Model Of Right Ventricular Failure Research Articles

Beneficial Effects of Low-Intensity Pulsed Ultrasound Therapy on Right Ventricular Dysfunction in Animal Models

Right ventricular failure (RVF) is a leading cause of death in patients with pulmonary hypertension; however, effective treatment remains to be developed. We have developed low-intensity pulsed ultrasound therapy for cardiovascular diseases. In this study, we demonstrated that the expression of endothelial nitric oxide synthase (eNOS) in RVF patients was downregulated and that eNOS expression and its downstream pathway were ameliorated through eNOS activation in 2 animal models of RVF. These results indicate that eNOS is an important therapeutic target of RVF, for which low-intensity pulsed ultrasound therapy is a promising therapy for patients with RVF.

The complement C3-complement factor D-C3a receptor signalling axis regulates cardiac remodelling in right ventricular failure

Failure of the right ventricle plays a critical role in any type of heart failure. However, the mechanism remains unclear, and there is no specific therapy. Here, we show that the right ventricle predominantly expresses alternative complement pathway-related genes, including Cfd and C3aR1. Complement 3 (C3)-knockout attenuates right ventricular dysfunction and fibrosis in a mouse model of right ventricular failure. C3a is produced from C3 by the C3 convertase complex, which includes the essential component complement factor D (Cfd). Cfd-knockout mice also show attenuation of right ventricular failure. Moreover, the plasma concentration of CFD correlates with the severity of right ventricular failure in patients with chronic right ventricular failure. A C3a receptor (C3aR) antagonist dramatically improves right ventricular dysfunction in mice. In summary, we demonstrate the crucial role of the C3-Cfd-C3aR axis in right ventricular failure and highlight potential therapeutic targets for right ventricular failure.

Abstract 13104: L-carnitine Supplementation Improves Right Ventricular Function in Two Models of Right Ventricular Failure

Introduction: Previous studies have shown that right ventricular (RV) failure in pulmonary arterial hypertension is characterized by diminished fatty acid oxidation and ultimate lipotoxicity due to accumulation of toxic lipid intermediates. Whether or not augmenting fatty acid oxidation can reverse lipotoxic RV failure in PAH is not known. Hypothesis: In this study, we tested the hypothesis that augmentation of fatty acid oxidation through L-carnitine supplementation reverses RV failure in two models of RV failure. Methods: BMPR2 (R899X) mice were allowed to develop PAH for 10 weeks prior to supplementation of L-carnitine or control in their water for 8 weeks. In a second model, wild type C57/BL6 mice underwent pulmonary artery banding and were treated with L-carnitine or control 2 weeks after banding surgery. Finally, L-carnitine supplementation was also tested on H9C2 cardiomyocyte-like cells transfected with mutant BMPR2. Lipid accumulation was measured by Oil Red O or BODIPY stain. Fatty acid-mediated mitochondrial respiration was measured by Oroboros Oxygraph or Seahorse analysis. Results: In vivo , L-carnitine in BMPR2 mice and pulmonary artery banded mice increased RV cardiac output, RV ejection fraction, and mitochondrial respiration of long-chain fatty acids. Hemodynamic improvement in RV cardiac output was confirmed in pulmonary artery banded mice. In vitro , L-carnitine reduced lipid accumulation and increased fatty acid oxidation in BMPR2 mutant H9C2 cells through a Cpt1-dependent mechanism. Conclusions: In summary, augmentation of fatty acid oxidation in right ventricular failure through L-carnitine supplementation improves RV function, increases fatty acid oxidation, and decreases lipid accumulation.

Abstract 10231: Parp1-Pkm2 Axis Mediates Right Ventricular Failure Associated with Pulmonary Arterial Hypertension

