Fatal Pulmonary Hypertension Research Articles

Pulmonary tumor thrombotic microangiopathy in occult early gastric cancer that was undetectable on upper endoscopy: a case report and review of similar cases

BackgroundPulmonary tumor thrombotic microangiopathy (PTTM), a rare manifestation of metastatic cancer with poor prognosis, is characterized by subacute/acute fatal pulmonary hypertension. The main cause of PTTM is gastric cancer, and cases of early gastric cancer confirmed using autopsy have been reported. Moreover, several cases of early gastric cancer that are undetectable on endoscopy or macroscopic postmortem examination have been reported.Case presentationA previously healthy 50-year-old man presented with progressive dyspnea and cough for 1 month. Echocardiography suggested pulmonary hypertension. Computed tomography revealed diffuse lymphadenopathy, whereas blood work revealed an elevation in several serum tumor marker levels. Despite normal upper endoscopic findings, a presumptive diagnosis of PTTM due to gastric cancer was made based on pathological findings of cervical lymph node biopsy, which indicated signet ring cell carcinoma. Imatinib and tegafur/gimeracil/oteracil plus oxaliplatin therapy were started on day 7. The patient’s condition was initially stable. However, his symptoms suddenly progressed, and the patient died on day 8. Macroscopic postmortem examination revealed no abnormal gastric wall findings. Microscopically, PTTM was confirmed, and multiple serial sections of the stomach revealed early gastric cancer.ConclusionsDespite normal endoscopic findings, micro-occult gastric cancer can lead to PTTM. Physicians should be aware of this disease presentation. Taking prompt action is needed when PTTM is suspected, even if the patient appears stable.

Macroscopic Characteristics of the Native Liver in Children With MPV17-Related Mitochondrial DNA Depletion Syndrome: An Indication for Performing Liver Transplantation?

Mitochondrial respiratory chain disorders (MRCDs) are rare conditions with various clinical manifestations that depend on the genetic type, with subsequent severity of the liver disease. Clinical presentations include acute liver failure or chronic liver failure with liver cirrhosis, which are cruelly progressive and fatal. We report six cases of LT for acute liver failure diagnosed pathogenic MPV17 variants. Three out of six cases were siblings with the MPV17-mutation (c.148C>T, p.R50W / c.149G>A; p.R50Q), also known as the childhood form of Navajo neurohepatopathy. Those three patients underwent LT for liver cirrhosis at the ages of 5, 7, and 7 years, respectively. All three recipients are currently doing well without any neurological sequelae. In contrast, the three additional patients that presented with an acute liver failure and subsequent diagnosis of mutation in MPV17 (homozygous c.451dupC: p.L151PfsX39; homozygous c.451dupC : p.L151PfsX39; c.451dupC : p.L151PfsX39 / c.71-2_79del11ins4), underwent LT at the ages of 4 months, 11 months, and 1 year, respectively. All three recipients died from pulmonary hypertension following successful LT. Interestingly, the intraoperative macroscopic findings of the native liver at the time of LT revealed distinctive, microgranular nodules and liver fibrosis with severe steatosis ("avocado-like" liver). LT might be contraindicated in MPV17 patients with c.451dupC mutation due to the extremely poor prognosis caused by fatal progressive pulmonary hypertension. The identification of the typical macroscopic finding ("avocado-like"), seen in such pediatric transplant candidates with acute liver failure, might be helpful to provide an early diagnosis of MPV17-related c.451dupC mutation.

Fatal Pulmonary Hypertension and Right-Sided Congestive Heart Failure in a Kitten Infected with Aelurostrongylus abstrusus.

Simple SummaryInfections caused by lungworms are an emerging issue in feline medicine. Clinical features in cats may vary from subclinical infections to a severe disease, occasionally including fatal pneumonia, depending on different factors, e.g., lungworm species, parasitic burden, and age of the animal. A case of infection caused by Aelurostrongylus abstrusus in a domestic kitten presenting acute dyspnoea and ascites is presented here. Clinical, radiological, echocardiographic, parasitological, molecular, and pathological data are described. This is the first report of life-threatening pulmonary hypertension inducing congestive heart failure caused by A. abstrusus infection in a domestic kitten.Aelurostrongylus abstrusus is considered the most important respiratory nematode of domestic cats worldwide. This parasite inhabits the alveoli, alveolar ducts, and bronchioles and causes a subacute to chronic respiratory clinical disease. Clinical signs may occur in domestic cats of any age, though they are more often described in young animals. Physical examination, echocardiography, thoracic radiography, pulmonary and cardiac pathological findings, classical, and molecular parasitological analysis of a six-month-old kitten referred at the Veterinary Teaching Hospital of the University of Pisa (Italy) led to a diagnosis of parasitic bronchopneumonia caused by A. abstrusus, which was complicated by severe pulmonary hypertension (PH) and right-sided congestive heart failure (R-CHF) that caused the death of the animal. Cases of reversible PH associated with A. abstrusus infection have been seldom reported in cats. This is the first report of fatal PH and R-CHF in a kitten with clinical aelurostrongylosis.

