Acute right ventricular failure (ARVF) refractory to optimal medical management may require rescue therapy with mechanical circulatory support (MCS). The RV exhibits a greater capacity for rapid ...recovery than the left ventricle, making devices designed specifically for temporary RV MCS attractive. We report our experience with the Impella Right Direct (RD) and Right Peripheral (RP) temporary ventricular assist devices (Abiomed, Danvers, MA) in patients with ARVF.
We conducted a retrospective cohort study examining the clinical outcomes of consecutive patients supported with the Impella RD or RP at 2 institutions during a 6-year period.
During the study period, 18 patients (67% men; mean age 57 ± 10 years) received MCS, 15 with the Impella RD and 3 with the Impella RP. Before RV MCS, all patients required intravenous inotropes, 7 (39%) required inhaled nitric oxide, 7 (39%) required intra-aortic balloon counterpulsation, and 2 (11%) had experienced a cardiac arrest. Device implantation resulted in an improvement in cardiac index (2.1 ± 0.1 liters/min/m(2) pre-implant vs 2.6 ± 0.2 liters/min/m(2) post-implant, p = 0.04) and reduced central venous pressure (22 ± 5 vs 15 ± 4 mm Hg, p < 0.01). Fourteen (78%) patients recovered sufficient RV function to facilitate device explanation after 7 days (range, 2-19 days) of support, and 4 (22%) patients died on support after 6 days (range 1-11 days). Survival to 30 days was 72% and to 1 year was 50%. At 1-year follow-up, the mean New York Heart Association functional classification was 1.3 ± 0.5, and only 1 patient demonstrated severe RV dysfunction on echocardiography.
Most patients with ARVF rapidly recover sufficient RV function to facilitate device explantation, highlighting an expanding role for minimally invasive temporary RV assist devices optimized for the treatment of recoverable ARVF.
Extracorporeal circulation (ECC) systems, including cardiopulmonary bypass, and extracorporeal membrane oxygenation have been an irreplaceable part of the cardiothoracic surgeries, and treatment of ...critically ill patients with respiratory and/or cardiac failure for more than half a century. During the recent decades, the concept of extracorporeal circulation has been extended to isolated machine perfusion of the donor organ including thoracic organs (
organ perfusion, ESOP) as a method for dynamic, semi-physiologic preservation, and potential improvement of the donor organs. The extracorporeal life support systems (ECLS) have been lifesaving and facilitating complex cardiothoracic surgeries, and the ESOP technology has the potential to increase the number of the transplantable donor organs, and to improve the outcomes of transplantation. However, these artificial circulation systems in general have been associated with activation of the inflammatory and oxidative stress responses in patients and/or in the exposed tissues and organs. The activation of these responses can negatively affect patient outcomes in ECLS, and may as well jeopardize the reliability of the organ viability assessment, and the outcomes of thoracic organ preservation and transplantation in ESOP. Both ECLS and ESOP consist of artificial circuit materials and components, which play a key role in the induction of these responses. However, while ECLS can lead to systemic inflammatory and oxidative stress responses negatively affecting various organs/systems of the body, in ESOP, the absence of the organs that play an important role in oxidant scavenging/antioxidative replenishment of the body, such as liver, may make the perfused organ more susceptible to inflammation and oxidative stress during extracorporeal circulation. In the present manuscript, we will review the activation of the inflammatory and oxidative stress responses during ECLP and ESOP, mechanisms involved, clinical implications, and the interventions for attenuating these responses in ECC.
Survival after pulmonary thromboendarterectomy: Effect of residual pulmonary hypertension Freed, Darren H., MD, PhD, FRCSC; Thomson, Bruce M., FRACS; Berman, Marius, MD ...