Introduction: Right ventricular (RV) function is the poor prognosis factor in pulmonary arterial hypertension (PAH) patients. Inflammation, oxidative DNA damage, and glycolysis are key triggering pathways that induce cardiomyocytes (CM) dysfunction. Oxidative DNA damage-dependent Poly (ADP ribose) Polymerase 1 (PARP1) activation was documented to promote glycolysis and inflammation through nuclear retention of Pyruvate Kinase Muscle isozyme 2 (PKM2). Despite PARP1/PKM2 axis is involved in many pathologies, their role in RV failure (RVF) remains unclear. We hypothesized that sustained PARP1 activation induces nuclear PKM2 localization, cardiac inflammation, and myocytes apoptosis resulting in transition from compensated (cRV) to decompensated RV (dRV). Methods and Results: We found that PARP1/PKM2 expression/activity (IF, WB) is upregulated in dRV patients (died of RVF, n=11) compared to cRV patients (CI>2.2, n=12) and control donors (n=19). Similar findings were seen in two rat models of RVF (monocrotaline, PA banding). In vitro , we confirmed that oxidative DNA damage (ET-1+H 2 O 2 ) as well as inflammatory stress (ET-1+LPS) induced nuclear expression of PARP1/PKM2 (IF, WB) leading to inflammation (NF-κB nuclear translocation) and CM death (TUNEL). These effects were prevented by treatment with PARP1 inhibitor (ABT-888, Olaparib) or enforced cytosolic retention of PKM2 (TEPP-46, DASA-58). Cardiomyocytes isolated from neonatal Parp1 deficient mice were resistant to myocyte dysfunction (PKM2 nuclear upregulation, NF-κB nuclear translocation, TUNEL) induced by oxidative DNA damage (ET-1+H 2 O 2 ). In vivo , Olaparib (10mg/kg) as well as TEPP-46 (25mg/kg) prevented RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis) induced by PAB in rats (n=8~12 per group). Moreover, we confirmed that global Parp1 loss-of-function confers protection against PAB induced-RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis, n=10 per group). (All p<0.05) Conclusions: We demonstrated for the first time that PARP1/PKM2 axis is a critical signal pathway RV decompensation. Targeting PARP1/PKM2 axis may represent a promising avenue for tackling maladaptive RV remodeling and pulmonary circulation, simultaneously.

Abstract 13700: Role of Parp1-pkm2 Axis in the Pathogenesis of Right Ventricular Failure Associated With Pulmonary Arterial Hypertension

Background: Right ventricular failure (RVF) is a poor prognostic factor for pulmonary arterial hypertension (PAH) patients. Inflammation, oxidative stress-induced DNA damage, and glycolysis are key RVF-driven pathways triggering cardiomyocytes (CM) dysfunction. Persistent DNA damage-dependent Poly (ADP ribose) Polymerase 1 (PARP1) activation was documented to promote glycolysis and pro-inflammatory responses through nuclear retention of Pyruvate Kinase Muscle isozyme 2 (PKM2). Despite the tremendous attention to PARP1/PKM2 axis in many pathologies, their implication in RVF remains unexplored. We hypothesized sustained PARP1 activation accounts for nuclear PKM2 localization, contributing to CM dysfunction and transition from compensated (cRVH) to decompensated RVH(dRVH). Methods and Results: We found by WB and IF that PARP1/PKM2 expression/activity is increased in dRVH (patients died from RVF, n=9) compared to cRVH (Cardiac index >2.2, n=14) and control donors (n=14) and correlates with RV hypertrophy and fibrosis. Similar findings were found in two rat models of RVF (monocrotaline; MCT, pulmonary artery banding; PAB). In addition, cardiac inflammation (NF-kB, HMGB1, IL-8, CCL-2, SOCS3, CD68), oxidative DNA damage (MTH1, 8-oxodG), and apoptosis (TUNEL) were significantly increased in dRVH compared to cRVH (human and rat models). In vitro , we confirmed by WB and IF that oxidative DNA damage (H 2 O 2 ) induce nuclear expression of PARP1/PKM2 in CM leading to the release of inflammatory mediators (NFkB, HMGB1) and cell death. These effects were prevented by pharmacological inhibition of PARP1 (ABT888) and enforced cytosolic retention of PKM2 (TEPP46 and DASA58). In vivo , PARP1 inhibition (Olaparib; 10mg/kg) as well as TEPP46 (25mg/kg) delayed progression of RVF (CO, hypertrophy, fibrosis, inflammation, DNA damage, apoptosis) in PAB rats (n=8 per groups). Preliminary data indicate CM-specific inactivation of PARP1 induces resistance to RVF in PAB mice (All p<0.05). Conclusions: We demonstrated for the first time that PARP1/PKM2 axis is a critical integrator of oxidative stress, inflammation, and metabolic dysfunction during pathological RVF. Modulating PARP1/PKM2 axis may represent a promising avenue for ameliorating RVF in PAH.

