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Background: Pulmonary hypertension (PH) is a serious cardiopulmonary disease with significant morbidity and mortality. Vascular obstruction leads to a continuous increase in pulmonary vascular resistance, vascular remodeling, and right ventricular hypertrophy and failure, which are the main pathological features of PH. Currently, the treatments for PH are very limited, so new methods are urgently needed. Msenchymal stem cells-derived exosomes have been shown to have significant therapeutic effects in PH, however, the mechanism still very blurry. Here, we investigated the possible mechanism by which umbilical cord mesenchymal stem cell-derived exosomes (hUC-MSC-EXO) inhibited monocrotaline (MCT)-induced pulmonary vascular remodeling in a rat model of PH by regulating the NF-κB/BMP signaling pathway. Our data revealed that hUC-MSC-EXO could significantly attenuate MCT-induced PH and right ventricular hypertrophy. Moreover, the protein expression level of BMPR2, BMP-4, BMP-9 and ID1 was significantly increased, but NF-κB p65, p-NF-κB-p65 and BMP antagonists Gremlin-1 was increased in vitro and vivo. Collectively, this study revealed that the mechanism of hUC-MSC-EXO attenuates pulmonary hypertension may be related to inhibition of NF-κB signaling to further activation of BMP signaling. The present study provided a promising therapeutic strategy for PH vascular remodeling., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pulmonary arterial hypertension (PAH) is characterized by the remodeling of pulmonary arteries, with an increased pulmonary arterial pressure and right ventricle (RV) overload. This work investigated the benefit of the association of human umbilical cord mesenchymal stem cells (hMSCs) with lodenafil, a phosphodiesterase-5 inhibitor, in an animal model of PAH. Male Wistar rats were exposed to hypoxia (10% O 2 ) for three weeks plus a weekly i.p. injection of a vascular endothelial growth factor receptor inhibitor (SU5416, 20 mg/kg, SuHx). After confirmation of PAH, animals received intravenous injection of 5.10 5 hMSCs or vehicle, followed by oral treatment with lodenafil carbonate (10 mg/kg/day) for 14 days. The ratio between pulmonary artery acceleration time and RV ejection time reduced from 0.42 ± 0.01 (control) to 0.24 ± 0.01 in the SuHx group, which was not altered by lodenafil alone but was recovered to 0.31 ± 0.01 when administered in association with hMSCs. RV afterload was confirmed in the SuHx group with an increased RV systolic pressure (mmHg) of 52.1 ± 8.8 normalized to 29.6 ± 2.2 after treatment with the association. Treatment with hMSCs + lodenafil reversed RV hypertrophy, fibrosis and interstitial cell infiltration in the SuHx group. Combined therapy of lodenafil and hMSCs may be a strategy for PAH treatment.

Background: Pulmonary hypertension (PH) is a life-threatening disease characterized by pulmonary vascular remodeling, right ventricular hypertrophy and failure. So far no effective treatment exists for this disease; hence, novel approaches are urgently needed. The aim of the present research was to observe the treatment effect of mesenchymal stromal cell derived exosomes and reveal the mechanism., Methods: Monocrotaline (MCT)-induced PH in rats and hypoxia-induced cell damage model were established, respectively. Exosomes derived from the supernatant of human umbilical cord mesenchymal stem cells (MSC-exo) were injected into MCT-PH model rat or added into the cells cultured medium. Immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR) and western blot methods were used in vivo and vitro., Results: The results showed that MSC-exo could significantly attenuate right ventricular (RV) hypertrophy and pulmonary vascular remodelling in MCT-PH rats. In the cell culture experiments, we found that MSC-exo could significantly inhibit hypoxia-induced pulmonary arterial endothelial cell (PAEC) apoptosis and pulmonary arterial smooth muscle cells (PASMC) proliferation. Furthermore, the pulmonary arterioles endothelial-to-mesenchymal transition (EndMT) was obviously suppressed. Moreover, the present study suggest that MSC-exo can significantly upregulate the expression of Wnt5a in MCT-PH rats and hypoxic pulmonary vascular cells. Furthermore, with Wnt5a gene silencing, the therapeutic effect of MSC-exo against hypoxia injury was restrained., Conclusions: Synthetically, our data provide a strong evidence for the therapeutic of MSC-exo on PH, more importantly, we confirmed that the mechanism was associated with up-regulation of the expression of Wnt5a. These results offer a theoretical basis for clinical prevention and treatment of PH.

Background: Tricuspid regurgitation (TR) and pulmonary hypertension (PHT) are highly dynamic cardiovascular lesions that may progress rapidly, particularly in the orthotopic liver transplantation (OLT) waitlist population. Severe TR and PHT are associated with poor outcomes in these patients, however it is rare for the two to be newly diagnosed intraoperatively at the time of OLT. Without preoperative information on pulmonary vascular and right heart function, the potential for reversibility of severe TR and PHT is unclear, making the decision to proceed to transplant fraught with difficulty., Case Presentation: We present a case of successful orthotopic liver transplantation (OLT) in a 48 year old female with severe (PHT) (mean pulmonary arterial pressure > 55 mmHg) and severe TR diagnosed post induction of anaesthesia. The degree of TR was associated with systemic venous pressures of > 100 mmHg resulting in massive haemorrhage during surgery and difficulty in distinguishing venous from arterial placement of vascular access devices. Intraoperative transoesophageal echocardiography (TOE) proved crucial in diagnosing functional TR due to tricuspid annular and right ventricular (RV) dilatation, and dynamically monitoring response to treatment. In response to positioning, judicious volatile anaesthesia administration, pulmonary vasodilator therapy and permissive hypovolemia during surgery we noted substantial improvement of the TR and pulmonary arterial pressures, confirming the reversibility of the TR and associated PHT., Conclusion: TR and PHT are co-dependent, dynamic, load sensitive right heart conditions that are interdependent with chronic liver disease, and may progress rapidly in patients waitlisted for OLT. Use of intraoperative TOE and pulmonary artery catheterisation on the day of surgery will detect previously undiagnosed severe TR and PHT, enable rapid assessment of the cause and the potential for reversibility. These dynamic monitors permit real-time assessment of the response to interventions or events affecting right ventricular (RV) preload and afterload, providing critical information for prognosis and management. Furthermore, we suggest that TR and PHT should be specifically sought when waitlisted OLT patients present with hepatic decompensation.

The role of right ventricular (RV) fibrosis in pulmonary hypertension (PH) remains a subject of ongoing discussion. Alterations of the collagen network of the extracellular matrix may help prevent ventricular dilatation in the pressure-overloaded RV. At the same time, fibrosis impairs cardiac function, and a growing body of experimental data suggests that fibrosis plays a crucial role in the development of RV failure. In idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, the RV is exposed to a ≈5 times increased afterload, which makes these conditions excellent models for studying the impact of pressure overload on RV structure. With this review, we present clinical evidence of RV fibrosis in idiopathic pulmonary arterial hypertension and chronic thromboembolic PH, explore the correlation between fibrosis and RV function, and discuss the clinical relevance of RV fibrosis in patients with PH. We postulate that RV fibrosis has a dual role in patients with pressure-overloaded RVs of idiopathic pulmonary arterial hypertension and chronic thromboembolic PH: as part of an adaptive response to prevent cardiomyocyte overstretch and to maintain RV shape for optimal function, and as part of a maladaptive response that increases diastolic stiffness, perturbs cardiomyocyte excitation-contraction coupling, and disrupts the coordination of myocardial contraction. Finally, we discuss potential novel therapeutic strategies and describe more sensitive techniques to quantify RV fibrosis, which may be used to clarify the causal relation between RV fibrosis and RV function in future research.