Unexpected Autopsy Finding as a Cause of Fatal Pulmonary Hypertension Post Transplant

Unexpected Autopsy Finding as a Cause of Fatal Pulmonary Hypertension Post Transplant

Lung Vascular Remodeling, Cardiac Hypertrophy, and Inflammatory Cytokines in SHIVnef-Infected Macaques.

Fatal pulmonary arterial hypertension (PAH) affects HIV-infected individuals at significantly higher frequencies. We previously showed plexiform-like lesions characterized by recanalized lumenal obliteration, intimal disruption, medial hypertrophy, and thrombosis consistent with PAH in rhesus macaques infected with chimeric SHIVnef but not with the parental SIVmac239, suggesting that Nef is implicated in the pathophysiology of HIV-PAH. However, the current literature on non-human primates as animal models for SIV(HIV)-associated pulmonary disease reports the ultimate pathogenic pulmonary outcomes of the research efforts; however, the variability and features in the actual disease progression remain poorly described, particularly when using different viral sources for infection. We analyzed lung histopathology, performed immunophenotyping of cells in plexogenic lesions pathognomonic of PAH, and measured cardiac hypertrophy biomarkers and cytokine expression in plasma and lung of juvenile SHIVnef-infected macaques. Here, we report significant hematopathologies, changes in cardiac biomarkers consistent with ventricular hypertrophy, significantly increased levels of interleukin-12 and GM-CSF and significantly decreased sCD40 L, CCL-2, and CXCL-1 in plasma of the SHIVnef group. Pathway analysis of inflammatory gene expression predicted activation of NF-κB transcription factor RelB and inhibition of bone morphogenetic protein type-2 in the setting of SHIVnef infection. Our findings highlight the utility of SHIVnef-infected macaques as suitable models of HIV-associated pulmonary vascular remodeling as pathogenetic changes are concordant with features of idiopathic, familial, scleroderma, and HIV-PAH.

Current drugs for weight loss

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Comparative Analysis of Tyrosine Kinase Inhibitors-Related Pulmonary Hypertension in the Patients Treated By Imatinib, Dasatinib and Nilotinib