A Large Animal Model of Right Ventricular Failure due to Chronic Thromboembolic Pulmonary Hypertension: A Focus on Function.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a debilitating disease that progresses to right ventricular (RV) failure and death if left untreated. Little is known regarding the progression of RV failure in this disease, greatly limiting effective prognoses, and therapeutic interventions. Large animal models enable the use of clinical techniques and technologies to assess progression and diagnose failure, but the existing large animal models of CTEPH have not been shown to replicate the functional consequences of the RV, i.e., RV failure. Here, we created a canine embolization model of CTEPH utilizing only microsphere injections, and we used a combination of right heart catheterization (RHC), echocardiography (echo), and magnetic resonance imaging (MRI) to quantify RV function. Over the course of several months, CTEPH led to a 6-fold increase in pulmonary vascular resistance (PVR) in four adult, male beagles. As evidenced by decreased cardiac index (0.12 ± 0.01 v. 0.07 ± 0.01 [L/(min*kg)]; p < 0.05), ejection fraction (0.48 ± 0.02 v. 0.31 ± 0.02; p < 0.05), and ventricular-vascular coupling ratio (0.95 ± 0.09 v. 0.45 ± 0.05; p < 0.05), as well as decreased tricuspid annular plane systolic excursion (TAPSE) (1.37 ± 0.06 v. 0.86 ± 0.05 [cm]; p < 0.05) and increased end-diastolic volume index (2.73 ± 0.06 v. 2.98 ± 0.02 [mL/kg]; p < 0.05), the model caused RV failure. The ability of this large animal CTEPH model to replicate the hemodynamic consequences of the human disease suggests that it could be utilized for future studies to gain insight into the pathophysiology of CTEPH development, following further optimization.

Reversal of right ventricular failure by chronic α1A-subtype adrenergic agonist therapy.

Right ventricular (RV) failure (RVF) is a serious disease with no effective treatment available. We recently reported a disease prevention study showing that chronic stimulation of α1A-adrenergic receptors (α1A-ARs), started at the time of RV injury, prevented the development of RVF. The present study used a clinically relevant disease reversal design to test if chronic α1A-AR stimulation, started after RVF was established, could reverse RVF. RVF was induced surgically by pulmonary artery constriction in mice. Two weeks after pulmonary artery constriction, in vivo RV fractional shortening as assessed by MRI was reduced by half relative to sham-operated controls (25 ± 2%, n = 27, vs. 52 ± 2%, n = 13, P < 10-11). Subsequent chronic treatment with the α1A-AR agonist A61603 for a further 2 wk resulted in a substantial recovery of RV fractional shortening (to 41 ± 2%, n = 17, P < 10-7 by a paired t-test) along with recovery of voluntary exercise capacity. Mechanistically, chronic A61603 treatment resulted in increased activation of the prosurvival kinase ERK, increased abundance of the antiapoptosis factor Bcl-2, and decreased myocyte necrosis evidenced by a decreased serum level of cardiac troponin. Moreover, A61603 treatment caused increased abundance of the antioxidant glutathione peroxidase-1, decreased level of reactive oxygen species, and decreased oxidative modification (carbonylation) of myofilament proteins. Consistent with these effects, A61603 treatment resulted in increased force development by cardiac myofilaments, which might have contributed to increased RV function. These findings suggest that the α1A-AR is a therapeutic target to reverse established RVF. NEW & NOTEWORTHY Currently, there are no effective therapies for right ventricular (RV) failure (RVF). This project evaluated a novel therapy for RVF. In a mouse model of RVF, chronic stimulation of α1A-adrenergic receptors with the agonist A61603 resulted in recovery of in vivo RV function, improved exercise capacity, reduced oxidative stress-related carbonylation of contractile proteins, and increased myofilament force generation. These results suggest that the α1A-adrenergic receptor is a therapeutic target to treat RVF.