Background: Right ventricular (RV) end-systolic dimensions provide information on both size and function. We investigated whether an internally scaled index of end-systolic dimension is incremental to well-validated prognostic scores in pulmonary arterial hypertension., Methods and Results: From 2005 to 2014, 228 patients with pulmonary arterial hypertension were prospectively enrolled. RV end-systolic remodeling index (RVESRI) was defined by lateral length divided by septal height. The incremental values of RV free wall longitudinal strain and RVESRI to risk scores were determined. Mean age was 49±14 years, 78% were female, 33% had connective tissue disease, 52% were in New York Heart Association class ≥III, and mean pulmonary vascular resistance was 11.2±6.4 WU. RVESRI and right atrial area were strongly connected to the other right heart metrics. Three zones of adaptation (adapted, maladapted, and severely maladapted) were identified based on the RVESRI to RV systolic pressure relationship. During a mean follow-up of 3.9±2.4 years, the primary end point of death, transplant, or admission for heart failure was reached in 88 patients. RVESRI was incremental to risk prediction scores in pulmonary arterial hypertension, including the Registry to Evaluate Early and Long-Term PAH Disease Management score, the Pulmonary Hypertension Connection equation, and the Mayo Clinic model. Using multivariable analysis, New York Heart Association class III/IV, RVESRI, and log NT-proBNP (N-Terminal Pro-B-Type Natriuretic Peptide) were retained (χ 2 , 62.2; P <0.0001). Changes in RVESRI at 1 year (n=203) were predictive of outcome; patients initiated on prostanoid therapy showed the greatest improvement in RVESRI. Among right heart metrics, RVESRI demonstrated the best test-retest characteristics., Conclusions: RVESRI is a simple reproducible prognostic marker in patients with pulmonary arterial hypertension., (© 2017 American Heart Association, Inc.)

Introduction: Severe right ventricular hypertrophy (SRVH) is a rare phenotype in hypertrophic cardiomyopathy (HCM) for which limited information is available. This study was undertaken to investigate the clinical, prognostic and genetic characteristics of HCM patients with SRVH., Methods: HCM with SRVH was defined as HCM with a maximum right ventricular wall thickness ≥10 mm. Whole-genome sequencing (WGS) was performed in HCM patients with SRVH. Multivariate Cox proportional hazards regression models were used to identify risk factors for cardiac death and events in HCM with SRVH. Patients with apical hypertrophic cardiomyopathy (ApHCM) were selected as a comparison group. The clinical features and outcomes of 34 HCM patients with SRVH and 273 ApHCM patients were compared., Results: Compared with the ApHCM group, the HCM with SRVH group included younger patients and a higher proportion of female patients and also displayed higher cardiovascular morbidity and mortality. The multivariate Cox proportional hazards regression models identified 2 independent predictors of cardiovascular death in HCM patients with SRVH, a New York Heart Association class ≥III (hazard ratio [HR] = 8.7, 95% confidence interval (CI): 1.43-52.87, p = 0.019) and an age at the time of HCM diagnosis ≤18 (HR = 5.5, 95% CI: 1.24-28.36, p = 0.026). Among the 11 HCM patients with SRVH who underwent WGS, 10 (90.9%) were identified as carriers of at least one specific sarcomere gene mutation. MYH7 and TTN mutations were the most common sarcomere mutations noted in this study. Two or more HCM-related gene mutations were observed in 9 (82%) patients, and mutations in either other cardiomyopathy-related genes or ion-channel disease-related genes were found in 8 (73%) patients., Conclusions: HCM patients with SRVH were characterized by poor clinical outcomes and the presentation of multiple gene mutations.

Background: Cell-based gene therapy has become a subject of interest for the treatment of pulmonary arterial hypertension (PAH), a devastating disease characterized by pulmonary artery smooth muscle cell (PASMC) hyperplasia. Mesenchymal stem cells (MSCs) have been recently acknowledged as a potential cell vector for gene therapy. Here, we investigated the effect of MSC-based let-7a for PAH., Methods: After isolation and identification of MSCs from rat bone marrow, cells were infected with recombinant adenovirus vector Ad-let-7a. Lewis rats were subcutaneously injected with monocrotaline (MCT) to induce PAH, followed by the administration of MSCs, MSCs-NC (miR-control), or MSC-let-7a, respectively. Then, right ventricular systolic pressure (RVSP), right ventricular hypertrophy, and pulmonary vascular remodeling were evaluated. Rat pulmonary artery smooth muscle cells (rPASMCs) under hypoxia were co-cultured with MSCs or MSC-let-7a. Cell proliferation and apoptosis were separately determined by 3 H thymidine incorporation and flow cytometry analysis. The underlying mechanism was also investigated., Results: MSC transplantation enhanced let-7a levels in MCT-induced PAH rats. After injection with MSC-let-7a, RVSP, right ventricular hypertrophy, and pulmonary vascular remodeling were notably ameliorated, indicating a protective effect of MSC-let-7a against PAH. When co-cultured with MSC-let-7a, hypoxia-triggered PASMC proliferation was obviously attenuated, concomitant with the decrease in cell proliferation-associated proteins. Simultaneously, the resistance of PASMCs to apoptosis was remarkably abrogated by MSC-let-7a administration. A mechanism assay revealed that MSC-let-7a restrained the activation of signal transducers and activators of transcription 3 (STAT3) and increased its downstream bone morphogenetic protein receptor 2 (BMPR2) expression. Importantly, preconditioning with BMPR2 siRNA dramatically abated the suppressive effects of MSC-let-7a on PASMC proliferation and apoptosis resistance., Conclusions: Collectively, this study suggests that MSCs modified with let-7a may ameliorate the progression of PAH by inhibiting PASMC growth through the STAT3-BMPR2 signaling, supporting a promising therapeutic strategy for PAH patients.

Exercise is beneficial in pulmonary arterial hypertension (PAH), although studies to date indicate little effect on the elevated pulmonary pressures or maladaptive right ventricle (RV) hypertrophy associated with the disease. For chronic left ventricle failure, high-intensity interval training (HIIT) promotes greater endothelial stimulation and superior benefit than customary continuous exercise training (CExT); however, HIIT has not been tested for PAH. Therefore, here we investigated acute and chronic responses to HIIT vs. CExT in a rat model of monocrotaline (MCT)-induced mild PAH. Six weeks of treadmill training (5 times/wk) were performed, as either 30 min HIIT or 60 min low-intensity CExT. To characterize acute hemodynamic responses to the two approaches, novel recordings of simultaneous pulmonary and systemic pressures during running were obtained at pre- and 2, 4, 6, and 8 wk post-MCT using long-term implantable telemetry. MCT-induced decrement in maximal aerobic capacity was ameliorated by both HIIT and CExT, with less pronounced pulmonary vascular remodeling and no increase in RV inflammation or apoptosis observed. Most importantly, only HIIT lowered RV systolic pressure, RV hypertrophy, and total pulmonary resistance, and prompted higher cardiac index that was complemented by a RV increase in the positive inotrope apelin and reduced fibrosis. HIIT prompted a markedly pulsatile pulmonary pressure during running and was associated with greater lung endothelial nitric oxide synthase after 6 wk. We conclude that HIIT may be superior to CExT for improving hemodynamics and maladaptive RV hypertrophy in PAH. HIIT's superior outcomes may be explained by more favorable pulmonary vascular endothelial adaptation to the pulsatile HIIT stimulus.

