ultimately valve leaflet stenosis. Although the lipoprotein(a)-autotaxin (ATX)-lysophosphatidic acid axis has been suggested as a potential therapeutic target to prevent the development of FCAVD, supportive evidence using ATX inhibitors is lacking. We here evaluated the therapeutic potency of an ATX inhibitor to attenuate valvular calcification in the FCAVD animal models.MethodsATX level and activity in healthy participants and patients with FCAVD were analyzed using a bioinformatics approach using the Gene Expression Omnibus datasets, enzyme-linked immunosorbent assay (ELISA), immunohistochemistry, and western blotting. To evaluate the efficacy of ATX inhibitor, interleukin-1 receptor antagonist-deficient (Il1rn-/-) mice and cholesterol-enriched diet-induced rabbits were used as the FCAVD models, and primary human valvular interstitial cells (VICs) from patients with calcification were employed.ResultsThe global gene expression profiles of the aortic valve tissue of patients with severe FCAVD demonstrated that ATX gene expression was significantly upregulated and correlated with lipid retention (r = 0.96) or fibro-calcific remodeling-related genes (r = 0.77) in comparison to age-matched non-FCAVD controls. Orally available ATX inhibitor, BBT-877, markedly ameliorated the osteogenic differentiation and further mineralization of primary human VICs in vitro. Additionally, ATX inhibition significantly attenuated fibrosis-related factors’ production, with a detectable reduction of osteogenesis-related factors, in human VICs. Mechanistically, ATX inhibitor prohibited fibrotic changes in human VICs via both canonical and non-canonical TGF-β signaling, and subsequent induction of CTGF, a key factor in tissue fibrosis. In the in vivo FCAVD model system, ATX inhibitor exposure markedly reduced calcific lesion formation in interleukin-1 receptor antagonist-deficient mice (Il1rn-/-, P = 0.0210). This inhibition ameliorated the rate of change in the aortic valve area (P = 0.0287) and mean pressure gradient (P = 0.0249) in the FCAVD rabbit model. Moreover, transaortic maximal velocity (Vmax) was diminished with ATX inhibitor administration (mean Vmax = 1.082) compared to vehicle control (mean Vmax = 1.508, P = 0.0221). Importantly, ATX inhibitor administration suppressed the effects of a high-cholesterol diet and vitamin D2-driven fibrosis, in association with a reduction in macrophage infiltration and calcific deposition, in the aortic valves of this rabbit model.ConclusionsATX inhibition attenuates the development of FCAVD while protecting against fibrosis and calcification in VICs, suggesting the potential of using ATX inhibitors to treat FCAVD.

Increased left ventricular remodelling index in paradoxical low-flow severe aortic stenosis with preserved left ventricular ejection fraction compared to normal-flow severe aortic stenosis.

Patients with paradoxical low-flow (LF) severe aortic stenosis (AS) despite preserved left ventricular ejection fraction (LVEF) appear distinct from normal-flow (NF) patients, showing worse prognosis, more concentric hypertrophy and smaller left ventricular (LV) cavities. The left ventricular remodelling index (LVRI) has been demonstrated to reliably discriminate between physiologically adapted athlete's heart and pathological LV remodelling. We studied patients with index echocardiographic diagnosis of severe AS (aortic valve area <1 cm2) with preserved LVEF (>50%). The LVRI was determined by the ratio of the LV mass to the end-diastolic volume, as previously reported, and was compared between patients with LF and NF AS. Patients were prospectively followed up for at least 3 years, and clinical outcomes were examined in association with LVRI. Of the 450 patients studied, 112 (24.9%) had LF AS. While there were no significant differences in baseline clinical profile between LF and NF patients, LVRI was significantly higher in the LF group. Patients with high LVRI (>1.56 g/mL) had increased all-cause mortality (log-rank 9.18, P = 0.002) and were more likely to be admitted for cardiac failure (log-rank 7.61, P = 0.006) or undergo aortic valve replacement (log-rank 18.4, P < 0.001). After adjusting for the effect of age, hypertension, aortic valve area and mean pressure gradient on multivariate Cox regression, high LVRI remained independently associated with poor clinical outcomes (hazard ratio 1.64, 95% confidence interval 1.19-2.25, P = 0.002). Pathological LV remodelling (increased LVRI) was more common in patients with LF AS, and increased LVRI independently predicts worse clinical outcomes.

Modelling and Simulation of the Combined Use of IABP and Impella as a Rescue Procedure in Cardiogenic Shock: An Alternative for Non-Transplant Centres?