Analysis of the microRNA signature driving adaptive right ventricular hypertrophy in an ovine model of congenital heart disease

The right ventricular (RV) response to pulmonary arterial hypertension (PAH) is heterogeneous. Most patients have maladaptive changes with RV dilation and RV failure, whereas some, especially patients with PAH secondary to congenital heart disease, have an adaptive response with hypertrophy and preserved systolic function. Mechanisms for RV adaptation to PAH are unknown, despite RV function being a primary determinant of mortality. In our congenital heart disease ovine model with fetally implanted aortopulmonary shunt (shunt lambs), we previously demonstrated an adaptive physiological RV response to increased afterload with hypertrophy. In the present study, we examined small noncoding microRNA (miRNA) expression in shunt RV and characterized downstream effects of a key miRNA. RV tissue was harvested from 4-wk-old shunt and control lambs ( n = 5), and miRNA, mRNA, and protein were quantitated. We found differential expression of 40 cardiovascular-specific miRNAs in shunt RV. Interestingly, this miRNA signature is distinct from models of RV failure, suggesting that miRNAs might contribute to adaptive RV hypertrophy. Among RV miRNAs, miR-199b was decreased in the RV with eventual downregulation of nuclear factor of activated T cells/calcineurin signaling. Furthermore, antifibrotic miR-29a was increased in the shunt RV with a reduction of the miR-29 targets collagen type A1 and type 3A1 and decreased fibrosis. Thus, we conclude that the miRNA signature specific to shunt lambs is distinct from RV failure and drives gene expression required for adaptive RV hypertrophy. We propose that the adaptive RV miRNA signature may serve as a prognostic and therapeutic tool in patients with PAH to attenuate or prevent progression of RV failure and premature death. NEW & NOTEWORTHY This study describes a novel microRNA signature of adaptive right ventricular hypertrophy, with particular attention to miR-199b and miR-29a.

Sisyphus’s Dilemma: Measurement of Ventricular-Arterial Coupling by Doppler Echocardiography Predicts the Incidence of Right Ventricular Failure after Heart Transplantation Better than Right Catheterization

Background: Increased pulmonary vascular resistance, assessed by right catheterization, is usually mentioned as a relative contraindication for inclusion in the list of heart transplantation since it is associated with failure of the implanted right ventricle. There is evidence suggesting that the behavior of the pulmonary circulation depends on its interaction with theright ventricle, so a parameter that evaluates ventricular-arterial coupling could predict right ventricular failure better than isolated hemodynamic parameters. Objective: The aim of this study was to assess the ability of the tricuspid annular plane systolic excursion/pulmonary systolic pressure ratio (TAPSE/PSP) to predict the incidence of post-transplantation right ventricular failure compared with invasive hemodynamic parameters measured before transplantation. Methods: This was a retrospective cohort study using variables prospectively collected from the heart transplantation database of a University Hospital of the City of Buenos Aires. A total of 56 consecutive patients with complete echocardiographic and hemodynamic tests, undergoing heart transplantation between January 2012 and April 2017, were included in the study. Patients with more than one parenchymal transplantation, retransplantation, congenital heart disease, those requiring ventricular assistance at the time of pre-transplantation assessment or with incomplete data were excluded. Results: Three patients (5.3%) died within the first 30 days, 2 from right ventricular failure. No preoperative hemodynamic or echocardiographic parameters were associated with mortality. The incidence of right ventricular failure in the immediate postoperative period was 28.5% (16 patients). All the hemodynamic variables of pulmonary pressure and resistance, and the TAPSE/PSP ratio measured by echocardiography were associated with the development of right ventricular failure after heart transplantation. In a multivariate analysis including hemodynamic and echocardiographic variables, the TAPSE/PSP ratio was the only one independently associated with right ventricular failure (0R>10, 95% CI 2.2->100, p=0.03). A TAPSE/PSP cut-off value of 0.26 showed sensitivity of 81% and specificity of 88% to predict right ventricular failure, with an area under the ROC curve of 0.84 ± 0.06 and X2=0 in the Hosmer-Lemeshow test (p=1) when considering quartiles of TAPSE/PSP. A predictive model of right ventricular failure composed of hemodynamic variables showed a sensitivity of 38% and a specificity of 97.5%, with an area under the ROC curve of 0.78±0.06 and X2=2.37 (p=0.3) in the Hosmer-Lemeshow test. Conclusions: We can conclude that the TAPSE/PSP ratio showed better discrimination and calibration to predict right ventricular failure, with 0.26 as the best prognostic performance value.