Limited therapies exist for patients with congenital heart disease (CHD) who develop right ventricular (RV) dysfunction. Bone marrow-derived mesenchymal stem cells (MSCs) have not been evaluated in a preclinical model of pressure overload, which simulates the pathophysiology relevant to many forms of CHD. A neonatal swine model of RV pressure overload was utilized to test the hypothesis that MSCs preserve RV function and attenuate ventricular remodeling. Immunosuppressed Yorkshire swine underwent pulmonary artery banding to induce RV dysfunction. After 30 min, human MSCs (1 million cells, n = 5) or placebo (n = 5) were injected intramyocardially into the RV free wall. Serial transthoracic echocardiography monitored RV functional indices including 2D myocardial strain analysis. Four weeks postinjection, the MSC-treated myocardium had a smaller increase in RV end-diastolic area, end-systolic area, and tricuspid vena contracta width (P < 0.01), increased RV fractional area of change, and improved myocardial strain mechanics relative to placebo (P < 0.01). The MSC-treated myocardium demonstrated enhanced neovessel formation (P < 0.0001), superior recruitment of endogenous c-kit+ cardiac stem cells to the RV (P < 0.0001) and increased proliferation of cardiomyocytes (P = 0.0009) and endothelial cells (P < 0.0001). Hypertrophic changes in the RV were more pronounced in the placebo group, as evidenced by greater wall thickness by echocardiography (P = 0.008), increased cardiomyocyte cross-sectional area (P = 0.001), and increased expression of hypertrophy-related genes, including brain natriuretic peptide, β-myosin heavy chain and myosin light chain. Additionally, MSC-treated myocardium demonstrated increased expression of the antihypertrophy secreted factor, growth differentiation factor 15 (GDF15), and its downstream effector, SMAD 2/3, in cultured neonatal rat cardiomyocytes and in the porcine RV myocardium. This is the first report of the use of MSCs as a therapeutic strategy to preserve RV function and attenuate remodeling in the setting of pressure overload. Mechanistically, transplanted MSCs possibly stimulated GDF15 and its downstream SMAD proteins to antagonize the hypertrophy response of pressure overload. These encouraging results have implications in congenital cardiac pressure overload lesions., (Copyright © 2016 the American Physiological Society.)

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a high incidence of ventricular tachyarrhythmia and sudden death. The mainstay of management is the implantable cardioverter defibrillator (ICD). A small number of patient cohorts have generated a large number of reports., Methods: Prospective registry data supplemented with clinical and ICD records of 30 patients with ARVC fulfilling the 2010 modified Task Force Criteria. This cohort has not been reported on previously., Results: Median age at diagnosis: 46yrs (range 21-68); 20 (80%) male; six (19%) Maori. Duration of follow-up: 7.4yrs (range 1.7-23). Implantable cardioverter defibrillator implantation in 26; three (12%) for resuscitated sudden cardiac death; 17 (65%) for symptomatic ventricular tachyarrhythmia; three (12%) for syncope; and three (12%) for family history of sudden death attributable to ARVC. Two patients died during follow-up, one had an ICD, though died of a carcinoma. Thirteen (50%) experienced appropriate ICD therapy with median time to therapy 12 months, and four (15%) experienced inappropriate shock therapy. Male gender was an independent predictor of appropriate ICD therapy (HR 1.6, 95% CI 1.5-2.7, P=0.01)., Conclusions: The long-term prognosis of patients with ARVC is favourable although high proportions receive appropriate ICD therapy. Male gender is an independent predictor of appropriate ICD therapy., (Copyright © 2015 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Pulmonary arterial hypertension (PAH) is characterized by progressive increases in vascular resistance and the remodeling of pulmonary arteries. The accumulation of inflammatory cells in the lung and elevated levels of inflammatory cytokines in the bloodstream suggest that inflammation may play a role in PAH. In this study, the benefits of induced pluripotent stem cells (iPSCs) and iPSC-conditioned medium (iPSC CM) were explored in monocrotaline (MCT)-induced PAH rats. We demonstrated that both iPSCs and iPSC CM significantly reduced the right ventricular systolic pressure and ameliorated the hypertrophy of the right ventricle in MCT-induced PAH rats in models of both disease prevention and disease reversal. In the prevention of MCT-induced PAH, iPSC-based therapy led to the decreased accumulation of inflammatory cells and down-regulated the expression of the IL-1β, IL-6, IL-12α, IL-12β, IL-23 and IFNγ genes in lung specimens, which implied that iPSC-based therapy may be involved in the regulation of inflammation. NF-κB signaling is essential to the inflammatory cascade, which is activated via the phosphorylation of the NF-κB molecule. Using the chemical inhibitor specifically blocked the phosphorylation of NF-κB, and in vitro assays of cultured human M1 macrophages implied that the anti-inflammation effect of iPSC-based therapy may contribute to the disturbance of NF-κB activation. Here, we showed that iPSC-based therapy could restore the hemodynamic function of right ventricle with benefits for preventing the ongoing inflammation in the lungs of MCT-induced PAH rats by regulating NF-κB phosphorylation.

Only in recent years has the right ventricle (RV) function become appreciated to be equally important to the left ventricle (LV) function to maintain cardiac output. Right ventricular failure is, irrespectively of the etiology, associated with impaired exercise tolerance and poor survival. Since the anatomy and physiology of the RV is distinctly different than that of the LV, its adaptive mechanisms and the pathways involved are different as well. RV hypertrophy is an important mechanism of the RV to preserve cardiac output. This review summarizes the current knowledge on the right ventricle and its response to pathologic situations. We will focus on the adaptive capacity of the right ventricle and the molecular pathways involved, and we will discuss potential therapeutic interventions., (Copyright © 2015 the American Physiological Society.)

To date, no transcatheter valve has been approved for placement in the pulmonary position in Japan. Consequently, percutaneous balloon dilatation may be advised for stenotic right ventricular outflow lesions; however, technical difficulties persist, particularly in adults. We describe the acute haemodynamic changes and outcome of balloon dilatation of right ventricular outflow obstruction using triple ultra-high pressure balloons. This is the first report of such a technical development, which seems to be safe and effective. A total of three adult patients, aged 25, 29, and 37 years, with severe conduit obstruction were referred for balloon dilatation. A triple ultra-high-pressure balloon technique was used in the three patients after unsuccessful double-balloon dilatation, or for highly calcified lesions, which were expected to require ultra-high pressure for effective relief. Following balloon dilatation, the pressure gradient decreased from 24, 30, 65 to 3, 25, 30 mmHg, respectively. There were no procedural complications except slightly increased pulmonary regurgitation. Balloon dilatation using a triple ultra-high pressure balloon technique can be a safe and effective palliative procedure for conduit obstruction in adult patients.

Background: Patients with pulmonary arterial hypertension (PAH) are treated with vasodilators, including endothelin receptor antagonists (ERAs), phosphodiesterase-5 (PDE-5) inhibitors, soluble guanylyl cyclase activators, and prostacyclin. Despite recent advances in pharmacotherapy for individuals with PAH, morbidity and mortality rates in this patient population remain unacceptably high. Here, we tested the hypothesis that combination therapy with two PAH drugs that target distinct biochemical pathways will provide superior efficacy relative to monotherapy in the rat SU5416 plus hypoxia (SU-Hx) model of severe angioproliferative PAH, which closely mimics the human condition., Methods: Male Sprague Dawley rats were injected with a single dose of SU5416, which is a VEGF receptor antagonist, and exposed to hypobaric hypoxia for three weeks. Rats were subsequently housed at Denver altitude and treated daily with the PDE-5 inhibitor, tadalafil (TAD), the type A endothelin receptor (ETA) antagonist, ambrisentan (AMB), or a combination of TAD and AMB for four additional weeks., Results: Monotherapy with TAD or AMB led to modest reductions in pulmonary arterial pressure (PAP) and right ventricular (RV) hypertrophy. In contrast, echocardiography and invasive hemodynamic measurements revealed that combined TAD/AMB nearly completely reversed pulmonary hemodynamic impairment, RV hypertrophy, and RV functional deficit in SU-Hx rats. Efficacy of TAD/AMB was associated with dramatic reductions in pulmonary vascular remodeling, including suppression of endothelial cell plexiform lesions, which are common in human PAH., Conclusions: Combined therapy with two vasodilators that are approved for the treatment of human PAH provides unprecedented efficacy in the rat SU-Hx preclinical model of severe, angioproliferative PAH.

Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary arterial pressure and vascular resistance. Despite advances in therapy for PAH, its treatment and prognosis remain poor. We aimed to investigate whether the transplantation of bone marrow mesenchymal stem cells (MSCs) overexpressing hepatocyte growth factor (HGF), alone or in combination with granulocyte colony-stimulating factor (G-CSF), attenuates the development of experimental monocrotaline (MCT)-induced PAH. Three weeks after MCT administration, rats were divided into the following groups: (1) untreated (PAH); (2) HGF treated; (3) MSCs administered; (4) HGF-MSCs treated; and (5) HGF-MSCs plus G-CSF treated. After 3 weeks, hemodynamic changes, histomorphology, and angiogenesis were evaluated. To elucidate the molecular mechanisms of vascular remodeling and angiogenesis, serum levels of transforming growth factor (TGF)-β and endothelin-1 (ET-1) were measured, and the gene and protein expression levels of vascular cell adhesion molecule-1 (VCAM-1) and matrix metalloproteinase-9 (MMP-9) were determined. Compared with the PAH, MSC, and G-CSF groups, the HGF and HGF+G-CSF groups exhibited significantly reduced right ventricular hypertrophy and mean pulmonary arterial pressure (P < 0.05). Histologically, vessel muscularization or thickening and collagen deposition were also significantly decreased (P < 0.05). The number of vessels in the HGF+G-CSF group was higher than that in the other groups (P < 0.05). The TGF-β and ET-1 concentrations in the plasma of pulmonary hypertensive rats were markedly lower in the HGF and HGF+G-CSF groups (P < 0.05). Furthermore, HGF induced the expression of VCAM-1, and HGF treatment together with G-CSF synergistically stimulated MMP-9 expression. Transplanted HGF-MSCs combined with G-CSF potentially offer synergistic therapeutic benefit for the treatment of PAH.

Chronic pulmonary hypertension in the neonate and infant frequently presents with right-ventricular (RV) failure. Current clinical management may include protracted treatment with inhaled nitric oxide (iNO), with the goal of reducing RV afterload. We have previously reported that prolonged exposure to iNO causes RV systolic dysfunction in the chronic hypoxia-exposed juvenile rat, which was prevented by a peroxynitrite decomposition catalyst. Given that inhalation of CO2 (therapeutic hypercapnia) may limit oxidative stress and upregulated cytokine expression in the lung and other organs, we hypothesized that therapeutic hypercapnia would attenuate cytokine-mediated nitric oxide synthase (NOS) upregulation, thus limiting peroxynitrite generation. Sprague-Dawley rat pups were exposed to chronic hypoxia (13% O2) from postnatal day 1 to 21, while receiving iNO (20 ppm) from day 14 to 21, with or without therapeutic hypercapnia (10% CO2). Therapeutic hypercapnia completely normalized RV systolic function, RV hypertrophy, and remodeling of pulmonary resistance arteries in animals exposed to iNO. Inhaled nitric oxide-mediated increases in RV peroxynitrite, apoptosis, and contents of tumor necrosis factor (TNF)-α, interleukin (IL)-1α, and NOS-2 were all attenuated by therapeutic hypercapnia. Inhibition of NOS-2 activity with 1400 W (1 mg/kg/day) prevented iNO-mediated upregulation of peroxynitrite and led to improved RV systolic function. Blockade of IL-1 receptor signaling with anakinra (500 mg/kg/day) decreased NOS-2 content and had similar effects compared to NOS-2 inhibition on iNO-mediated effects, whereas blockade of TNF-α signaling with etanercept (0.4 mg/kg on alternate days) had no effects on these parameters. We conclude that therapeutic hypercapnia prevents the adverse effects of sustained exposure to iNO on RV systolic function by limiting IL-1-mediated NOS-2 upregulation and consequent nitration. Therapeutic hypercapnia also acts synergistically with iNO in normalizing RV hypertrophy, vascular remodeling, and raised pulmonary vascular resistance secondary to chronic hypoxia., (Copyright © 2014 Elsevier Inc. All rights reserved.)

We present a unique case of a 32-year-old woman with severe biventricular hypertrophy and acute heart failure with reduced left ventricular ejection fraction of 25-30% due to Cushing's disease. The patient was admitted to a specialised cardiac unit and treated with conventional therapy against heart failure. The department of endocrinology was consulted because of clinical suspicion of Cushing's syndrome. Initial biochemistry indicated the presence of adrenocorticotropic hormone (ACTH) dependent Cushing's syndrome and a dexamethasone suppression test confirmed the diagnosis. A cerebral MRI scan revealed a pituitary adenoma and a sinus petrosus inferior catheterisation confirmed increased production of ACTH from the pituitary. The patient was referred to the neurosurgical department and the adenoma was successfully removed by transsphenoidalic catheterisation and ablation. Five months following the initial hospitalisation the patient was nearly in full recovery with respect to her cardiac function and biochemically there were no signs of Cushing's syndrome.

Background: Intravenous prostacyclin is approved for treating pulmonary arterial hypertension (PAH), but it has a short half-life and must be delivered systemically via an indwelling intravenous catheter. We hypothesize that localized jugular vein delivery of prostacyclin-producing cells may provide sustained therapeutic effects without the limitations of systemic delivery., Methods and Results: We generated a vector expressing a human cyclooxygenase isoform 1 and prostacyclin synthase fusion protein that produces prostacyclin from arachidonic acid. Endothelial-like progenitor cells (ELPCs) were transfected with the cyclooxygenase isoform 1-prostacyclin synthase plasmid and labeled with lentivirus expressing nuclear-localized red fluorescent protein (nuRFP). The engineered ELPCs (expressing cyclooxygenase isoform 1-prostacyclin synthase and nuRFP) were tested in rats with monocrotaline (MCT)-induced PAH. In PAH prevention studies, treatment with engineered ELPCs or control ELPCs (expressing nuRFP alone) attenuated MCT-induced right ventricular systolic pressure increase, right ventricular hypertrophy, and pulmonary vessel wall thickening. Engineered ELPCs were more effective than control ELPCs in all variables evaluated. In PAH reversal studies, engineered ELPCs or control ELPCs increased the survival rate of rats with established PAH and decreased right ventricular hypertrophy. Engineered ELPCs provided a survival benefit 2 weeks earlier than did control ELPCs. Microarray-based gene ontology analysis of the right ventricle revealed that a number of MCT-altered genes and neurotransmitter pathways (dopamine, serotonin, and γ-aminobutyric acid) were restored after ELPC-based prostacyclin gene therapy., Conclusions: Cyclooxygenase isoform 1-prostacyclin synthase-expressing ELPCs reversed MCT-induced PAH. A single jugular vein injection offered survival benefits for at least 4 weeks and may provide a promising option for PAH patients.