▪Introduction:Tyrosine kinase inhibitors (TKIs) have dramatically improved outcome of patients with chronic myeloid leukemia (CML) and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) with lesser incidence of serious adverse events. Recently, cases with fatal pulmonary hypertension (PH) have been sporadically documented in association with dasatinib treatment. French group reported incidence of PH diagnosed by cardiac catheterization as 0.45% (13 of 2900 patients) in the symptomatic patients treated with dasatinib. In contrast, a Korean group prospectively evaluated PH by non-invasive echocardiography in CML patients treated with dasatinib, and demonstrated 8 of 66 patients (12.1%) exhibited a significant increase in right ventricular systolic pressure, indicating subclinical PH might be more common event in dasatinib-treated patients. In this study, we prospectively examined the patients treated with three TKIs by echocardiography to clarify incidence of clinical and subclinical PH as well as factors associated with PH.Patients and Methods:Total of 108 patients (99 with CML, 9 with Ph+ ALL) receiving TKIs in our institutions were enrolled to this study. Forty-one patients have been on treatment with dasatinib (38%), 37 with imatinib (34%) and 30 with nilotinib (28%). Patients underwent echocardiography to evaluate values of tricuspid regurgitation pressure gradient (TRPG), which relates to severity of PH. Patients with higher values of TRPG than the upper limit (30mmHg) was suspected of PH by European Society of Cardiology criteria.Results:Among 108 patients, median age was 63 years old, and median duration of TKIs treatment was 26.5 months. Median daily dosage was 100 mg for dasatinib, 300 mg for imatinib, 600 mg for nilotinib groups, respectively (Table 1). In imatinib group, patients' age was significantly higher, and duration of treatment was also longer than those of the 2nd generation TKIs. Echocardiography revealed mean values of TRPG as 23.2, 23.2 and 23.1 mmHg in dasatinib, imatinib and nilotinib groups, respectively. There was no significant difference in TRPG values among 3 groups (p=0.99). We also found no relationship between TRPG values and duration of TKIs treatment in each group. Interestingly, we detected a significant inverse correlation between daily dosage of imatinib and TRPG values (p=0.012, Figure 1), while such relationship was not observed in dasatinib and nilotinib groups (p=0.68 and p=0.49). TRPG values higher than 30 mmHg were documented in 13 of 108 patients (12.0%); 5 of 41 (12.2%) in dasatinib group, 4 of 37 (10.8%) in imatinib group, and 4 of 30 (13.3%) in nilotinib group (p=0.95).Discussion:PH is characterized by proliferation of pulmonary vascular smooth muscle cells (SMCs). Recent reports showed that imatinib suppresses abnormal proliferation of SMCs through inhibiting platelet-derived growth factor receptors (PDGFR), resulting in improvement of PH in animal models. Clinical studies in symptomatic PH patients reported that imatinib considerably improved pulmonary hemodynamics. Of note, in our study, dosage of imatinib was significantly correlated with lower values of TRPG, suggesting imatinib possibly decreases TRPG values in a dose-dependent manner. This finding strongly supports the reports indicating imatinib as a therapeutic agent of PH. In contrast, in vitro studies have shown that dasatinib has stronger potential to inhibit PDGFR compared to imatinib; nevertheless, onsets of PH have been reported in dasanitib-treated patients, but not with imatinib nor nilotinib. Our study demonstrated the incidence of TRPG elevation as 12.0% in dasatinib group, which was consistent with Korean report (12.1%). However, there was no significant difference in TRPG values among 3 groups, indicating no apparent evidence which dasatinib treatment might be specifically associated with occurrence of PH. These results suggested that subclinical PH might be more common than expected. Careful follow-ups with echocardiography are necessary for the patients under any TKI treatments.Table 1Patient characteristicsDasatinib group (n=41)Imatinib group (n=37)Nilotinib group (n=30)pMedian age55(17-77)68(22-92)62.5(24-85)0.0004Median dosage (mg/day)100(18-100)300(100-600)600(300-800)Mean months from start of TKI68.5(2-287)104.8(2-228)61.3(3-153)0.007Mean TRPG(mmHg)23.2(9-40)23.2(8-46)23.1(7-35)0.995 [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical, biochemical, and genetic spectrum of seven patients with NFU1 deficiency.

Disorders of the mitochondrial energy metabolism are clinically and genetically heterogeneous. An increasingly recognized subgroup is caused by defective mitochondrial iron–sulfur (Fe–S) cluster biosynthesis, with defects in 13 genes being linked to human disease to date. Mutations in three of them, NFU1, BOLA3, and IBA57, affect the assembly of mitochondrial [4Fe–4S] proteins leading to an impairment of diverse mitochondrial metabolic pathways and ATP production. Patients with defects in these three genes present with lactic acidosis, hyperglycinemia, and reduced activities of respiratory chain complexes I and II, the four lipoic acid-dependent 2-oxoacid dehydrogenases and the glycine cleavage system (GCS). To date, five different NFU1 pathogenic variants have been reported in 15 patients from 12 families. We report on seven new patients from five families carrying compound heterozygous or homozygous pathogenic NFU1 mutations identified by candidate gene screening and exome sequencing. Six out of eight different disease alleles were novel and functional studies were performed to support the pathogenicity of five of them. Characteristic clinical features included fatal infantile encephalopathy and pulmonary hypertension leading to death within the first 6 months of life in six out of seven patients. Laboratory investigations revealed combined defects of pyruvate dehydrogenase complex (five out of five) and respiratory chain complexes I and II+III (four out of five) in skeletal muscle and/or cultured skin fibroblasts as well as increased lactate (five out of six) and glycine concentration (seven out of seven). Our study contributes to a better definition of the phenotypic spectrum associated with NFU1 mutations and to the diagnostic workup of future patients.

