The Role of Nonglycolytic Glucose Metabolism in Myocardial Recovery Upon Mechanical Unloading and Circulatory Support in Chronic Heart Failure.

BACKGROUND: Significant improvements in myocardial structure and function have been reported in some patients with advanced heart failure (termed responders [R]) following left ventricular assist device (LVAD)-induced mechanical unloading. This therapeutic strategy may alter myocardial energy metabolism in a manner that reverses the deleterious metabolic adaptations of the failing heart. Specifically, our previous work demonstrated a post-LVAD dissociation of glycolysis and oxidative-phosphorylation characterized by induction of glycolysis without subsequent increase in pyruvate oxidation through the tricarboxylic acid cycle. The underlying mechanisms responsible for this dissociation are not well understood. We hypothesized that the accumulated glycolytic intermediates are channeled into cardioprotective and repair pathways, such as the pentose-phosphate pathway and 1-carbon metabolism, which may mediate myocardial recovery in R. METHODS: We prospectively obtained paired left ventricular apical myocardial tissue from nonfailing donor hearts as well as R and nonresponders at LVAD implantation (pre-LVAD) and transplantation (post-LVAD). We conducted protein expression and metabolite profiling and evaluated mitochondrial structure using electron microscopy. RESULTS: Western blot analysis shows significant increase in rate-limiting enzymes of pentose-phosphate pathway and 1-carbon metabolism in post-LVAD R (post-R) as compared with post-LVAD nonresponders (post-NR). The metabolite levels of these enzyme substrates, such as sedoheptulose-6-phosphate (pentose phosphate pathway) and serine and glycine (1-carbon metabolism) were also decreased in Post-R. Furthermore, post-R had significantly higher reduced nicotinamide adenine dinucleotide phosphate levels, reduced reactive oxygen species levels, improved mitochondrial density, and enhanced glycosylation of the extracellular matrix protein, α-dystroglycan, all consistent with enhanced pentose-phosphate pathway and 1-carbon metabolism that correlated with the observed myocardial recovery. CONCLUSIONS: The recovering heart appears to direct glycolytic metabolites into pentose-phosphate pathway and 1-carbon metabolism, which could contribute to cardioprotection by generating reduced nicotinamide adenine dinucleotide phosphate to enhance biosynthesis and by reducing oxidative stress. These findings provide further insights into mechanisms responsible for the beneficial effect of glycolysis induction during the recovery of failing human hearts after mechanical unloading.

Predicting mortality in cardiogenic shock secondary to ACS requiring short-term mechanical circulatory support: The ACS-MCS score.

OBJECTIVE: To identify predictors of 30-day all-cause mortality for patients with cardiogenic shock secondary to acute coronary syndrome (ACS-CS) who require short-term mechanical circulatory support (ST-MCS). BACKGROUND: ACS-CS mortality is high. ST-MCS is an attractive treatment option for hemodynamic support and stabilization of deteriorating patients. Mortality prediction modeling for ACS-CS patients requiring ST-MCS has not been well-defined. METHODS: The Utah Cardiac Recovery (UCAR) Shock database was used to identify patients admitted with ACS-CS requiring ST-MCS devices between May 2008 and August 2018. Pre-ST-MCS clinical, laboratory, echocardiographic, and angiographic data were collected. The primary endpoint was 30-day all-cause mortality. A weighted score comprising of pre-ST-MCS variables independently associated with 30-day all-cause mortality was derived and internally validated. RESULTS: A total of 159 patients (mean age, 61 years; 78% male) were included. Thirty-day all-cause mortality was 49%. Multivariable analysis resulted in four independent predictors of 30-day all-cause mortality: age, lactate, SCAI CS classification, and acute kidney injury. The model had good calibration and discrimination (area under the receiver operating characteristics curve 0.80). A predictive score (ranging 0-4) comprised of age ≥ 60 years, pre-ST-MCS lactate ≥2.5 mmol/L, AKI at time of ST-MCS implementation, and SCAI CS stage E effectively risk stratified our patient population. CONCLUSION: The ACS-MCS score is a simple and practical predictive score to risk-stratify CS secondary to ACS patients based on their mortality risk. Effective mortality risk assessment for ACS-CS patients could have implications on patient selection for available therapeutic strategy options.

