Low Mean Perfusion Pressure Indexed to Body Surface Area is a Powerful Predictor of Poor Outcomes After Heart Transplantation in Patients With High Pre-Transplant Venous Pressure: A Clinical Study With Physiological Insights From Mathematical Modelling of Biventricular Heart Failure.

BACKGROUND & AIM: The deleterious consequences of chronically elevated venous pressure in patients with profound right ventricular or biventricular dysfunction are well known, including renal and hepatic dysfunction, and volume overload. The only option for these patients, if they fail optimal medical treatment, is a heart transplant, as they are not candidates for left ventricular assist device therapy. Mean perfusion pressure (MPP) is important in the outcomes of critically ill patients with high venous pressure. The question arises whether MPP is important for the outcomes of heart transplants in patients with elevated pre-transplant venous pressure. Medical management of heart failure patients with reduced ejection fraction involves lowering the systemic afterload with vasodilators while awaiting a transplant. We hypothesised that when venous pressure is elevated prior to transplant, a substantial reduction in systemic arterial elastance (Ea) through vasodilation may significantly decrease MPP, resulting in compromised end-organ function and consequent unfavourable outcomes after heart transplantation. This study aims to investigate whether a low MPP serves as a risk factor for adverse outcomes in heart transplant recipients with high venous pressure. METHOD: A retrospective analysis was conducted on 250 heart transplant recipients undergoing isolated heart transplantation at a single institution from October 2012 to March 2020. Right atrial pressure (RAP) of more than 15 mmHg was considered high. Additionally, Ea calculated as the ratio of end-systolic pressure to stroke volume, and MPP calculated as the difference between mean arterial pressure and RAP were considered in our analysis. The outcomes of transplantation were measured in terms of 90-day mortality and survival up to 7 years. RESULTS: High RAP was a significant risk factor for short-term and medium-term survival if Ea was low (<2.7 mmHg/mL, the median value). This group had 39.39% in-hospital mortality compared to 14.49% for RAP<15 mmHg (p∼0.005). When Ea was high, this difference in survival was not evident: 8% for RAP<15 mmHg vs 4.8% for RAP>15 mmHg (p∼0.550). This effect was mediated through a lower MPP, and the mortality due to lower MPP increased strikingly with higher body surface area (BSA). A negative correlation was observed between MPP indexed to BSA (MPPI) and the Model for End-Stage Liver Disease score (r∼-0.3580, p<0.0001) as well as creatinine (r∼-0.3551, p<0.0001). MPPI less than 40 mmHg/m2 was associated with poorer short-term (23.2% for MPPI<40 mmHg/m2 vs 7.1% for MPPI>40 mmHg/m2, p∼0.001) and medium-term survival. The impact of high RAP and low Ea on survival was evident even on medium-term follow-up; only 30% survival at 7 years follow-up for high RAP and low Ea vs 75% for RAP<15 mmHg (p∼0.0033). CONCLUSION: The acceptable blood pressure during vasodilator therapy in patients with high RAP needs to be higher, especially in those with higher BSA. MPPI less than 40 mmHg/m2 is a risk factor for survival, in the short and medium-term, after heart transplantation.

An open label randomized clinical trial of Indomethacin for mild and moderate hospitalised Covid-19 patients.

Indomethacin, a non-steroidal anti-inflammatory drug (NSAID), has been presented as a broad-spectrum antiviral agent. This randomised clinical trial in a hospital setting evaluated the efficacy and safety of this drug in RT-PCR-positive coronavirus disease 2019 (COVID-19) patients. A total of 210 RT-PCR-positive COVID-19 patients who provided consent were allotted to the control or case arm, based on block randomisation. The control arm received standard of care comprising paracetamol, ivermectin, and other adjuvant therapies. The patients in the case arm received indomethacin instead of paracetamol, with other medications retained. The primary endpoint was the development of hypoxia/desaturation with SpO2 ≤ 93, while time to become afebrile and time for cough and myalgia resolution were the secondary endpoints. The results of 210 patients were available, with 103 and 107 patients in the indomethacin and paracetamol arms, respectively. We monitored patient profiles along with everyday clinical parameters. In addition, blood chemistry at the time of admission and discharge was assessed. As no one in either of the arms required high-flow oxygen, desaturation with a SpO2 level of 93 and below was the vital goal. In the indomethacin group, none of the 103 patients developed desaturation. On the other hand, 20 of the 107 patients in the paracetamol arm developed desaturation. Patients who received indomethacin also experienced more rapid symptomatic relief than those in the paracetamol arm, with most symptoms disappearing in half the time. In addition, 56 out of 107 in the paracetamol arm had fever on the seventh day, while no patient in the indomethacin group had fever. Neither arm reported any adverse event. The fourteenth-day follow-up revealed that the paracetamol arm patients had faced several discomforts; indomethacin arm patients mostly complained only of tiredness. Indomethacin is a safe and effective drug for treating patients with mild and moderate covid-19.

Proximal and Distal Occlusion of Complex Cerebral Aneurysms-Implications of Flow Modeling by Fluid-Structure Interaction Analysis.