Limitations and pitfalls in measurements of right ventricular stroke volume in an animal model of right heart failure

Right heart failure occurs in various heart and pulmonary vascular diseases and may be fatal. We aimed to identify limitations in non-invasive measurements of right ventricular stroke volume in an animal model of right ventricular failure. Data from previous studies randomising rats to pulmonary trunk banding (PTB, n = 33) causing pressure-overload right ventricular failure or sham operation (n = 16) was evaluated retrospectively. We measured right ventricular stroke volume by high frequency echocardiography and magnetic resonance imaging (MRI). We found correlation between right ventricular stroke volume measured by echocardiography and MRI in the sham animals (r = 0.677, p = 0.004) but not in the PTB group. Echocardiography overestimated the stroke volume compared to MRI in both groups. Intra- and inter-observer variation did not explain the difference. Technical, physiological and anatomical issues in the pulmonary artery might explain why echocardiography over-estimates stroke volume. Flow acceleration close to the pulmonary artery banding can cause uncertainties in the PTB model and might explain the lack of correlation. In conclusion, we found a correlation in right ventricular stroke volume measured by echocardiography versus MRI in the sham group but not the PTB group. Echocardiography overestimated right ventricular stroke volume compared to MRI.

Alternative approach for right ventricular failure after left ventricular assist device placement in animal model.

Right ventricular failure after left ventricular assist device (LVAD) implantation is associated with high mortality. This study was designed to evaluate the effectiveness of an atrial septostomy with a membrane oxygenator incorporated in an LVAD as a novel approach for right ventricular failure after LVAD implantation. The outflow and inflow cannulae were placed in the carotid artery and left ventricular apex, respectively. A centrifugal pump and an oxygenator were sequentially placed between the inflow and outflow cannulae in seven anesthetized goats. While right ventricular failure was induced by pulmonary artery banding, a balloon atrial septostomy was performed using a 19-mm balloon catheter under echocardiographic guidance. We investigated the effects of the interatrial shunt on LVAD flow and haemodynamics. Development of right ventricular failure decreased LVAD flow (2.7 ± 0.6-0.9 ± 0.6 l/min), causing a state of shock [mean arterial pressure (MAP) of 41 ± 12 mmHg]. Following a balloon atrial septostomy, LVAD flow and MAP were significantly improved to 2.7 ± 0.4 l/min (P < 0.001) and 53 ± 18 mmHg (P = 0.006), respectively, while right atrial pressure decreased from 18 ± 5 to 15 ± 5 mmHg (P = 0.001). Furthermore, arterial blood oxygenation was maintained by the membrane oxygenator incorporated in the LVAD. In the present model of right ventricular failure after LVAD implantation, LVAD flow was significantly increased and haemodynamics improved without compromising systemic oxygenation by the use of an interatrial shunt and a membrane oxygenator incorporated in the LVAD. Our results indicate that this novel approach may be less invasive for a right ventricular failure after LVAD implantation.

Experimental Models of Right Heart Failure: A Window for Translational Research in Pulmonary Hypertension

The right ventricle (RV) faces major changes in loading conditions associated with cardiovascular and pulmonary vascular disorders. Despite major pharmacological advances since the last decade, pulmonary arterial hypertension remains a deadly disease mainly secondary to the development of right ventricular failure (RVF). Several experimental models of RVF have been developed over the past three decades providing a particular insight in RV pathophysiology. Mechanisms involved in the transition from RV adaptive hypertrophy to maladaptive remodeling and failure in conditions of chronic RV pressure or volume overload are of a great interest but not yet completely understood. Further investigations are needed to find new therapeutic approaches for RVF. Current animal models and emerging concepts of translational RV research will be detailed in this review.

Exercise preconditioning prevents skeletal muscle wasting in monocrotaline‐induced cardiac cachexia

Cardiac cachexia is characterized by an imbalance between anabolic and catabolic factors that lead to weight loss. The present study addresses the preventive effect of exercise training on muscle wasting in an animal model of right ventricular failure induced by monocrotaline (MCT) administration. After 4 weeks of training or cage living, male Wistar rats were injected with MCT (60mg/kg) (ExMCT and SedMCT, respectively) or saline (ExC and SedC, respectively), and sacrificed after an additional 4week‐period of movement confined to cage's space. Gastrocnemius and blood samples were collected for biochemical analysis. Sed+MCT showed decreased body weight, cross sectional area and MHC‐I isoform. Total Akt and mTOR protein levels were normal while its phosphorylated forms were increased in exercised groups. Increased Atrogin‐1 protein expression was found only in Sed+MCT, as well as higher serum levels of CRP and IL‐1b. The present study provides evidence that exercise preconditioning prevents cardiac cachexia by averting proteolysis and inflammation.