Constrictive pericarditis in the setting of repeated chest trauma in a mixed martial arts fighter.

BACKGROUND: Constrictive pericarditis (CP) is characterized by scarring and loss of elasticity of the pericardium. This case demonstrates that mixed martial arts (MMA) is a previously unrecognized risk factor for CP, diagnosis of which is supported by cardiac imaging, right and left heart catheterization, and histological findings of dense fibrous tissue without chronic inflammation. CASE PRESENTATION: A 47-year-old Caucasian male former mixed martial arts (MMA) fighter from the Western United States presented to liver clinic for elevated liver injury tests (LIT) and a 35-pound weight loss with associated diarrhea, lower extremity edema, dyspnea on exertion, and worsening fatigue over a period of 6 months. Past medical history includes concussion, right bundle branch block, migraine headache, hypertension, chronic pain related to musculoskeletal injuries and fractures secondary to MMA competition. Involvement in MMA was extensive with an 8-year history of professional MMA competition and 13-year history of MMA fighting with recurrent trauma to the chest wall. The patient also reported a 20-year history of performance enhancing drugs including testosterone. Physical exam was notable for elevated jugular venous pressure, hepatomegaly, and trace peripheral edema. An extensive workup was performed including laboratory studies, abdominal computerized tomography, liver biopsy, echocardiogram, and cardiac magnetic resonance imaging. Finally, right and left heart catheterization-the gold standard-confirmed discordance of the right ventricle-left ventricle, consistent with constrictive physiology. Pericardiectomy was performed with histologic evidence of chronic pericarditis. The patient's hospital course was uncomplicated and he returned to NYHA functional class I. CONCLUSIONS: CP can be a sequela of recurrent pericarditis or hemorrhagic effusions and may have a delayed presentation. In cases of recurrent trauma, CP may be managed with pericardiectomy with apparent good outcome. Further studies are warranted to analyze the occurrence of CP in MMA so as to better define the risk in such adults.

Longitudinal assessment of the platelet transcriptome in advanced heart failure patients following mechanical unloading.

Patients with heart failure (HF) and left ventricular assist devices (LVAD) have dysregulated thrombo-inflammatory responses, mediated in part by platelets. While studies of platelet activation have been undertaken in HF, changes in the platelet transcriptome in HF patients following mechanical unloading with an LVAD have not been investigated. We prospectively enrolled and longitudinally followed advanced HF patients (n = 32) for a mean of 57 months post-LVAD implantation. For comparison, healthy donors were also enrolled (n = 20). Platelets were hyperactive in HF, as evidenced by significantly increased formation of circulating platelet-monocyte aggregate formation. Platelet transcriptome interrogation by next-generation RNA-sequencing identified that the expression of numerous genes (n = 588) was significantly (FDR < 0.05) altered in HF patients prior to LVAD implantation. Differentially expressed genes were predicted to have roles in angiogenesis, immune and inflammatory responses, apoptosis, and cardiac muscle contraction. 90 days following LVAD implantation, the majority (80%) of differentially expressed genes in HF patients normalized, as compared to the platelet transcriptomes of healthy donors. In conclusion, advanced HF is associated with marked alterations in the platelet transcriptome. While LVAD implantation to off load the failing heart results in resolution in the majority of differentially expressed genes, a subset of the platelet transcriptome remains persistently altered.

Echocardiography-Guided Dual-Lumen Venovenous Extracorporeal Membrane Oxygenation Cannula Placement in the ICU-A Retrospective Review.

OBJECTIVE: The most effective method of image guidance for venovenous extracorporeal membrane oxygenation is not known. The authors' objectives were to define the frequency of successful initial cannulation using echocardiographic guidance in the intensive care unit, as well as to determine the frequency of subsequent adjustments. Additional aims were to illustrate cannula malposition problems and to describe features associated with difficult cannulation. DESIGN: Retrospective consecutive case series analysis. SETTING: Single tertiary care university hospital. PARTICIPANTS: Forty-five patients treated with venovenous extracorporeal membrane oxygenation. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The most common causes of respiratory failure were pneumonia, aspiration, and inhalational burn injury. Sixty-two percent survived to discharge. Initial cannulation was successful in 39 cases (87%). Adverse events included 5 cases of cannula malposition and 1 case of hemorrhagic shock. During the course of extracorporeal membrane oxygenation, 17 patients (38%) required echo-guided cannula position adjustments. There were no fatal complications. Factors associated with difficult cannulation included extremes of size, a prominent Eustachian valve, and an anterior guidewire bending in the right atrium. Younger age was associated positively with survival. There was no significant association between adverse events during cannulation and survival. CONCLUSIONS: Dual-lumen venovenous extracorporeal membrane oxygenation cannulation in the intensive care unit under echo guidance has a high initial success rate, but many patients require subsequent repositioning. Echocardiography can define cannula position in sufficient detail to identify malposition precisely and to guide repositioning.