The treatment of critically ill patients remains an evolving and controversial issue. Mechanical circulatory support through a percutaneous approach for the management of cardiogenic shock has taken place in recent years. The combined use of IABP and the Impella 2.5 device may have a role to play for this group of patients. A simulation approach may help with a quantitative assessment of the achievable degree of assistance. In this paper, we analyse the interaction between the Impella 2.5 pump applied as the LVAD and IABP using the numerical simulator of the cardiovascular system developed in our laboratory. Starting with pathological conditions reproduced using research data, the simulations were performed by setting different rotational speeds for the LVAD and driving the IABP in full mode (1:1) or partial mode (1:2, 1:3 and 1:4). The effects induced by drug administration during the assistance were also simulated. The haemodynamic parameters under investigation were aa follows: mean aortic pressure, systolic and diastolic aortic pressure, mean pulmonary arterial pressure, mean left and right atrial pressure, cardiac output, cardiac index, left and right ventricular end-systolic volume, left ventricular end-diastolic volume and mean coronary blood flow. The energetic variables considered in this study were as follows: left and right ventricular external work and left and right atrial pressure-volume area. The outcome of our simulations shows that the combined use of IABP and Impella 2.5 achieves adequate support in the acute phase of cardiogenic shock compared to each standalone device. This would allow further stabilisation and transfer to a transplant centre should the escalation of treatment be required.

Prognostic Relevance of Global Myocardial Work Index in Patients with Moderate Aortic Valve Stenosis.

A reduced global myocardial work index (GWI) ≤ 1951 mmHg% is associated with increased mortality in patients with severe aortic valve stenosis (AS). However, parameters predicting the outcome in patients with moderate AS are limited. Therefore, the aim of this study was to evaluate the prognostic value of the GWI in patients with moderate AS. In this prospective study, 103 patients with moderate AS (mean age 72 ± 10 years; male: 69%) underwent standardized transthoracic echocardiography. The primary endpoint was survival without an aortic valve replacement (AVR). After a median follow-up of 30 ± 5 months, 37 patients (36%) were referred for an AVR. Survival without an AVR was 96% at 12 months and 80% at 30 months (>1951 mmHg%) versus 96% and 68% (≤1951 mmHg%). A GWI ≤ 1951 mmHg% did not predict the need for an AVR (hazard ratio 1.31 (95% CI, 0.63-2.72), p = 0.49). Furthermore, there was no significant correlation between the mean GWI (1644 ± 448 mmHg%) and mean aortic valve pressure gradient (24.2 mmHg ± 6.2, p = 0.615) or effective aortic orifice area (1.24 cm2 ± 0.11, p = 0.678). There was no difference between the AVR and non-AVR groups in the occurrence of clinical symptoms. In contrast to patients with severe AS, a GWI ≤ 1951 mmHg% did not predict the need for an AVR. Further research is needed to improve the risk stratification in patients with moderate AS.

Short- and Long-term Clinical Outcomes of Balloon-expandable Versus Self-expanding Valves in Patients Undergoing Transcatheter Aortic Valve Replacement: A Meta-analysis

Background: Distinct clinical differences exist between balloon-expandable valves (BEVs) and self-expanding valves (SEVs) used in transcatheter aortic valve replacement (TAVR) for aortic stenosis. However, randomised data on comparative outcomes are limited. The aim of this meta-analysis was to analyse the differences in short- and longer-term clinical outcomes between the two valve designs. Methods: A comprehensive literature search for all studies up to and including April 2020 on the clinical outcomes of BEVs versus SEVs was performed. Study outcomes were divided into short term (in-hospital or 30 days), intermediate term (1 year) and long term (3 years). The primary outcome was all-cause mortality. Secondary endpoints were stroke or transient ischaemic attack (TIA), life-threatening or major bleeding, at least moderate paravalvular leak (PVL), permanent pacemaker (PPM) implantation, aortic valve area (AVA) and aortic valve mean pressure gradient (AV MPG). Results: A total of 41 studies (BEV, n=23,892; SEV, n=22,055) were included. At in-hospital/30 days, all-cause mortality favoured BEV (OR 0.85; 95% CI [0.75–0.96]). BEV had lower rates of PVL (OR 0.42; 95% CI [0.35–0.51]) and PPM (OR 0.56; 95% CI [0.44–0.72]), but smaller AVA (mean −0.09 cm2; 95% CI [−0.17, 0.00]) and higher AV MPG (mean 2.54 mmHg; 95% CI [1.84–3.23]). There were no significant differences in the incidence of stroke/TIA or bleeding between the two valve designs. At 1 year a lower PPM implantation rate (OR 0.44; 95% CI [0.37–0.52]), fewer PVLs (OR 0.26; 95% CI [0.09–0.77]), smaller AVA (mean −0.23 cm2; 95% CI [−0.35, −0.10]) and higher AV MPG (mean 6.05 mmHg; 95% CI [1.74–10.36]) were observed with BEV. No significant differences were observed in mortality, stroke/TIA or bleeding. There was no significant difference in mortality at 3 years between the two valve designs. Conclusion: In the short–intermediate term, SEVs had better valve haemodynamics but had higher PVL and PPM implantation rates than BEVs. However, there were no differences in intermediate–long-term mortality, stroke or TIA, or bleeding complications. A better understanding of these differences will enable TAVR operators to tailor their valve choice based on individual patient profile.

