Regression Of Pulmonary Arterial Hypertension Research Articles

Early and long-term results of ventricular septal defect repair in children with severe pulmonary hypertension and elevated pulmonary vascular resistance by the double or traditional patch technique.

In upper-income countries, infants undergo low-risk ventricular septal defect (VSD) repair. Children in low- and middle-income countries frequently present at older ages with elevated pulmonary vascular resistance (PVR) and pulmonary arterial hypertension (PAH). Expensive interventions for pulmonary hypertensive crisis are not available, and children are often denied an operation due to the mortality risk. We report our early and late experiences with these patients who underwent VSD closure by traditional patch (TP) or double patch (DP) techniques. We extracted data from patients with VSD and PAH who underwent VSD closure operations from 1996 to 2016. Information regarding cardiac catheterizations, operations, time in the intensive care unit and follow-up information was found. We identified 129 children and analysed the differences between the TP (89/129) and the DP (40/129) in unidirectional groups. After 2005, the patients were pretreated with sildenafil 3 months before catheterization. The TP group was younger (P < 0.001). Hospital mortality (2.5%, DP; 10.1%,TP) was not significantly different (P = 0.17) between the 2 groups despite significant differences in baseline PVR, PVR/systemic vascular resistance and the number of children with a saturation less than 90%. The long-term survival and regression of PAH were better in the DP group (survival over 97% vs 93% in the TP group). Moreover, 61% of children with DP and 75% of those with TP had normal to mild elevations in pulmonary artery pressures at the last follow-up examination (P = 0.046). The DP operation is a low-risk procedure. Moreover, the long-term outcome with the use of this technique in high-risk patients with VSD and high PVR and PAH is favourable with respect to survival and showed a decrease in PAH at the last follow-up.

Novel Mutations and Decreased Expression of the Epigenetic Regulator TET2 in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a lethal vasculopathy. Hereditary cases are associated with germline mutations in BMPR2 and 16 other genes; however, these mutations occur in <25% of patients with idiopathic PAH and are rare in PAH associated with connective tissue diseases. Preclinical studies suggest epigenetic dysregulation, including altered DNA methylation, promotes PAH. Somatic mutations of Tet-methylcytosine-dioxygenase-2 (TET2), a key enzyme in DNA demethylation, occur in cardiovascular disease and are associated with clonal hematopoiesis, inflammation, and adverse vascular remodeling. The role of TET2 in PAH is unknown. To test for a role of TET2, we used a cohort of 2572 cases from the PAH Biobank. Within this cohort, gene-specific rare variant association tests were performed using 1832 unrelated European patients with PAH and 7509 non-Finnish European subjects from the Genome Aggregation Database (gnomAD) as control subjects. In an independent cohort of 140 patients, we quantified TET2 expression in peripheral blood mononuclear cells. To assess causality, we investigated hemodynamic and histological evidence of PAH in hematopoietic Tet2-knockout mice. We observed an increased burden of rare, predicted deleterious germline variants in TET2 in PAH patients of European ancestry (9/1832) compared with control subjects (6/7509; relative risk=6; P=0.00067). Assessing the whole cohort, 0.39% of patients (10/2572) had 12 TET2 mutations (75% predicted germline and 25% somatic). These patients had no mutations in other PAH-related genes. Patients with TET2 mutations were older (71±7 years versus 48±19 years; P<0.0001), were more unresponsive to vasodilator challenge (0/7 versus 140/1055 [13.2%]), had lower pulmonary vascular resistance (5.2±3.1 versus 10.5±7.0 Wood units; P=0.02), and had increased inflammation (including elevation of interleukin-1β). Circulating TET2 expression did not correlate with age and was decreased in >86% of PAH patients. Tet2-knockout mice spontaneously developed PAH, adverse pulmonary vascular remodeling, and inflammation, with elevated levels of cytokines, including interleukin-1β. Long-term therapy with an antibody targeting interleukin-1β blockade resulted in regression of PAH. PAH is the first human disease related to potential TET2 germline mutations. Inherited and acquired abnormalities of TET2 occur in 0.39% of PAH cases. Decreased TET2 expression is ubiquitous and has potential as a PAH biomarker.