Rapid-deployment aortic valve replacement after aortic root replacement: A safe alternative to redo root replacement.

Reoperative aortic root replacement, following prior biologic or mechanical valved conduit aortic root prosthesis, presents a technical challenge. The rapid-deployment aortic valve prosthesis is an approved alternative to traditional bioprosthetic aortic valve replacement. We present three clinical cases in which rapid-deployment aortic valve prostheses were utilized in lieu of reoperative full aortic root replacement. All three patients recovered uneventfully. The rapid-deployment valve insertion in a prior surgical aortic root prosthesis is a safe option to avoid reoperative full aortic root replacement.

Outcomes of Asian-Americans Implanted With Left Ventricular Assist Devices: An Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Analysis.

BACKGROUND: Studies have indicated differences between Asians and Whites in their propensity for stroke, coronary artery disease, heart failure, bleeding and thrombosis. We investigated whether Asian-Americans on durable left ventricular assist devices (LVADs) exhibit differential morbidity and mortality when compared to Whites. METHODS: We analysed prospectively collected data from the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) database to compare the outcomes after LVAD implantation of Asians versus Whites. RESULTS: In total, 7,018 patients were included, 130 were identified as Asian-Americans. Asian-Americans were younger, had lower body mass index, higher serum bilirubin and lower albumin levels. In a multivariable regression model, there was no difference in survival between the two groups. Asian-Americans had lower incidence of device malfunction and after adjusting for multiple factors this remained lower. The adjusted risk of a major safety composite outcome, including major bleeding, major infection, stroke and device malfunction, revealed no difference between the two groups. CONCLUSIONS: Although prior studies have reported worse cardiac surgery outcomes in Asians, in this INTERMACS analysis Asian-Americans appear to have similar survival and risk of adverse events as their White counterparts. The incidence of device malfunction was lower in the Asian-Americans, both in a univariate model and after adjusting for multiple clinical factors. Future, larger studies of Asian-Americans with end-stage heart failure and LVAD support are warranted to confirm these results.

Right Ventricular Involution: Big Changes in Small Hearts.

BACKGROUND: Before birth, the fetal right ventricle (RV) is the pump for the systemic circulation and is about as thick as the left ventricle (LV). After birth, the RV becomes the pump for the lower pressure pulmonary circulation, and the RV chamber elongates without change in its wall thickness. We hypothesize that the fetal RV may be a model of compensated RV hypertrophy, and understanding this process may aid in discovering therapeutic strategies for RV failure. METHODS: We performed a literature review and identified pertinent articles from 1980 to present. RESULTS: The following topics were identified to be most pertinent in right ventricular involution: morphologic and histologic changes of the RV, cellular proliferation and terminal differentiation, the effect of stress on RV development, excitation contraction coupling and inotropic response change over time, and the amount of apoptosis through RV development. CONCLUSIONS: The RV changes on multiple levels after its transition from systemic to pulmonary circulation. Although published literature has variable results due partly from differences between animal models, the literature shows a clear need for more research in the field.

Acid Suppression to Prevent Gastrointestinal Bleeding in Patients With Ventricular Assist Devices.