Molecular Signature of a Right Heart Failure Program in Chronic Severe Pulmonary Hypertension

Right heart failure is the cause of death of most patients with severe pulmonary arterial hypertensive (PAH) disorders, yet little is known about the cellular and molecular causes of right ventricular failure (RVF). We first showed a differential gene expression pattern between normal rat right and left ventricles, and postulated the existence of a molecular right heart failure program that distinguishes RVF from adaptive right ventricular hypertrophy (RVH), and that may differ in some respects from a left heart failure program. By means of microarrays and transcriptional sequencing strategies, we used two models of adaptive RVH to characterize a gene expression pattern reflective of growth and the maintenance of myocardial structure. Moreover, two models of RVF were associated with fibrosis, capillary rarefaction, the decreased expression of genes encoding the angiogenesis factors vascular endothelial growth factor, insulin-like growth factor 1, apelin, and angiopoeitin-1, and the increased expression of genes encoding a set of glycolytic enzymes. The treatment of established RVF with a β-adrenergic receptor blocker reversed RVF, and partly reversed the molecular RVF program. We conclude that normal right and left ventricles demonstrate clearly discernable differences in the expression of mRNA and microRNA, and that RVH and RVF are characterized by distinct patterns of gene expression that relate to cell growth, angiogenesis, and energy metabolism.

Right Ventricular Failure Following Chronic Pressure Overload Is Associated With Reduction in Left Ventricular Mass: Evidence for Atrophic Remodeling

We sought to study whether patients with right ventricular failure (RVF) secondary to chronic thromboembolic pulmonary hypertension (CTEPH) have reduced left ventricular (LV) mass, and whether LV mass reduction is caused by atrophy.The LV in patients with CTEPH is underfilled (unloaded). LV unloading may cause atrophic remodeling that is associated with diastolic and systolic dysfunction.We studied LV mass using cardiac magnetic resonance imaging (MRI) in 36 consecutive CTEPH patients (before/after pulmonary endarterectomy [PEA]) and 11 healthy volunteers selected to match age and sex of patients. We studied whether LV atrophy is present in monocrotaline (MCT)-injected rats with RVF or controls by measuring myocyte dimensions and performing in situ hybridization.At baseline, CTEPH patients with RVF had significantly lower LV free wall mass indexes than patients without RVF (35 ± 6 g/m(2) vs. 44 ± 7 g/m(2), p = 0.007) or volunteers (42 ± 6 g/m(2), p = 0.006). After PEA, LV free wall mass index increased (from 38 ± 6 g/m(2) to 44 ± 9 g/m(2), p = 0.001), as right ventricular (RV) ejection fraction improved (from 31 ± 8% to 56 ± 12%, p < 0.001). Compared with controls, rats with RVF had reduced LV free wall mass and smaller LV free wall myocytes. Expression of atrial natriuretic peptide was higher, whereas that of α-myosin heavy chain and sarcoplasmic reticulum calcium ATPase-2 were lower in RVF than in controls, both in RV and LV.RVF in patients with CTEPH is associated with reversible reduction in LV free wall mass. In a rat model of RVF, myocyte shrinkage due to atrophic remodeling contributed to reduction in LV free wall mass.

Levosimendan improves right ventriculovascular coupling in a porcine model of right ventricular dysfunction*