Background: Traditional pulmonary artery banding (PAB) is not always suitable for mature subpulmonary ventricle retraining. We sought to assess in detail the myocardial morphologic adaptations of two different protocols for inducing right ventricular (RV) hypertrophy in an adult animal model., Methods: Eighteen adult goats were distributed into three groups: sham (no systolic overload), traditional (continuous systolic overload), and intermittent (daily 12-hour systolic overload). Systolic overload was adjusted to achieve a 0.7 RV-to-aortic pressure ratio. All animals underwent weekly echocardiographic studies, and hemodynamic evaluations were performed 3 times a week. After 4 weeks, the animals were humanely killed for morphologic assessment., Results: A 37.2% increase was observed in the RV wall thickness of the intermittent group (p<0.05), but no significant echocardiographic changes were observed in the other two groups. The intermittent and traditional groups had a 55.7% and 36.7% increase in RV mass, respectively, compared with the sham group (p<0.05). No differences were observed in myocardial water content of the three groups (p=0.27). RV myocardial fiber and nuclei diameters were increased in the intermittent group compared with the sham group (p<0.05). The area of collagen deposition in the RV interstitium was increased 98% in traditional group compared with the sham group (p<0.05). No significant cellular proliferation occurred in any group., Conclusions: This study suggests that a more effective and harmless hypertrophy can be achieved in adult animals using intermittent PAB compared with the traditional approach., (Copyright © 2013 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Prostaglandin I(2) (PGI(2)) plays an important role in the clinical treatment of pulmonary arterial hypertension (PAH). However, the administration of PGI(2) involves continuous intravenous infusion using an indwelling catheter, which limits the patient's quality of life and increases the risk of infection. We therefore investigated whether human PGI(2) synthase (hPGIS) gene transfer using an adeno-associated virus (AAV) vector is still effective in a mouse model of PAH and tested for differences in the therapeutic efficacy of PAH among AAV serotypes. The PAH was induced by subjecting mice to hypoxia (10% O(2)). Type 1 AAV expressing hPGIS (AAV1-hPGIS) or type 2 AAV expressing hPGIS (AAV2-hPGIS) was injected into the thigh muscle of mice. Both vectors expressing hPGIS produced strong hPGIS protein expression in the mouse thigh skeletal muscles after 8 weeks of hypoxia. The administration of AAV1-hPGIS or AAV2-hPGIS also significantly inhibited the hypoxia-induced increase in right ventricular systolic pressure, the ratio of right ventricular weight to body weight (RV/BW), and the ratio of RV weight to left ventricular plus septal weight (RV/LV + S), and significantly attenuated the hypoxia-induced increase in medial wall thickness of peripheral pulmonary arteries. Furthermore, there were no significant differences in the degree of amelioration in RV systolic pressure, RV/BW, RV/LV + S, and percentage of wall thickness of peripheral pulmonary arteries between AAV1-hPGIS and AAV2-hPGIS administrations. In conclusion, we revealed that type 1 and type 2 AAV are equally effective for the treatment of PAH in a hypoxia-induced mouse model. Gene-transfer therapy using AAV expressing hPGIS is, therefore, a potential therapeutic breakthrough for PAH.

Congenital pulmonary valvular dysplasia is an unusual condition typically associated with Noonan syndrome. Among its other cardiac manifestations, occasional patients with Noonan syndrome have been demonstrated to have hypertrophic nonobstructive cardiomyopathy, which may be biventricular. We report a unique case of pulmonary valvular dysplasia, dynamic right ventricular outflow tract obstruction and profound right ventricular hypertrophy with only mild left ventricular hypertrophy, in a patient without Noonan syndrome., (© 2011 Wiley Periodicals, Inc.)

Background: In this study we investigated the effect of human amniotic fluid stem (hAFS) cells and rat adipose tissue stromal vascular fraction GFP-positive cell (rSVC-GFP) therapy and the contribution of the paracrine and neurohormonal milieu to cardiac and pulmonary vascular remodeling in a rat model of pulmonary hypertension (PH) and right heart failure (RHF)., Methods: Sprague-Dawley rats were injected with monocrotaline (MCT). Four million hAFS or rSVC-GFP cells were injected via the tail vein 3 weeks after MCT. RHF was confirmed by RV hypertrophy/dilation and by brain natriuretic peptide (BNP) level. Cytokine profile was assessed by Multiplex array. Stem cell (SC) differentiation was studied by immunofluorescence., Results: MCT rats showed eccentric RV hypertrophy with increased RV dilation (measured as right ventricular mass/right ventricular volume [RVM/RVV]: MCT, 1.46 ± 0.12; control, 2.33 ± 0.24; p = 0.01), and increased RV hypertrophy (measured as LVM/RVM: MCT, 1.58 ± 0.06; control, 2.83 ± 0.1; p < 0.00001), increased BNP (MCT, 5.2 ± 1.2; control, 1.5 ± 0.1; p < 0.001) and both pro- and anti-inflammatory cytokines. SC produced a fall of BNP (hAFS, 2.1 ± 0.7; rSVC-GFP, 1.98 ± 1.3; p < 0.001) and pro-inflammatory cytokines. Positive RV remodeling with decreased RV dilation (RVM/RVV: hAFS, 1.87 ± 0.44; rSVC-GFP, 2.12 ± 0.24; p < 0.03 and p < 0.05 vs MCT) and regression of RV hypertrophy (LVM/RVM: hAFS, 2.06 ± 0.08; rSVC-GFP, 2.16 ± 0.08; p < 0.00001 vs MCT) was seen together with a decrease in medial wall thickness of pulmonary arterioles (hAFS, 35.33 ± 2.78%; rSVC-GFP, 37.15 ± 2.92%; p = 0.0001 vs MCT)., Conclusions: SC engrafted in the lung, heart and skeletal muscle modulated the pro- and anti-inflammatory cytokine milieu, and produced a positive neurohormonal response. This was accompanied by positive cardiac and pulmonary vascular remodeling, with formation mainly of new vascular cells., (2011 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Background/purpose: Pediatric patients with atrial septal defect (ASD) may have failure to thrive. This study aimed to investigate body weight changes in pediatric patients after transcatheter closure of ASD., Methods: From June 2003 to September 2008, we enrolled 60 pediatric patients who underwent transcatheter closure of ASD. Changes in body weight percentile, heart rate, and resolution of right ventricular hypertrophy were compared before and after ASD closure. Patients were divided into two groups according to initial weight percentile: group A, <50(th) percentile (n = 39) and group B, ≥50(th) percentile (n = 21). Echocardiography and routine weight measurements were performed before the procedure and at 3, 6, and 12 months during follow-up. Clinical presentations, laboratory data, and outcomes were measured., Results: Increased body weight percentile (41±4 vs. 48±4, p<0.01), lower heart rate (100±2 beats/min vs. 89±2beats/min, p<0.01), and resolution of right ventricular hypertrophy (59/60 vs. 1/60, p<0.01) were achieved after ASD closure at the 12-month follow-up. Patients in group A were significantly younger (4.6±0.5 years vs. 7.0±0.9 years, p = 0.016), had a higher pulmonary/systemic blood flow ratio (2.2±0.1 vs. 1.8±0.l, p = 0.044), a largerratio of ASD diameter/body surface area (25.0±1.4 vs. 16.4±1.9, p<0.01), and higher percentage of weight gain increase ≥ 5 percentile compared with patients in group B (22/39 vs. 6/21, p = 0.039)., Conclusion: Transcatheter closure of ASD positively affects weight gain. An increase of 7 percentile weight was observed at 1 year of follow-up. Patients with a younger age, higher pulmonary/systemic blood flow ratio, and a larger ratio of ASD diameter/body surface area may have better weight gain after ASD closure., (Copyright © 2011 Formosan Medical Association & Elsevier. Published by Elsevier B.V. All rights reserved.)