BACKGROUND: The high incidence of gastrointestinal bleeding (GIB) in patients with ventricular assist devices (VAD) is well known, but there is limited evidence to support the use of proton pump inhibitors (PPIs) or histamine receptor antagonists (H2RA) for preventing GIB in patients with VAD. MATERIALS AND METHODS: The surgical ICU and VAD databases within a large regional academic cardiac mechanical support and transplant center were queried for patients who underwent VAD implantation between 2010 and 2014. An observational cohort study was conducted to identify which acid suppressing drug regimen was associated with the fewest number of GIB events within 30 d after VAD implantation: PPI, H2RA, or neither. Secondary outcomes included timing, etiology, and location of GIB. Multivariable logistic regression was used to compare treatment cohorts to GIB. Odds ratios, 95% confidence intervals, and P-values were reported from the model. RESULTS: One hundred thirty-eight patients were included for final analysis, 19 of which had a GIB within 30 days of VAD implantation. Both H2RA and PPI use were associated with reduced GIB compared with the cohort with no acid suppressive therapy. In the multivariate analysis, the PPI cohort showed a statistically significant reduction in GIB (Odds ratio 0.18 [95% confidence interval 0.04-0.79] P = 0.026). CONCLUSIONS: Using PPI postoperatively in patients with new VAD was associated with a reduced incidence of GIB. Given that GIB is a known complication after VAD placement, clinicians should consider the use of acid suppressive therapy for primary prevention.

Safety of long-distance transfers of patients on acute mechanical circulatory support.

BACKGROUND: Acute mechanical circulatory support (aMCS) can be a lifesaving therapy for patients with refractory cardiogenic shock. As device safety and technology improve, so will the ability to extend aMCS to patients at remote hospitals. The Intermountain West is unique because of the large geographical area, making transport of critically ill patients a logistical challenge. METHODS: We reviewed our experience of transporting patients in cardiogenic shock over long distances who had already been placed on aMCS: Impella and extracorporeal membrane oxygenator devices. Survival data was compared to international benchmark data published by the Extracorporeal Life Support Organization. RESULTS: A total of 11 patients (91% male; mean age 56 ± 5.4 y) were transported via fixed-wing aircraft to our center. The etiology of cardiogenic shock was ST-elevation myocardial infarction (n = 4), acutely decompensated chronic systolic heart failure (n = 4), postcardiotomy shock (n = 2), and acute myocarditis (n = 1). Average transport distance was 364 ± 139 miles (585 ± 264 km) and flight time was 170 ± 29 min. All patients were safely transported with no in-transit adverse events. The average duration of aMCS was 6.4 ± 3.3 d. Six patients (54.5%) survived to device explantation and 3 (27.2%) survived to hospital discharge. For comparison, Extracorporeal Life Support Organization benchmark data for adult cardiogenic shock patients report 56% survival to device explantation and 41% to hospital discharge. CONCLUSIONS: Patient transport with aMCS over long distances can be done safely without serious adverse events using good protocols and well-trained personnel. Although survival data are slightly below benchmark data, they appear reasonable, given the severity of illness and challenges of transferring critically ill patients to an expert center.

Health characteristics of heart transplant recipients surviving into their 80s.

BACKGROUND: Heart transplantation (HTx) is the preferred treatment for patients with end-stage heart failure and has been successful for >30 y. The clinical course of recipients at the extreme of age is unknown. We reviewed our experience to determine the overall health and prevalence of Tx-related medical problems for recipients in their ninth decade. METHODS: We reviewed the UCTP experience from 1985 to present to identify patients who survived into their 80s and matched (1:1) with other recipients for gender and age at HTx, but did not survive to ≥80 y. The end point was the prevalence of medical problems. RESULTS: Since 1985, 1129 adult HTx have been performed and 14 patients (1.2%) survived to ≥80 y old. The mean age at HTx was 63 ± 4 y. Of octogenarians, the majority were males with ischemic cardiomyopathy. The average survival after transplant was 19 ± 5 y in the octogenarians and 5 ± 5 y in the controls (P < 0.01). Over time, the prevalence of comorbidities increased. Compared with nonoctogenarians, we observed higher prevalence of dyslipidemia (P = 0.02), and chronic renal insufficiency (P = 0.02) during follow-up. Cardiac function was normal (ejection fraction > 55%) for all octogenarians at age 80 y. CONCLUSIONS: Despite improvements in posttransplant care, survival of HTx patients into the ninth decade is rare (1%). For those surviving into their 80s, cardiac function is preserved but dyslipidemia, renal insufficiency, and skin cancers are common. As the age of Htx patients continues to increase, posttransplant care should be tailored to minimize post-HTx complications and further extend survival.

Right Ventricular Fiber Structure as a Compensatory Mechanism in Pressure Overload: A Computational Study.