BACKGROUND: In complex cerebral aneurysms, adequate treatment by complete occlusion is not always possible. Partial occlusion by either proximal or distal occlusion is an alternative. However, the hemodynamic consequences of these partial occlusion options are often not easily predictable. OBJECTIVE: To assess the feasibility of fluid-structure interaction (FSI) analysis to investigate the hemodynamic changes after partial occlusion in cerebral aneurysms. METHODS: Two patients were analyzed. One was treated by proximal occlusion and 1 by distal occlusion. In both, flow replacement bypass surgery was performed. Three-dimensional models were constructed from magnetic resonance angiography (MRA) scans and used for FSI analysis. A comparative study was done for pre- and postoperative conditions. Postoperative thrombosis was modeled and analyzed for the distal occlusion. FSI results were compared to postoperative angiograms and computed tomography (CT)-scans. RESULTS: Proximal occlusion resulted in reduction of velocity, wall shear stresses, and disappearance of helical flow patterns in the complete aneurysm. Distal occlusion showed a decrease of velocity and wall shear stress in the dome of the aneurysm. Results were validated against postoperative CT-scans and angiograms at 1-, 7-, and 9-mo follow-up. Addition of thrombus to the distal occlusion model showed no change in velocities and luminal pressure but resulted in decrease in wall tension. CONCLUSION: This pilot study showed hemodynamic changes in 2 patients with proximal and distal occlusion of complex cerebral aneurysms. The FSI results were in line with the follow-up CT scans and angiograms and indicate the potential of FSI as a tool in patient-specific surgical interventions.

Aortic valve dynamics using a fluid structure interaction model--The physiology of opening and closing.

Comparative study among aortic valves requires the use of an unbiased and relevant boundary condition. Pressure and flow boundary conditions used in literature are not sufficient for an unbiased analysis. We need a different boundary condition to analyze the valves in an unbiased, relevant environment. The proposed boundary condition is a combination of the pressure and flow boundary condition methods, which is chosen considering the demerits of the pressure and flow boundary conditions. In order to study the valve in its natural environment and to give a comparative analysis between different boundary conditions, a fluid-structure interaction analysis is made using the pressure and the proposed boundary conditions for a normal aortic valve. Commercial software LS-DYNA is used in all our analysis. The proposed boundary condition ensures a full opening of the valve with reduced valve regurgitation. It is found that for a very marginal raise in the ventricular pressure caused by pumping a fixed stroke volume, the cardiac output is considerably raised. The mechanics of the valve is similar between these two boundary conditions, however we observe that the importance of the root to raise the cardiac output may be overstated, considering the importance of the fully open nodule of arantius. Our proposed boundary condition delivers all the insights offered by the pressure and flow boundary conditions, along with providing an unbiased framework for the analysis of different valves and hence, more suitable for comparative analysis.

Normal aortic valves stay open much longer in systole than porcine substitutes.

OBJECTIVE: To compare the opening mechanics of porcine valve substitutes with those of a normal human aortic valve. BACKGROUND: All commercially available porcine valves are pretreated with glutaraldehyde. This study was undertaken to evaluate the consequences of such treatment on valve mechanics. METHODS: The opening mechanics of the aortic valve, especially the time taken to open fully from a closed position, and the duration for which the valve is maximally open, were compared in a normal aortic valve, a stent-mounted porcine valve, and a stentless porcine valve, using a finite element model. RESULTS: Despite a 4-fold higher gradient, stent-mounted porcine valves were slower in attaining the fully open position, and the time for which the valve was fully open was almost 25% less than a normal valve. In stentless valves, the compliant root made the initial opening mechanics similar to those of a normal valve. Once this effect was over, the effect of porcine leaflet properties took over, and there was a corresponding delay in the valve opening. CONCLUSIONS: Fixing the root with a stent and stiffening the leaflets with glutaraldehyde result in delayed valve opening and decrease the duration for which the valve is fully open, thus contributing to inferior hemodynamics.

Further insights into normal aortic valve function: role of a compliant aortic root on leaflet opening and valve orifice area.

BACKGROUND: This study aims to find the fundamental differences in the mechanism of opening and closing of a normal aortic valve and a valve with a stiff root, using a dynamic finite element model. METHODS: A dynamic, finite element model with time varying pressure was used in this study. Shell elements with linear elastic properties for the leaflet and root were used. Two different cases were analyzed: (1) normal leaflets inside a compliant root, and (2) normal leaflets inside a stiff root. RESULTS: A compliant aortic root contributes substantially to the smooth and symmetrical leaflet opening with minimal gradients. In contrast, the leaflet opening inside a stiff root is delayed, asymmetric, and wrinkled. However, this wrinkling is not associated with increased leaflet stresses. In compliant roots, the effective valve orifice area can substantially increase because of increased root pressure and transvalvular gradients. In stiff roots this effect is strikingly absent. CONCLUSIONS: A compliant aortic root contributes substantially to smooth and symmetrical leaflet opening with minimal gradients. The compliance also contributes much to the ability of the normal aortic valve to increase its effective valve orifice in response to physiologic demands of exercise. This effect is strikingly absent in stiff roots.

Dynamic analysis of the aortic valve using a finite element model.

BACKGROUND: The major aim of this study was to examine the leaflet/aortic root interaction during the cardiac cycle, including the stresses developed during the interaction. METHODS: Dynamic finite element analysis was used along with a geometrically accurate model of the aortic valve and the sinuses. Shell elements along with proper contact conditions were also used in the model. Pressure patterns during the cardiac cycle were given as an input, and a linear elastic model was assumed for the material. RESULTS: We found that aortic root dilation starts before the opening of the leaflet and is substantial by the time leaflet opens. Dilation of the root alone helps in opening the leaflet to about 20%. The equivalent stress pattern shows an instantaneous increase in stress at the coaptation surface during closure. Stresses increase as the point of attachment is approached from the free surface. CONCLUSIONS: The complex interplay of the geometry of the valve system can be effectively analyzed using a sophisticated dynamic finite element model. Results not previously brought out by the earlier static analysis shed new light on the root/valve interaction.