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
02/2011, Letnik:
141, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Objective Pulmonary endarterectomy is the treatment of choice for chronic thromboembolic pulmonary hypertension. In many patients hemodynamics are normalized early after surgical intervention. ...However, the effect of residual pulmonary hypertension on postoperative clinical status and survival is unknown. Methods Data were collected prospectively on all patients who underwent pulmonary endarterectomy in a continuous national series between 1997 and December 2007. Postoperatively, patients underwent scheduled reinvestigation, including functional testing and right heart catheterization, at 3 months after the operation. They were divided into 2 groups based on mean pulmonary artery pressure: group 1, less than 30 mm Hg; group 2, 30 mm Hg or greater. Results Three hundred fourteen patients underwent pulmonary endarterectomy, survived to hospital discharge, and completed the 3-month follow-up period. At 3 months after pulmonary endarterectomy, there was a significant reduction in mean pulmonary artery pressure for the whole cohort (48 ± 12 to 26 ± 10 mm Hg, P < .001). However, 31% of the patients had residual pulmonary hypertension. Group 1 patients enjoyed significantly better exercise capacity and improved symptoms compared with group 2 patients. In addition, there were significantly fewer patients receiving targeted medical therapy in group 1 versus group 2 (0% vs 25%, P < .001). Conditional survival after discharge from the hospital for the whole cohort was 90.0% at 5 years and was not different between groups (90.3% for group 1 vs 89.9% for group 2, P = .36). Conclusions For patients undergoing pulmonary endarterectomy, survival after hospital discharge is excellent. Residual pulmonary hypertension significantly compromised symptom status and functional capacity but did not appear to adversely affect medium-term survival. The effect of targeted medical therapy in patients with residual pulmonary hypertension after pulmonary endarterectomy needs to be evaluated further.
Pulmonary arterial hypertension (PAH) is a progressive vascular disease with a high mortality rate. It is characterized by an occlusive vascular remodeling due to a pro-proliferative and ...antiapoptotic environment in the wall of resistance pulmonary arteries (PAs). Proliferating cells exhibit a cancer-like metabolic switch where mitochondrial glucose oxidation is suppressed, whereas glycolysis is up-regulated as the major source of adenosine triphosphate production. This multifactorial mitochondrial suppression leads to inhibition of apoptosis and downstream signaling promoting proliferation. We report an increase in pyruvate dehydrogenase kinase (PDK), an inhibitor of the mitochondrial enzyme pyruvate dehydrogenase (PDH, the gatekeeping enzyme of glucose oxidation) in the PAs of human PAH compared to healthy lungs. Treatment of explanted human PAH lungs with the PDK inhibitor dichloroacetate (DCA) ex vivo activated PDH and increased mitochondrial respiration. In a 4-month, open-label study, DCA (3 to 6.25 mg/kg b.i.d.) administered to patients with idiopathic PAH (iPAH) already on approved iPAH therapies led to reduction in mean PA pressure and pulmonary vascular resistance and improvement in functional capacity, but with a range of individual responses. Lack of ex vivo and clinical response was associated with the presence of functional variants of
and
that predict reduced protein function. Impaired function of these proteins causes PDK-independent mitochondrial suppression and pulmonary hypertension in mice. This first-in-human trial of a mitochondria-targeting drug in iPAH demonstrates that PDK is a druggable target and offers hemodynamic improvement in genetically susceptible patients, paving the way for novel precision medicine approaches in this disease.
There is international variability in the determination of death. Death in donation after circulatory death (DCD) can be defined by the permanent cessation of brain circulation. Post‐mortem ...interventions that restore brain perfusion should be prohibited as they invalidate the diagnosis of death. Retrieval teams should develop protocols that ensure the continued absence of brain perfusion during DCD organ recovery. In situ normothermic regional perfusion (NRP) or restarting the heart in the donor's body may interrupt the permanent cessation of brain perfusion because, theoretically, collateral circulations may restore it. We propose refinements to current protocols to monitor and exclude brain reperfusion during in situ NRP. In abdominal NRP, complete occlusion of the descending aorta prevents brain perfusion in most cases. Inserting a cannula in the ascending aorta identifies inadequate occlusion of the descending aorta or any collateral flow and diverts flow away from the brain. In thoracoabdominal NRP opening the aortic arch vessels to atmosphere allows collateral flow to be diverted away from the brain, maintaining the permanence standard for death and respecting the dead donor rule. We propose that these hypotheses are correct when using techniques that simultaneously occlude the descending aorta and open the aortic arch vessels to atmosphere.