Right ventricular failure (RVF) is a lethal condition in diverse pathologies. Pressure overload is the most common etiology of RVF, but our understanding of the tissue structure remodeling and other biomechanical factors involved in RVF is limited. Some remodeling patterns are interpreted as compensatory mechanisms including myocyte hypertrophy, extracellular fibrosis, and changes in fiber orientation. However, the specific implications of these changes, especially in relation to clinically observable measurements, are difficult to investigate experimentally. In this computational study, we hypothesized that, with other variables constant, fiber orientation alteration provides a quantifiable and distinct compensatory mechanism during RV pressure overload (RVPO). Numerical models were constructed using a rabbit model of chronic pressure overload RVF based on intraventricular pressure measurements, CINE magnetic resonance imaging (MRI), and diffusion tensor MRI (DT-MRI). Biventricular simulations were conducted under normotensive and hypertensive boundary conditions using variations in RV wall thickness, tissue stiffness, and fiber orientation to investigate their effect on RV pump function. Our results show that a longitudinally aligned myocardial fiber orientation contributed to an increase in RV ejection fraction (RVEF). This effect was more pronounced in response to pressure overload. Likewise, models with longitudinally aligned fiber orientation required a lesser contractility for maintaining a target RVEF against elevated pressures. In addition to increased wall thickness and material stiffness (diastolic compensation), systolic mechanisms in the forms of myocardial fiber realignment and changes in contractility are likely involved in the overall compensatory responses to pressure overload.

Bleeding and thrombosis in chronic ventricular assist device therapy: focus on platelets.

PURPOSE OF REVIEW: Left ventricular assist devices (LVADs) have markedly improved the survival for patients with advanced heart failure but are plagued with significant morbidity, including pump thrombosis and bleeding. Better understanding of the platelet, and its role in the balance of bleeding and thrombosis, stands to impact the frequency and treatment of these significant complications. RECENT FINDINGS: In patients with LVADs, there is little consistency linking traditional biomarkers of platelet activation and clinical events. A number of innovative methods of assessing platelet functionality, including shedding of platelet receptors and formation of microparticle complexes as well as measuring mitochondrial membrane potentials, exist and appear to be clinically relevant. Acquired von Willebrand syndrome, while not explaining all bleeding events, is a central feature of mechanical support and offers a target for innovative therapies. SUMMARY: Although the platelet is only one component of impacting thrombosis and bleeding in patients supported with LVADs, it plays a central role in mediating these two opposing forces. Innovations in understanding platelet physiology as well as manipulating genomic and receptor interactions for an individual patient will be critical if we are to decrease these serious adverse events in the future.

Physiologic effects of continuous-flow left ventricular assist devices.

BACKGROUND: Within the past 10 years, continuous-flow left ventricular assist devices (LVADs) have replaced pulsatile-flow LVADs as the standard of care for both destination therapy and bridging patients to heart transplantation. Despite the rapid clinical adoption of continuous-flow LVADs, an understanding of the effects of continuous-flow physiology, as opposed to more natural pulsatile-flow physiology, is still evolving. MATERIALS AND METHODS: A thorough review of the relevant scientific literature regarding the physiological and clinical effects of continuous-flow physiology was performed. These effects were analyzed on an organ system basis and include an evaluation of the cardiovascular, respiratory, hematologic, gastrointestinal, renal, hepatic, neurologic, immunologic, and endocrine systems. RESULTS: Continuous-flow physiology is, generally speaking, well tolerated over the long term. However, several changes are manifest at the organ system level. Although many of these changes are without appreciable clinical significance, other changes, such as an increased rate of gastrointestinal bleeding, appear to be associated with continuous-flow physiology. CONCLUSIONS: Continuous-flow LVADs confer a significant advantage over their pulsatile-flow counterparts with regard to size and durability. From a physiological standpoint, continuous-flow physiology has limited clinical effects at the organ system level. Although improved over previous generations, challenges with this technology remain. Approaching these problems with a combination of clinical and engineering solutions may be needed to achieve continued progression in the field of durable mechanical circulatory support.

Resection of a Large Innominate Vein Aneurysm in a Patient with Neurofibromatosis Type 1.