Despite advances in the treatment of pulmonary arterial hypertension, a truly restorative therapy has not been achieved. Attention has been given to circulating angiogenic cells (CACs, also termed early endothelial progenitor cells) because of their ability to home to sites of vascular injury and regenerate blood vessels. We studied the efficacy of human CAC therapy in the treatment of pulmonary arterial hypertension at two different stages of disease severity. Cells were isolated from peripheral blood and administered to nude rats on day 14 ("early") or day 21 ("late") after monocrotaline injection. The control group received monocrotaline but no cell treatment. Disease progression was assessed using right heart catheterization and echocardiography at multiple time points. Survival differences, right ventricular hypertrophy (RVH), and vascular hypertrophy were analyzed at the study endpoint. Quantitative PCR was performed to evaluate cell engraftment. Treatment with human CACs either at the early or late time points did not result in increased survival, and therapy did not prevent or reduce the severity of disease compared with control. Histological analysis of RVH and vascular muscularization showed no benefit with therapy compared with control. No detectable signal was seen of human transcript in transplanted lungs at 14 or 21 days after cell transplant. In conclusion, CAC therapy was not associated with increased survival and did not result in either clinical or histological benefits. Future studies should be geared toward either earlier therapeutic time points with varying doses of unmodified CACs or genetically modified cells as a means of delivery of factors to the pulmonary arterial circulation.

We report an unknown complication of peripherally inserted central venous catheter in a patient with Ventricular Assist Device. This rare complication led to the failure of the right ventricular assist device, which could be detrimental in patients with dilated cardiomyopathy.

Objective: Prenatal constriction of the ductus arteriosus associated with maternal drug ingestion was reported several decades ago. There are fewer reports of the complete closure of the ductus arteriosus; therefore, the clinical features of the latter are poorly understood. The aim of this study is to clarify the clinical features of complete ductal closure and postnatal pulmonary hypertension by performing echocardiography of the fetus., Patients: We diagnosed four fetuses with complete ductal closure by performing fetal echocardiography and reviewed the prenatal and postnatal medical records of the mother and fetus., Results: One mother each had bronchial asthma, ulcerative colitis, and idiopathic thrombocytopenic purpura, and they had received nonsteroidal anti-inflammatory drugs and/or corticosteroids during pregnancy. The fourth mother did not have basal disease and had not ingested any drugs. Fetal diagnosis was performed at 32-38 weeks of gestation. All fetuses had right heart dilatation with tricuspid regurgitation in the absence of any cardiac defects, and Doppler echocardiography indicated that the right ventricular pressure was elevated. Two of the fetuses had fetal hydrops, which suggested severe right heart dysfunction. All fetuses were delivered by emergent cesarean delivery. After birth, all the infants developed persistent pulmonary hypertension and required oxygen inhalation. Of these, three required mechanical ventilation, and two, nitric oxide inhalation. All infants improved within 2 weeks, and they had no neurological and cardiac complications after discharge., Conclusion: Right heart dilatation and severe tricuspid regurgitation in the absence of a cardiac defect in the fetus strongly suggested ductal dysfunction. Careful evaluation of ductal patency and right ventricular function can lead to precise early diagnosis and good prognosis., (© 2011 Copyright the Authors. Congenital Heart Disease © 2011 Wiley Periodicals, Inc.)

Background: The beneficial effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) remodeling have been extensively described. Few data are available about the effects of CRT on right ventricular (RV) function and remodeling., Hypothesis: We hypothesized that CRT could also induce reverse remodeling in the right ventricle and that RV baseline functional status expressed as tricuspidal annular plane systolic excursion (TAPSE) could affect CRT response., Methods: Echocardiographic investigation was performed before and 6 months after CRT. In 192 patients, TAPSE, LV, and RV dimensions with functional parameters and LV dyssynchrony index were evaluated., Results: At 6 months' follow-up, 86 patients (45%) were responders to CRT according to at least 15% LV end-systolic volume reduction. Among baseline echocardiographic parameters, responders had significantly lower TAPSE, larger LV volumes, and higher LV dyssynchrony index. In responders, LV volume reduction, ejection fraction increase, and mitral regurgitation improvement were associated with RV dimensions reduction, increased TAPSE, and improved LV dyssynchrony. Receiver operating characteristic curve analysis showed that TAPSE, at 17 mm optimal cutoff, yielded 64% sensitivity and 60% specificity in predicting CRT response; similarly, LV dyssynchrony index, at 41.25 ms optimal cutoff, predicted CRT response with 60% sensitivity and 62% specificity. A subgroup analysis demonstrated that the coexistence of high TAPSE and high dyssynchrony index values increased probability of CRT response., Conclusions: Our results show that CRT induces RV and LV reverse remodeling and that CRT patient selection can be improved by simply measuring TAPSE value., (Copyright © 2010 Wiley Periodicals, Inc.)

Right ventricular hypertrophy (RVH) and RV failure contribute to morbidity and mortality in pulmonary arterial hypertension (PAH). The cause of RV dysfunction and the feasibility of therapeutically targeting the RV are uncertain. We hypothesized that RV dysfunction and electrical remodeling in RVH result, in part, from a glycolytic shift in the myocyte, caused by activation of pyruvate dehydrogenase kinase (PDK). We studied two complementary rat models: RVH + PAH (induced by monocrotaline) and RVH + without PAH (induced by pulmonary artery banding (PAB)). Monocrotaline RVH reduced RV O(2)-consumption and enhanced glycolysis. RV 2-fluoro-2-deoxy-glucose uptake, Glut-1 expression, and pyruvate dehydrogenase phosphorylation increased in monocrotaline RVH. The RV monophasic action potential duration and QT(c) interval were prolonged due to decreased expression of repolarizing voltage-gated K(+) channels (Kv1.5, Kv4.2). In the RV working heart model, the PDK inhibitor, dichloroacetate, acutely increased glucose oxidation and cardiac work in monocrotaline RVH. Chronic dichloroacetate therapy improved RV repolarization and RV function in vivo and in the RV Langendorff model. In PAB-induced RVH, a similar reduction in cardiac output and glycolytic shift occurred and it too improved with dichloroacetate. In PAB-RVH, the benefit of dichloroacetate on cardiac output was approximately 1/3 that in monocrotaline RVH. The larger effects in monocrotaline RVH likely reflect dichloroacetate's dual metabolic benefits in that model: regression of vascular disease and direct effects on the RV. Reduction in RV function and electrical remodeling in two models of RVH relevant to human disease (PAH and pulmonic stenosis) result, in part, from a PDK-mediated glycolytic shift in the RV. PDK inhibition partially restores RV function and regresses RVH by restoring RV repolarization and enhancing glucose oxidation. Recognition that a PDK-mediated metabolic shift contributes to contractile and ionic dysfunction in RVH offers insight into the pathophysiology and treatment of RVH.

We aimed to evaluate the feasibility and efficacy of autologous umbilical cord blood mononuclear cell (UCMNC) transplantation on right ventricular (RV) function in a novel model of chronic RV volume overload. Four-month-old sheep (n = 20) were randomized into cell (n = 10) and control groups (n = 10). After assessment of baseline RV function by the conductance catheter method, a transannular patch (TAP) was sutured to the right ventricular outflow tract (RVOT). Following infundibulotomy the ring of the pulmonary valve was transected without cardiopulmonary bypass. UCMNC implantation (8.22 +/- 6.28 x 10(7)) in the cell group and medium injection in the control group were performed into the RV myocardium around the TAP. UCMNCs were cultured for 2 weeks after fluorescence-activated cell sorting (FACS) analysis for CD34 antigen. Transthoracic echocardiography (TTE) and computed tomography were performed after 6 weeks and 3 months, respectively. RV function was assessed 3 months postoperatively before the hearts were excised for immunohistological examinations. FACS analysis revealed 1.2 +/- 0.22% CD34(+) cells within the isolated UCMNCs from which AcLDL(+) endothelial cells were cultured in vitro. All animals survived surgery. TTE revealed grade II-III pulmonary regurgitation in both groups. Pressure-volume loops under dobutamine stress showed significantly improved RV diastolic function in the cell group (dP/dt(min): p = 0.043; E(ed): p = 0.009). CD31 staining indicated a significantly enhanced number of microvessels in the region of UCMNC implantation in the cell group (p < 0.001). No adverse tissue changes were observed. TAP augmentation and pulmonary annulus distortion without cardiopulmonary bypass constitutes a valid large animal model mimicking the surgical repair of tetralogy of Fallot. Our results indicate that the chronically volume-overloaded RV profits from autologous UCMNC implantation by enhanced diastolic properties with a probable underlying mechanism of increased angiogenesis.