The authors present techniques to prevent the restoration of brain perfusion during in situ normothermic regional perfusion by ensuring the diversion of any possible collateral supply.
The cholesterol biosynthesis pathway, also known as the mevalonate (MVA) pathway, is an essential cellular pathway that is involved in diverse cell functions. The enzyme ...3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMGCR) is the rate-limiting step in cholesterol biosynthesis and catalyzes the conversion of HMG-CoA to MVA. Given its role in cholesterol and isoprenoid biosynthesis, the regulation of HMGCR has been intensely investigated. Because all cells require a steady supply of MVA, both the sterol (i.e. cholesterol) and non-sterol (i.e. isoprenoid) products of MVA metabolism exert coordinated feedback regulation on HMGCR through different mechanisms. The proper functioning of HMGCR as the proximal enzyme in the MVA pathway is essential under both normal physiologic conditions and in many diseases given its role in cell cycle pathways and cell proliferation, cholesterol biosynthesis and metabolism, cell cytoskeletal dynamics and stability, cell membrane structure and fluidity, mitochondrial function, proliferation, and cell fate. The blockbuster statin drugs ('statins') directly bind to and inhibit HMGCR, and their use for the past thirty years has revolutionized the treatment of hypercholesterolemia and cardiovascular diseases, in particular coronary heart disease. Initially thought to exert their effects through cholesterol reduction, recent evidence indicates that statins also have pleiotropic immunomodulatory properties independent of cholesterol lowering. In this review we will focus on the therapeutic applications and mechanisms involved in the MVA cascade including Rho GTPase and Rho kinase (ROCK) signaling, statin inhibition of HMGCR, geranylgeranyltransferase (GGTase) inhibition, and farnesyltransferase (FTase) inhibition in cardiovascular disease, pulmonary diseases (e.g. asthma and chronic obstructive pulmonary disease (COPD)), and cancer.
Demand for heart transplants far exceeds supply of donated organs. This is attributed to the high percentage of donor hearts that are discarded and to the narrow six-hour time window currently ...available for transplantation. Ex-vivo heart perfusion (EVHP) provides the opportunity for resuscitation of damaged organs and extended transplantation time window by enabling functional assessment of the hearts in a near-physiologic state. Present work investigates the fluid mechanics of the ex-vivo flow loop and corresponding impact on cardiac performance. A mechanical flow loop is developed that is analogous to the region of the EVHP system that mimics in-vivo systemic circulation, including the body's largest and most compliant artery, the aorta. This investigation is focused on determining the effect of mock aortic tubing compliance on pump performance. A custom-made silicone mock aorta was developed to simulate a range of in-vivo conditions and a physiological flow was generated using a commercial ventricular assist device (VAD). Monitored parameters, including pressure, tube distension and downstream velocity, acquired using time-resolved particle imaging velocimetry (PIV), were applied to an unsteady Bernoulli analysis of the flow in a novel way to evaluate pump performance as a proxy for cardiac workload. When compared to the rigid case, the compliant mock aorta case demonstrated healthier physiologic pressure waveforms, steadier downstream flow and reduced energetic demands on the pump. These results provide experimental verification of Windkessel theory and support the need for a compliant mock aorta in the EVHP system.