BACKGROUND: Venous aneurysms are exceedingly rare manifestations of neurofibromatosis type 1 (NF1). There are only a handful of cases reported, and no prior cases describing treatment of mediastinal venous aneurysms in this patient population exist. CASE REPORT: A 58-year-old woman with NF1 presented with a right neck mass. The mass had recently doubled in size and was associated with cough, hoarseness of voice, and pain. Her pertinent medical history included untreated obstructive sleep apnea, severe pulmonary hypertension, and a recent hospital admission for pneumonia. On physical examination, numerous cutaneous neurofibromas were noted. The mass encompassed her right neck and supraclavicular area with marked respiratory variation. Computed tomography showed a complex 7-cm venous aneurysm including her right innominate, internal jugular, and subclavian veins. Surgical approach involved median sternotomy with right cervical extension and a right infraclavicular counter incision. Extracorporeal circulation was established through the left groin. Ligation of the right internal jugular vein was required. The aneurysm was completely excised, and venous reconstruction consisted of cryopreserved femoral vein anastomosed to right innominate and infraclavicular subclavian veins. Intraoperatively, her preexisting pulmonary hypertension resulted in acute right heart failure requiring placement of a right ventricular assist device (RVAD). She subsequently returned to the operating room for RVAD weaning and sternal closure. Her postoperative course was lengthy; however, many of her aneurysm-related symptoms resolved. CONCLUSIONS: This case represents management of the only innominate vein aneurysm in the setting of NF1 described in the literature. Vascular reconstruction is possible, however difficult. Careful preoperative planning and use of extracorporeal circulation was necessary in this case.

Emergency physician-performed transesophageal echocardiography for extracorporeal life support vascular cannula placement.

INTRODUCTION: There is growing interest and application of extracorporeal membrane oxygenation (ECMO) as a life-saving procedure for out-of-hospital cardiac arrest (OHCA), also called extracorporeal life support (ECLS). Extracorporeal membrane oxygenation cannulation with ongoing chest compressions is challenging, and transesophageal echocardiography (TEE) is an invaluable tool with which to guide ECMO wire guidance and cannula positioning. METHODS: We describe our protocol for TEE guidance by emergency physicians in our hospital. RESULTS: Of our first 12 cases of ECLS, 10 have had TEE guidance by an emergency physician with successful placement and without complication or need for repositioning. Emergency physician-performed TEE for ECLS vascular cannula placement has been both feasible and useful in our experience and warrants further study.

Minimally Invasive Temporary Right Ventricular Assist Device for Acute Right Ventricular Failure.

Minimally invasive approaches to acute mechanical circulatory support are needed to reduce hemorrhagic and other complications. We describe our minimally invasive approach to right ventricular assist device placement in patients with acute, non-postcardiotomy, right ventricular failure.

Animal model of reversible, right ventricular failure.

BACKGROUND: Heart failure is a leading cause of death but very little is known about right ventricular (RV) failure (RVF) and right ventricular recovery (RVR). A robust animal model of reversible, RVF does not exist, which currently limits research opportunities and clinical progress. We sought to develop an animal model of reversible, pressure-overload RVF to study RVF and RVR. MATERIALS AND METHODS: Fifteen New Zealand rabbits underwent implantation of a fully implantable, adjustable, pulmonary artery band. Animals were assigned to the control, RVF, and RVR groups (n = 5 for each). For the RVF and RVR groups, the pulmonary artery bands were serially tightened to create RVF and released for RVR. Echocardiographic, cardiac magnetic resonance imaging, and histologic analysis were performed. RESULTS: RV chamber size and wall thickness increased during RVF and regressed during RVR. RV volumes were 1023 µL ± 123 for control, 2381 µL ± 637 for RVF, and 635 µL ± 549 for RVR, and RV wall thicknesses were 0.98 mm ± 0.12 for controls (P = 0.05), 1.72 mm ± 0.60 for RVF, and 1.16 mm ± 0.03 for RVR animals (P = 0.04), respectively. Similarly, heart weight, liver weight, cardiomyocyte size, and the degree of cardiac and hepatic fibrosis increased with RVF and decreased during RVR. CONCLUSIONS: We report an animal model of chronic, reversible, pressure-overload RVF to study RVF and RVR. This model will be used for preclinical studies that improve our understanding of the mechanisms of RVF and that develop and test RV protective and RVR strategies to be studied later in humans.