Objectives: The right ventricle fails quickly after increases in its afterload (ie, pulmonary hypertension) compared with the left ventricle (ie, systemic hypertension), resulting in significant morbidity and mortality. We hypothesized that the poor performance of the hypertrophied right ventricle is caused, at least in part, by a suboptimal mitochondrial/metabolic remodeling., Methods/results: We studied mitochondrial membrane potential, a surrogate for mitochondrial function, in human (n = 11) and rat hearts with physiologic (neonatal) and pathologic (pulmonary hypertension) right ventricular hypertrophy in vivo and in vitro. Mitochondrial membrane potential is higher in the normal left ventricle compared with the right ventricle but is highest in the hypertrophied right ventricle, both in myocardium and in isolated cardiomyocytes (P < .01). Mitochondrial membrane potential correlated positively with the degree of right ventricular hypertrophy in vivo and was recapitulated in phenylephrine-treated neonatal cardiomyocytes, an in vitro model of hypertrophy. The phenylephrine-induced mitochondrial hyperpolarization was reversed by VIVIT, an inhibitor of the nuclear factor of activated T lymphocytes, a transcription factor regulating the expression of several mitochondrial enzymes during cardiac development and hypertrophy. The clinically used drug dichloroacetate, known to increase the mitochondria-based glucose oxidation, reversed both the phenylephrine-induced mitochondrial hyperpolarization and nuclear factor of activated T lymphocytes (NFAT) activation. In Langendorff perfusions, dichloroacetate increased rat right ventricular inotropy in hypertrophied right ventricles (P < .01) but not in normal right ventricles, suggesting that mitochondrial hyperpolarization in right ventricular hypertrophy might be associated with its suboptimal performance., Conclusions: The dynamic changes in mitochondrial membrane potential during right ventricular hypertrophy are chamber-specific, associated with activation of NFAT, and can be pharmacologically reversed leading to improved contractility. This mitochondrial remodeling might provide a framework for development of novel right ventricle-specific therapies.

Chronic chagasic cardiomyopathy, which is caused by the protozoan Trypanosoma cruzi, is a major cause of heart failure in Latin America. It is a disease for which effective treatment in its advanced clinical forms is lacking. We have previously shown that bone marrow mononuclear cell (BMC) transplantation is effective in reducing inflammation and fibrosis in the mouse model of Chagas disease. The present study used magnetic resonance imaging to assess changes in the cardiac morphology of infected mice after therapy with BMCs. Serial imaging of the BMC-treated mice revealed regression of the right ventricular dilatation typically observed in the chagasic mouse model.

Background: Pulmonary arterial hypertension (PAH) is a life-threatening disease, characterized by vascular smooth muscle cell hyperproliferation. The calcium/calmodulin-dependent phosphodiesterase 1 (PDE1) may play a major role in vascular smooth muscle cell proliferation., Methods and Results: We investigated the expression of PDE1 in explanted lungs from idiopathic PAH patients and animal models of PAH and undertook therapeutic intervention studies in the animal models. Strong upregulation of PDE1C in pulmonary arterial vessels in the idiopathic PAH lungs compared with healthy donor lungs was noted on the mRNA level by laser-assisted vessel microdissection and on the protein level by immunohistochemistry. In chronically hypoxic mouse lungs and lungs from monocrotaline-injected rats, PDE1A upregulation was detected in the structurally remodeled arterial muscular layer. Long-term infusion of the PDE1 inhibitor 8-methoxymethyl 3-isobutyl-1-methylxanthine in hypoxic mice and monocrotaline-injected rats with fully established pulmonary hypertension reversed the pulmonary artery pressure elevation, structural remodeling of the lung vasculature (nonmuscularized versus partially muscularized versus fully muscularized small pulmonary arteries), and right heart hypertrophy., Conclusions: Strong upregulation of the PDE1 family in pulmonary artery smooth muscle cells is noted in human idiopathic PAH lungs and lungs from animal models of PAH. Inhibition of PDE1 reverses structural lung vascular remodeling and right heart hypertrophy in 2 animal models. The PDE1 family may thus offer a new target for therapeutic intervention in pulmonary hypertension.

The most severe cardiac sequel to lung disease is the load on the right ventricle due to pulmonary hypertension with the development of a cor pulmonale. This is characterized by hypertrophy and/or dilatation of the right ventricle because of a primary impairment of lung function and/or lung structure. The most important pathomechanisms for the development of pulmonary hypertension are vessel obliteration, mechanical lesions, primary vascular or extra-vascular inflammation and hypoxic vasoconstriction. Chronic obstructive pulmonary disease (COPD) is one of the most important reasons for chronic cor pulmonale. A further very common reason is obstructive sleep apnea syndrome, especially if combined with a COPD. In this case, the prevalence of cor pulmonale can reach 80%. The development of a chronic cor pulmonale is the most striking negative prognostic factor for these patients. Only 30% of COPD patients with cor pulmonale survive longer than 5 years, and only early detection of the disturbances to respiration which might potentially lead to cor pulmonale and their subsequent therapy are able to improve the patient's prognosis. Furthermore, pulmonary diseases may also have an impact on the left heart side in terms of an impairment of left heart function or by inducing severe arrhythmias . Thus, lung diseases may have both a significant impact on right and left heart performance.

The Amplatzer duct occluder (ADO) provides a safe and effective therapy for patients with moderate- to large-sized patent ductus arteriosus (PDA), but there have been few reports of transcatheter closure of very large PDAs in young children and infants. We report a successful transcatheter closure of a very large PDA, 10.5 mm in diameter at the narrowest point, with a 14/12-mm ADO. To our knowledge, this is the largest PDA ever closed by an interventional method in such a young child.

Although hypertrophic cardiomyopathy (HCM) is classically considered a disease of the left ventricle, right ventricular (RV) abnormalities have also been reported. However, involvement of the right ventricle in HCM has not been extensively characterized. The literature regarding prevalence, genetics, patterns of involvement, histologic findings, symptoms, diagnosis, and treatment of RV abnormalities in HCM is reviewed. To highlight the salient points, a case is presented of apical HCM with significant RV involvement, with an RV outflow tract gradient and near obliteration of the RV cavity, in the absence of a left intraventricular gradient. Right ventricular involvement in HCM appears to be as heterogeneous as that of the left ventricle. The spectrum extends from mild concentric hypertrophy to more unusual severe, obstructive disease. While in some cases the extent of RV involvement correlates with left ventricular (LV) involvement, predominant RV disease can be seen as well. While the genetics of RV involvement have not been well characterized, histologic findings appear to be similar to those in the left ventricle, suggesting similar pathogenesis. Significant RV involvement may result in RV outflow obstruction and/or reduced RV diastolic filling, with potentially increased incidence of severe dyspnea, supraventricular arrhythmias, and pulmonary thromboembolism. The optimal treatment for patients with significant RV disease is unknown. Medical and surgical therapies have been attempted with variable success; experience with newer techniques such as percutaneous catheter ablation has not been reported. Further characterization of RV involvement in HCM is necessary to elucidate more clearly the clinical features and optimal treatments of this manifestation of HCM.