Effect of prosthesis patient mismatch in mitral position on pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is associated with poor outcome after mitral valve replacement (MVR). We proposed to evaluate the effect of valve prosthesis patient mismatch (PPM) on pulmonary arterial (PA) pressure following MVR. Five hundred patients who have undergone MVR were studied retrospectively. Postoperative PA systolic pressure (PASP) measured 6 months postoperatively by Doppler echocardiography was compared with preoperative values. PASP ≥ 40 mmHg was defined as PAH. Mitral valve effective orifice area was calculated by the continuity equation and indexed for body surface area. PPM was defined as indexed effective orifice area ≤ 1.2 cm2/m2. A multivariate model was constructed to ascertain the independent determinants of systolic PA pressure. Also, a propensity score model was constructed to overcome the baseline differences between the PPM and no PPM groups. The incidence of PPM in this study was 37.2%. The average postoperative PASPs were 30.49 and 42.35 mmHg in the no PPM and PPM groups, respectively; (P < 0.001). Regression of PAH in the PPM and no PPM groups was 76.26% and 20.64%, respectively; (P < 0.001). The indexed effective orifice area correlated well with postoperative PASP (r = 0.71). The overall survival and freedom from cardiac death at 10 years were 79.8% and 85.3%; and at 20 years were 66.5% and 74.3%, respectively. Both, overall survival and the freedom from cardiac death were higher in the no PPM group than in the PPM group; (P < 0.001). Propensity score matching analysis yielded 112 pairs of the PPM and no PPM cohorts, which revealed higher overall survival and freedom from cardiac death in the no PPM group; (P = 0.028 and 0.012, respectively). Mitral PPM is an independent predictor of persistent PAH after MVR along with associated morbidity and reduced survival.

Transverse Sternal Split: a Safe Mini-invasive Approach for Perventricular Device Closure of Ventricular Septal Defect.

ObjectivePerventricular device closure of ventricular septal defect through midline sternotomy avoids the cardiopulmonary bypass, however, lacks the cosmetic advantage. Perventricular device closure of ventricular septal defect with transverse split sternotomy was performed to add the cosmetic advantage of mini-invasive technique.MethodsThirty-six pediatric patients with mean age 7.14±3.24 months and weight 5.00±0.88 kg were operated for perventricular device closure of ventricular septal defect through transverse split sternotomy in 4th intercostal space under transesophageal echocardiography guidance. In case of failure or complication, surgical closure of ventricular septal defect was performed through the same incision with cervical cannulation of common carotid artery and internal jugular vein for commencement of cardiopulmonary bypass. All the patients were postoperatively followed, and then discharged from hospital due to their surgical outcome, morbidity and mortality.ResultsProcedure was successful in 35 patients. Two patients developed transient heart block. Surgical closure of ventricular septal defect was required in one patient. Mean duration of ventilation was 11.83±3.63 hours. Mean intensive care unit and hospital stay were 1.88±0.74 days and 6.58±1.38 days, respectively. There was no in-hospital mortality. A patient died one day after hospital discharge due to arrhythmia. No patients developed wound related, vascular or neurological complication. In a mean follow-up period of 23.3±18.45 months, all 35 patients were doing well without residual defect with regression of pulmonary artery hypertension as seen on transthoracic echocardiography.ConclusionTransverse split sternotomy incision is a safe and effective alternative to a median sternotomy for perventricular device closure of ventricular septal defect with combined advantage of better cosmetic outcomes and avoidance of cardiopulmonary bypass.

Reversal of abnormal cardiac parameters following mitral valve replacement for severe mitral stenosis- in relation to pulmonary artery pressure-A retrospective study of noninvasive parameters

Though the regression of Pulmonary Arterial Hypertension (PAH) in mitral stenosis (MS) has been studied over varying periods post-intervention, corresponding studies on the cardiac chamber alterations after surgery are very limited.

Regression of pulmonary artery hypertension due to development of a pulmonary arteriovenous malformation

Idiopathic Pulmonary Hypertension (IPAH) is characterized by elevated pulmonary arterial pressure in the absence of an identifiable underlying cause. The condition is usually relentlessly progressive with a short survival in the absence of treatment.1 We describe a patient of IPAH in whom the pulmonary artery pressures significantly abated with complete disappearance of symptoms, following spontaneous development of a pulmonary arterio-venous malformation (PAVM).