Clinical efficacy of permanent internal mammary artery occlusion in chronic coronary artery disease: a double-blind, randomized, sham-controlled trial

Abstract Introduction Natural internal mammary artery (IMA) bypasses to the coronary circulation have been shown to act as extracardiac sources of myocardial blood supply, which has been found augmented by right IMA device occlusion. The goal of this randomized, sham-controlled trial was to test the efficacy of permanent right or left IMA device occlusion on symptoms of chronic coronary artery disease (CAD), on coronary artery occlusive blood supply, as well as on myocardial ischemia. Methods This was a prospective superiority trial in 100 patients with chronic CAD randomly allocated (1:1) to IMA permanent vascular device occlusion (verum group) or to IMA sham intervention (placebo group). The primary study endpoint was the change in treadmill exercise time (DET in seconds, s) during 6 weeks of follow-up after trial intervention. Secondary study endpoints were the changes in simultaneously obtained collateral flow index (CFI), and angina pectoris during a 1-minute proximal balloon occlusion of the coronary artery of interest. CFI is the ratio between simultaneous mean coronary occlusive divided by mean aortic pressure both subtracted by central venous pressure. Results In the verum and placebo group, exercise time changed from 398±176s to from 421±198s in the verum group (p=0.1745), and from 426±162s to 430±166s in the placebo group (p=0.55); DET was +23±116s and +4±120s, respectively (p=0.44). CFI change during follow-up was +0.022±0.061 in the verum and -0.039±0.072 in the placebo group (p&amp;lt;0.0001). Angina pectoris at follow-up during the coronary balloon occlusion for CFI measurement had decreased or disappeared in 20/48 patients of the verum group, and in 10/47 patients of the placebo group (p=0.0336). Conclusion Permanent IMA device occlusion tends to augment treadmill exercise time in response to heightened coronary artery occlusive blood supply, the fact of which is reflected by mitigated signs of myocardial ischemia.

Angio-IMR identifies microvascular cardiac allograft vasculopathy in heart transplant recipients

Abstract Background/Introduction Microvascular cardiac allograft vasculopathy (mCAV) is a prognostic factor for long-term survival after heart transplantation, which can be assessed by endomyocardial biopsies (EMBs). (1) Routine diagnostic follow-up consists of coronary angiography and an EMB in selected patients. Non-biopsy methods for diagnosing microvascular dysfunction (MVD) have increasingly been proven valuable in these patients and avoid the inherent risk of repeated EMB. (2) Recently, an angiography-derived index of microcirculatory resistance (angio-IMR) has been reported as a novel, post-processing pressure-wire-free tool to assess coronary microvascular dysfunction in coronary angiograms. (3) Its usefulness in heart transplant recipients remains unknown. Purpose This analysis aimed to compare the assessment of mCAV with angio-IMR and EMB findings. Methods We retrospectively evaluated coronary angiograms of 27 asymptomatic heart transplant recipients (11% female, mean age 46.6 years ± 12.3 years) who underwent simultaneous coronary angiography and right ventricular biopsy within post-transplant aftercare at our institution. We derived angio-IMR from the left anterior descending coronary artery (LAD) using two views with at least a 30° angle to each other and invasively measured mean aortic pressure (MAP). Histopathologic mCAV was routinely evaluated by light microscopy (x200) and defined as no mCAV, obstructive or non-obstructive mCAV. The correlation between time after heart transplantation and angio-IMR was using Pearson's Correlation Coefficient and angio-IMR was compared between mCAV groups using Kruskal–Wallis test, assuming statistical significance at p&amp;lt;0.05. (1) Results Three patients (11%) showed obstructive, 13 (48%) non-obstructive, and 11 (41%) showed no mCAV. The mean time after heart transplantation was 1683 days ± 1140 days. The mean angio-IMR was 38.6 mmHg*s ± 10.2 mmHg*s, with a positive correlation between angio-IMR and time since heart transplantation (r[25] = 0.695, p &amp;lt; 0.001, figure A [green = no; yellow = non-obstructive and red = obstructive mCav]). Compared to patients without mCAV (29.7 mmHg*s ± 5.3 mmHg*s), angio-IMR was increased in patients with non-obstructive (42.4 mmHg*s ± 6.9 mmHg*s, p = 0.002) and obstructive mCAV (54.6 mmHg*s ± 8.5 mmhg*s, p = 0.002, figure B). Conclusion Angio-IMR correlates with histological mCAV and time since transplantation in heart transplant recipients. This value could potentially help in the clinical routine management of these patients and avoid the inherent risk of repeated EMB.Figure AFigure B