Severe Fatal Pulmonary Hypertension in Newborn with Idiopathic Arterial Calcification

Idiopathic congenital calcification of the great vessels is a rare genetic disorder affecting the infants during first months of live causing fatal complications [13] due to generalized calcification of the moderate to large vessels leading to decrease elasticity and occlusion of these vessels [4]. We prescribe 2 days old boy with respiratory distress and mild central cyanosis, his echocardiography reveal a calcified aorta and pulmonary arteries with sever pulmonary hypertension that was diagnosed later as idiopathic congenital arterial calcification of infancy.

A patient with Cantú syndrome associated with fatal bronchopulmonary dysplasia and pulmonary hypertension

A patient with Cantú syndrome associated with fatal bronchopulmonary dysplasia and pulmonary hypertension

Translational research in pulmonary hypertension: challenge and opportunity

The literature is filled with individual conclusions, and not many theories to tie them together . – Agus and Gell-Mann [1] The first World Health Organization conference on pulmonary hypertension, held in 1971 in Geneva, Switzerland [2], had been convened to investigate the first drug-induced epidemic of so-called “primary” pulmonary hypertension. The clinicians had noted an unusual increase in the number of patients with often fatal pre-capillary pulmonary hypertension and, by connecting the dots, they identified the drug menocil (aminorex fumarate) as the cause of the outbreak. This first epidemic of anorexigen drug-induced pulmonary hypertension moved the “lesser or small circulation” [3] into the visual field of cardiologists and pulmonologists. From the perspective of today's knowledge base a contemporary statement from Kenneth Moser is of historical interest: “The key historical event was the labeling of this vascular bed as the lesser circulation. Presumably, this description was not used in the pejorative sense; but it seems to have operated in that way, intentionally or not. Who would deign to study the lesser circulation when one could attack questions about the “greater circulation”? Furthermore, was not the lesser circulation simply a passive system of pipes leading from right ventricle to left atrium, where the really important events would occur? Of course, along the way, the blood perfusing these passive conduits did participate in gas exchange, but that was a “pulmonary” not a “hemodynamic” event. Which brings us to the political problems experienced by the pulmonary vascular bed; namely, under which aegis does concern with this bed properly fall?” [3]. Since the time of this writing, the universe of pulmonary hypertension has expanded, some say the field has exploded. Perhaps the “big bang” event was the success of the first treatment …

A Novel Vascular Homing Peptide Strategy to Selectively Enhance Pulmonary Drug Efficacy in Pulmonary Arterial Hypertension

A major limitation in the pharmacological treatment of pulmonary arterial hypertension (PAH) is the lack of pulmonary vascular selectivity. Recent studies have identified a tissue-penetrating homing peptide, CARSKNKDC (CAR), which specifically homes to hypertensive pulmonary arteries but not to normal pulmonary vessels or other tissues. Some tissue-penetrating vascular homing peptides have a unique ability to facilitate transport of co-administered drugs into the targeted cells/tissues without requiring physical conjugation of the drug to the peptide (bystander effect). We tested the hypothesis that co-administered CAR would selectively enhance the pulmonary vascular effects of i.v. vasodilators in Sugen5416/hypoxia/normoxia-exposed PAH rats. Systemically administered CAR was predominantly detected in cells of remodeled pulmonary arteries. Intravenously co-administered CAR enhanced pulmonary, but not systemic, effects of the vasodilators, fasudil and imatinib, in PAH rats. CAR increased lung tissue imatinib concentration in isolated PAH lungs without increasing pulmonary vascular permeability. Sublingual CAR was also effective in selectively enhancing the pulmonary vasodilation by imatinib and sildenafil. Our results suggest a new paradigm in the treatment of PAH, using an i.v./sublingual tissue-penetrating homing peptide to selectively augment pulmonary vascular effects of nonselective drugs without the potentially problematic conjugation process. CAR may be particularly useful as an add-on therapy to selectively enhance the pulmonary vascular efficacy of any ongoing drug treatment in patients with PAH.