Evaluation of Clinical Efficacy of Fasudil for the Treatment of Pulmonary Arterial Hypertension

Multiple cell types in the vascular wall rely upon the rho-kinase (ROCK) signaling pathway for homeostatic function and response to injury. These cell types include endothelial and vascular smooth muscle cells, inflammatory cells, and fibroblasts. Rho is a guanosine triphosphate binding protein that activates its downstream target rho-kinase, in response to activation of a variety of G-protein coupled receptors. When activated, ROCK inhibits myosin phosphatase and conversely upregulates the ezrin-radixin-moesin family of kinases. In vitro activation of these signaling cascades results in modulation of multiple cellular processes, including enhanced vasoconstriction, proliferation, impaired endothelial response to vasodilators, chronic pulmonary remodeling, and upregulation of vasoactive cytokines via the NF-κB transcription pathway. ROCK activity has also been linked specifically to a number of known effectors of pulmonary arterial hypertension (PAH), including endothelin-1, serotonin, and endothelial nitric oxide synthase, among others. Recently, elevated ROCK activity has been demonstrated in various animal models of PAH with ROCK inhibitors associated with pulmonary vasodilatation and regression of PAH. ROCK inhibitors are a new class of agents which may be beneficial in the treatment of PAH. Fasudil (Daiichi Chemical and Pharmacological Company, Ibaragi, Japan), a first generation ROCK inhibitor, has been widely studied. Emerging evidence from both animal and human studies suggests that fasudil can promote vasodilation independent of the mechanism that induces vasoconstriction and will be useful in conditions in which endothelial function is impaired including PAH. Several recent patents have described fasudil as a potential therapeutic option in PAH. This article provides an overview of the role of ROCK in the pathogenesis of PAH and discusses the clinical efficacy of fasudil as a therapeutic option for treating PAH.

The Role of K+ Channels in Determining Pulmonary Vascular Tone, Oxygen Sensing, Cell Proliferation, and Apoptosis: Implications in Hypoxic Pulmonary Vasoconstriction and Pulmonary Arterial Hypertension

Potassium channels are tetrameric, membrane-spanning proteins that selectively conduct K+ at near diffusion-limited rates. Their remarkable ionic selectivity results from a highly-conserved K+ recognition sequence in the pore. The classical function of K+ channels is regulation of membrane potential (EM) and thence vascular tone. In pulmonary artery smooth muscle cells (PASMC), tonic K+ egress, driven by a 145/5 mM intracellular/extracellular concentration gradient, contributes to a EM of about -60 mV. It has been recently discovered that K+ channels also participate in vascular remodeling by regulating cell proliferation and apoptosis. PASMC express voltage-gated (Kv), inward rectifier (Kir), calcium-sensitive (KCa), and two-pore (K2P) channels. Certain K+ channels are subject to rapid redox regulation by reactive oxygen species (ROS) derived from the PASMC's oxygen-sensor (mitochondria and/or NADPH oxidase). Acute hypoxic inhibition of ROS production inhibits Kv1.5, which depolarizes EM, opens voltage-sensitive, L-type calcium channels, elevates cytosolic calcium, and initiates hypoxic pulmonary vasoconstriction (HPV). Hypoxia-inhibited K+ currents are not seen in systemic arterial SMCs. Kv expression is also transcriptionally regulated by HIF-1alpha and NFAT. Loss of PASMC Kv1.5 and Kv2.1 contributes to the pathogenesis of pulmonary arterial hypertension (PAH) by causing a sustained depolarization, which increases intracellular calcium and K+, thereby stimulating cell proliferation and inhibiting apoptosis, respectively. Restoring Kv expression (via Kv1.5 gene therapy, dichloroacetate, or anti-survivin therapy) reduces experimental PAH. Electrophysiological diversity exists within the pulmonary circulation. Resistance PASMC have a homogeneous Kv current (including an oxygen-sensitive component), whereas conduit PASMC current is a Kv/KCa mosaic. This reflects regional differences in expression of channel isoforms, heterotetramers, splice variants, and regulatory subunits as well as mitochondrial diversity. In conclusion, K+ channels regulate pulmonary vascular tone and remodeling and constitute potential therapeutic targets in the regression of PAH.

Time course of changes in pulmonary vascular resistance and the mechanism of regression of pulmonary arterial hypertension after balloon mitral valvuloplasty

Time course of changes in pulmonary vascular resistance and the mechanism of regression of pulmonary arterial hypertension after balloon mitral valvuloplasty