An ex vivo heart perfusion device preserves the donor heart in a warm beating state during transfer between extraction and implantation surgeries. One of the current challenges includes the use of ...rigid and noncompliant plastic tubes, which causes injuries to the heart at the junction between the tissue and the tube. The compliant and rapidly strain-stiffening mechanical property that generates a “J-shaped” stress–strain behavior is necessary for producing the Windkessel effect, which ensures continuous flow of blood through the aorta. In this study, we mimic the J-shaped and anisotropic stress–strain behavior of human aorta in synthetic elastomers to replace the problematic noncompliant plastic tube. First, we assess the mechanical properties of human (n = 1) and porcine aorta (n = 14) to quantify the nonlinear and anisotropic behavior under uniaxial tensile stress from five different regions of the aorta. Second, fabric-reinforced elastomer composites were prepared by reinforcing silicone elastomers with embedded fabrics in a trilayer geometry. The knitted structures of the fabric provide strain-stiffening as well as anisotropic mechanical properties of the resulting composite in a deterministic manner. By optimizing the combination between different elastomers and fabrics, the resulting composites matched the J-shaped and anisotropic stress–strain behavior of natural human and porcine aorta. Finally, improved analytical constitutive models based on Gent’s and Mooney–Rivlin’s constitutive model (to describe the elastomer matrix) combined with Holzapfel–Gasser–Ogden’s model (to represent the stiffer fabrics) were developed to describe the J-shaped behavior of the natural aortas and the fabric-reinforced composites. We anticipate that the suggested fabric-reinforced silicone elastomer composite design concept can be used to develop complex soft biomaterials, as well as in emerging engineering fields such as soft robotics and microfluidics, where the Windkessel effect can be useful in regulating the flow of fluids.
Background
Despite efforts, pediatric HTx candidates continue to have high waitlist mortality due to limited donor availability. However, there is a significant number of offered hearts not used due ...to concerns of viability. ESHP is a method for continuous perfusion of the donor heart that allows assessment and extended out‐of‐body time. It is imperative to understand healthcare stakeholders' perspectives on ESHP for implementation. Therefore, the aims of this qualitative study were to: (1) Explore pediatric stakeholders' perspectives toward ESHP; and (2) Identify barriers to widespread adoption of this technology.
Methods
Virtual focus groups were completed with pediatric HTx healthcare professional stakeholders. Following transcription of audio‐recordings, the material was analyzed using content analysis.
Results
Four focus groups were completed with 17 participants, representing 12 institutions and three countries. Focus groups revealed varied understanding of both current and potential uses of ESHP. Participants did see the potential benefits of extending out‐of‐body time for and the ability to evaluate donor heart quality. However, concerns were expressed relating to patient selection, wait‐list times, post‐HTx outcomes, adverse events, and technical issues. These were felt to be important to understand in order to justify the costs of ESHP and impact on the healthcare system.
Conclusions
This project represents the first qualitative formative evaluation of ESHP in pediatrics. The knowledge gained from stakeholders will form the basis for education initiatives, clinical trial design, and roll‐out of new ESHP technologies designed for pediatrics.
One of the most promising applications of liver normothermic machine perfusion (NMP) is the potential to directly assess graft viability and injury. In most NMP studies, perfusate transaminases are ...utilized as markers of graft injury. Our aim was to further elucidate the metabolism of transaminases by healthy porcine livers during NMP, specifically whether such livers could clear circuit perfusate transaminases.
A highly concentrated transaminase solution was prepared from homogenized liver, with an aspartate aminotransferase (AST) level of 107,427 U/L. Three livers in the treatment group were compared to three controls, during 48 hours of NMP. In the treatment group, the circuit perfusate was injected with the transaminase solution to artificially raise the AST level to a target of 7,500 U/L. Perfusate samples were taken at two-hour intervals and analyzed for biochemistry until NMP end. Graft oxygen consumption and vascular parameters were monitored.
Compared to controls, treated perfusions demonstrated abrupt elevations in transaminase levels (p>0.0001) and lactate dehydrogenase (LDH) (p>0.0001), which decreased over time, but never to control baseline. Liver function, as demonstrated by lactate clearance and oxygen consumption was not different between groups. The treatment group demonstrated a higher portal vein resistance (p = 0.0003), however hepatic artery resistance was similar. Treated livers had higher bile production overall (p<0.0001).
Addition of high levels of transaminases and LDH to a healthy porcine liver during ex situ perfusion results in progressive clearance of these enzymes, suggesting preserved liver metabolism. Such tolerance tests may provide valuable indicators of prospective graft function.
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