Half of all patients with carcinoid syndrome develop cardiac involvement. Patients who have cardiac involvement have a significantly worse prognosis than those without, and death can occur directly as a result of cardiac involvement. A case of carcinoid syndrome in a 38 year old woman with lesions in the liver, who presented with right sided valvar abnormalities, a dilated right ventricle, and right ventricular pressure overload, is presented. In order to palliate the patient's symptoms and to decrease right sided pressures before major abdominal surgery, balloon pulmonary valvuloplasty was performed at the time of cardiac catheterisation. This resulted in a reduction in the pulmonary gradient and right ventricular pressure. Following the procedure, the patient's symptoms were completely relieved. She went on to laparotomy where the lesions in the liver were excised without complication.

Idiopathic dilatation is a rare abnormality corresponding to isolated aneurysmal dilatation of the right atrium, the outcome of which is not well known. Therefore a multicentric retrospective study was set up by the paediatric working group of the French Society of Cardiology recensing 7 boys and 8 girls who were diagnosed with this condition between 1971 and 1993. Ten of the children were asymptomatic and the diagnosis was suggested by the chest X-ray: one neonate had cardiac failure secondary to atrial tachycardia. The diagnosis has been facilitated by echocardiography since 1980. In this series, since 1993, four diagnoses were made antenatally. The outcome was variable : eight children are alive and well with follow-up periods ranging from 2 to 15 years (average 6 years) : four children have had cardiac arrhythmias : benign atrial extrasystoles (1 case), junctional reentrant tachycardia (1 case). The other two had more severe arrhythmias with flutter in a 7 year-old and one neonatal atrial tachycardia. The outcome was favourable with medical treatment. Three children underwent surgical atrial resection : the outcome has been good in these 3 cases with follow-up periods of 4, 13 and 18 years. This series shows that idiopathic dilatation of the right atrium is usually a well tolerated abnormality but unexpected complications may arise which can be severe such as arrhythmias, or which may be potentially threatening such as interatrial thrombosis. Management consists of either follow-up to diagnose complications which require appropriate treatment of systematic surgical correction as some authors suggest.

Arrhythmogenic right ventricular dysplasia is a cardiomyopathy with autopsy evidence of fibrous and fatty infiltration of the right ventricular. The disease, which shows familial clustering, causes electrical instability that may place affected subjects at risk of sudden death. It is characterized by ECG changes and right ventricular dysfunction. Death can occur due to ventricular arrhythmia. We describe a 46-year-old female Cypriot who presented with recurrent syncope and palpitation due to ventricular tachycardia with the LBBB pattern; T waves were inverted in V1-V3. Echocardiogram and cardiac catheterization revealed severe right ventricular dysfunction. Her sister had died several years before of a similar syndrome, including ventricular tachycardia. Family members should be screened for right ventricular dysplasia. Those currently asymptomatic should be given prophylactic therapy to prevent sudden death. Treatment is either medical: sotalol, beta-blockers or verapamil; or surgical: ablation of the arrhythmogenic focus in the right ventricle, total disconnection of the right ventricular free wall; or implantation of a cardioverter defibrillator.

Right ventricular dysplasia is being recognized with increasing frequency. It should be considered as a cause of ventricular tachycardia of left bundle branch block configuration and/or sudden unexpected death particularly during exercise in young men. The electrocardiogram (ECG) may show anterior precordial T wave inversion, particularly in lead V2 and/or a QRS complex duration > or = 110 ms in the right precordial leads. Echocardiographic studies focusing on the size and wall-motion abnormalities of the right ventricle are useful in confirming the diagnosis. Radionuclide angiography usually shows a moderately or markedly depressed right ventricular ejection fraction with normal or relatively well preserved left ventricular function. Cinemagnetic resonance imaging demonstrates abnormal fatty infiltration of the right ventricular myocardium and can show increased right ventricular dimensions as well as wall-motion abnormalities. Contrast ventricular angiography remains the gold standard to establish the diagnosis but must be performed with appropriate views and with care to avoid ventricular premature beats. Quantitative analysis of right ventricular dimensions can be performed in selected centers. Three-dimensional echocardiography is a promising approach to evaluate right ventricular wall-motion abnormalities as well as to demonstrate enlargement. The etiology and pathogenesis of this condition is not clear. A familial incidence has been well-documented in certain areas and an abnormal gene has been identified. Sporadic cases are the most common. In contrast to Uhl's anomaly, characterized pathologically by areas of paper thin myocardium, the right ventricular free wall is minimally decreased in thickness. Histologically there appears to be a replacement of musculature by fatty tissue. Medical therapy with sotalol or amiodarone, or combination therapy (Class Ic drugs plus beta-blocking drugs, or amiodarone plus beta-blocking drugs) is frequently effective in preventing recurrent ventricular tachycardia. Ablation using radiofrequency (RF) or direct current (DC) energy is reserved for patients who are unresponsive or intolerant of antiarrhythmic drugs. Ventricular arrhythmia recurrence of different morphology is not uncommon after apparent successful ablation. There appears to be a lower rate of successful ablation using RF energy. However, patients with this condition who have been resuscitated from sudden cardiac death or those refractory to medical treatment are candidates for ablation, implantation of an automatic cardioverter defibrillator, or cardiac transplantation. Surgery consisting of total disconnection of the right ventricle is a promising therapeutic modality.

Right ventricular (RV) failure is now accepted as a pathophysiological entity. This acceptance has stemmed from the increasing facility of bedside assessment of pump function using thermodilution techniques. The subsequent improvement in the assessment of RV volume changes has allowed existing theories to be confirmed. The anatomical disposition and geometry of the right ventricle allow it to adapt very well to wide variations in preload, but poorly to increases in afterload. In the presence of increased afterload, RV stroke volume decreases linearly with increasing resistance and the ventricle eventually dilates. This dilation is then responsible for further RV failure, due to decreased right coronary artery flow (from systolo-diastolic to diastolic only) at a time when myocardial oxygen consumption is increased. Furthermore, RV dilation shifts the interventricular septum to the left, decreasing left ventricular preload and, hence, the cardiac output. An often lethal vicious circle is induced. The main therapeutic goals aimed at breaking this circle are restoration of adequate oxygen delivery to the myocardium and diminution of RV afterload.

Recent technical developments in implantable cardioverter defibrillator (ICD) systems and reduced operative mortality and morbidity rates associated with ICD implantation have expanded the indications for ICD treatment of ventricular tachyarrhythmias. This review summarizes data regarding ICD therapy in patients with arrhythmogenic right ventricular cardiomyopathy, long QT syndrome, and idiopathic ventricular fibrillation and presents preliminary concepts for identification of patients who will benefit more from ICD therapy than from pharmacologic and other nonpharmacologic approaches. Recent studies suggest that ICD therapy may improve long-term prognosis by reliably terminating recurrences of life-threatening arrhythmias. Appropriate ICD therapies during mean follow-up periods of 12 to 36 months occurred in 30% of patients with idiopathic ventricular fibrillation to 50% of patients with arrhythmogenic right ventricular cardiomyopathy and long QT syndrome. At present no strict recommendations can be given for ICD implantation in these patients. However, at least in cardiac arrest survivors in whom the clinical arrhythmia is not reproducibly inducible during electrophysiologic study, ICD therapy appears to be superior to other treatment options with regard to long-term survival and thus should be considered as a first-line treatment. We are hopeful that continued study of long-term follow-up with and without ICD treatment and improved risk stratification will lead to better criteria for selection of treatment options.