Experimental data suggest that levosimendan has pulmonary vasodilatory properties which, in combination with its positive inotropic effects, would render it particularly attractive for the treatment of right ventricular dysfunction. To test this hypothesis, we developed an experimental model of right ventricular failure and analyzed the effects of levosimendan on ventriculovascular coupling between the right ventricle and pulmonary artery (PA). Prospective, randomized, placebo-controlled animal study. University hospital laboratory. Fourteen pigs (mean weight 36 +/- 1 kg). Pigs were instrumented with biventricular conductance catheters, a PA and right coronary artery flow probe, and a high-fidelity pulmonary pressure catheter. Right ventricular dysfunction was induced by repetitive episodes of ischemia/reperfusion in the presence of temporary PA constriction. Pigs were randomly assigned to receive levosimendan (120 mg/kg/hr [corrected] for 10 mins followed by continuous infusion of 60 mg/kg/hr [corrected] for 45 mins) or the placebo (control). Induction of right ventricular dysfunction resulted in a 42% decrease in contractility (reduction in slope of preload recruitable stroke work [Mw] from 2.5 +/- 0.4 to 1.8 +/- 0.5 mW x sec x mL(-1); p = .02) and a 60% increase in right ventricular afterload (effective pulmonary arterial elastance [PA-Ea] from 0.6 +/- 0.1 to 1.0 +/- 0.3 mm Hg x mL(-1); p < .01). Right ventriculovascular coupling, as assessed by the quotient of right ventricular end-systolic elastance (E(max)) over PA-Ea, decreased from 1.23 +/- 0.38 to 0.64 +/- 0.21 (p = .03). Treatment with levosimendan improved right ventricular contractility (Mw from 1.9 +/- 0.4 to 2.9 +/- 0.5 mW x sec x mL(-1); p < .01), lowered right ventricular afterload (PA-Ea from 1.1 +/- 0.3 to 0.8 +/- 0.3 mm Hg x mL(-1); p = .02), and restored right ventriculovascular coupling to normal values (E(max)/PA-Ea = 1.54 +/- 0.51). Levosimendan also significantly increased coronary blood flow and left ventricular contractility (Mw from 7.2 +/- 3.3 to 9.5 +/- 2.9 mW x sec x mL(-1); p = .01) but did not affect biventricular diastolic function. In an experimental model of acute right ventricular dysfunction, levosimendan improved global hemodynamics and optimized right ventriculovascular coupling via a moderate increase in right ventricular contractility and a mild reduction of right ventricular afterload.

Cardiovascular effects of AVP and ANG in experimental pulmonic stenosis in rats.

Our objectives were to examine the role of vasopressin and renin in the regulation of peripheral vascular tone in an animal model of right ventricular failure due to chronic (10 wk) pulmonic stenosis. We tested in chronically instrumented conscious control rats and in rats with pulmonic stenosis on a normal and a high-sodium diet both vasoconstrictor systems by applying specific inhibitors. The rats with pulmonic stenosis showed significant hemodynamic changes, a hypertrophy of the right ventricle, increased levels of plasma renin concentration, and inappropriately elevated plasma levels of vasopressin in comparison to control animals. Plasma renin concentration was suppressed in the sodium-loaded controls. After the administration of a specific inhibitor of the vascular receptors of arginine vasopressin [30 micrograms, d(CH2)5Tyr(Me)AVP], we found no hemodynamic changes in control rats on the normal diet, a reduction of mean arterial pressure in the sodium-loaded controls (4 +/- 4 mmHg; P less than 0.005), and in the animals with pulmonic stenosis and normal sodium intake (5 +/- 5 mmHg; P less than 0.001) and high-salt diet (6 +/- 7 mmHg; P less than 0.02). Intravenous bolus injection of teprotide (1 mg/kg) resulted in a decrease of mean arterial pressure in the control group (normal diet) of 9 +/- 8 mmHg (P less than 0.005). The fall of blood pressure (22 +/- 10 mmHg; P less than 0.001) in the rats with pulmonic stenosis was significantly greater (P less than 0.01) and was strongly related to plasma renin concentration. Therefore, vasopressin and the renin-angiotensin system contribute to an increase of peripheral vascular tone in chronic pulmonic stenosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary artery balloon counterpulsation in the management of right heart failure during left heart bypass

Pulmonary artery balloon counterpulsation was instituted in 10 pigs when right ventricular failure limited cardiac output. Global myocardial depression was produced by infusion of propranolol, and the left ventricle was fully supported by left heart bypass. A stable model of failure was achieved in six pigs. Following application of pulmonary artery balloon counterpulsation right atrial pressure decreased from 18.2 +/- 2.1 to 15.9 +/- 2.5 mm Hg (p less than 0.05). Cardiac output increased from 416 +/- 94 to 758 +/- 127 ml/min (p less than 0.001). Right ventricular stroke work increased from 0.29 +/- 0.07 to 0.65 +/- 0.12 gm X m. (p less than 0.05). There was no cardiac output before or after institution of balloon counterpulsation in four pigs studied during ventricular fibrillation or asystole. We conclude that pulmonary artery balloon counterpulsation improved cardiac output and right ventricular stroke work in a model of right ventricular failure where the pulmonary circulation was unaltered and the left ventricle supported by left heart bypass. Balloon counterpulsation was not effective during ventricular fibrillation or asystole. Pulmonary artery balloon counterpulsation should be considered when right ventricular failure limits cardiac output during left heart bypass.