Medial defects of the small pulmonary arteries in fatal pulmonary hypertension in infants with trisomy 13 and trisomy 18

Congestive heart failure is a major cause of early death in patients with trisomy 13 or 18 and congenital heart disease (CHD). Pulmonary artery banding for these patients early in life is preferred to protect the lungs from high pulmonary flow rates and improve survival. We performed open lung biopsies in 11 patients with trisomy 13 or 18 accompanied by CHD and severe pulmonary artery hypertension (PAH) between 2009 and 2011. Two (18.2%) of these 11 patients had medial defects of the small pulmonary arteries. One patient with trisomy 13 and an atrial septal defect developed lung hemorrhage and lung edema at the age of 9 months and died at the age of 13 months. The lumens of the small pulmonary arteries of the other patient with trisomy 18 and a ventricular septal defect became occluded due to the intimal proliferation of fibrous tissues at the age of 2 months. This patient died at the age of 27 months. The deaths of both patients were associated with heart-related factors. Patients with medial defects are vulnerable to intimal proliferation in the small pulmonary arteries. More patients with trisomy 13 or 18 and CHD might have similar pulmonary vascular changes. The small pulmonary arteries of patients with trisomy 13 and 18 should be further analyzed.

Pulmonary hypertension following haematopoietic stem cell transplantation for primary haemophagocytic lymphohistiocytosis

We report two children who developed severe, fatal pulmonary hypertension (PHT) after mismatched unrelated donor cord blood transplantation using reduced intensity conditioning for HLH. PHT was diagnosed on post mortem lung biopsies with no evidence of HLH, pulmonary veno-occlusive disease, infection or of idiopathic pulmonary hypertension. PHT may be an association with HLH and physicians treating HLH should be aware of this potential association.

A Fatal Mitochondrial Disease Is Associated with Defective NFU1 Function in the Maturation of a Subset of Mitochondrial Fe-S Proteins

We report on ten individuals with a fatal infantile encephalopathy and/or pulmonary hypertension, leading to death before the age of 15 months. Hyperglycinemia and lactic acidosis were common findings. Glycine cleavage system and pyruvate dehydrogenase complex (PDHC) activities were low. Homozygosity mapping revealed a perfectly overlapping homozygous region of 1.24 Mb corresponding to chromosome 2 and led to the identification of a homozygous missense mutation (c.622G > T) in NFU1, which encodes a conserved protein suggested to participate in Fe-S cluster biogenesis. Nine individuals were homozygous for this mutation, whereas one was compound heterozygous for this and a splice-site (c.545 + 5G > A) mutation. The biochemical phenotype suggested an impaired activity of the Fe-S enzyme lipoic acid synthase (LAS). Direct measurement of protein-bound lipoic acid in individual tissues indeed showed marked decreases. Upon depletion of NFU1 by RNA interference in human cell culture, LAS and, in turn, PDHC activities were largely diminished. In addition, the amount of succinate dehydrogenase, but no other Fe-S proteins, was decreased. In contrast, depletion of the general Fe-S scaffold protein ISCU severely affected assembly of all tested Fe-S proteins, suggesting that NFU1 performs a specific function in mitochondrial Fe-S cluster maturation. Similar biochemical effects were observed in Saccharomyces cerevisiae upon deletion of NFU1, resulting in lower lipoylation and SDH activity. Importantly, yeast Nfu1 protein carrying the individuals' missense mutation was functionally impaired. We conclude that NFU1 functions as a late-acting maturation factor for a subset of mitochondrial Fe-S proteins.

Cutis laxa and fatal pulmonary hypertension

Cutis laxa is a connective tissue disorder with distinctive lax, redundant, and inelastic skin. It is a genetically heterogenous disorder with autosomal dominant and recessive patterns of inheritance. We report a patient with cutis laxa supported by clinical, microscopic, and ultrastructural findings. Molecular analysis of fibulin-4 and -5, of the α2 subunit of the V-type H+ ATPase, and of the component of the oligomeric Golgi complex 7 (COG7) genes excluded the type I and type II autosomal recessive forms of cutis laxa, and congenital disorders of glycosylation associated with cutis laxa. Remarkably, our patient also presented severe and lethal pulmonary hypertension as a newborn. This case with cutis laxa, severe pulmonary hypertension, and no detectable mutations in fibulin-4 and -5 genes may represent a previously unrecognized syndrome.

The critical roles of platelet activation and reduced NO bioavailability in fatal pulmonary arterial hypertension in a murine hemolysis model

AbstractPulmonary arterial hypertension (PAH) is suspected to be a strong mortality determinant of hemolytic disorders. However, direct contribution of acute intravascular hemolysis to fatal PAH has not been investigated. The roles of nitric oxide (NO) insufficiency and platelet activation in hemolysis-associated fatal PAH have been suspected but not been experimentally studied. We recently generated a unique intravascular hemolysis mouse model in which the membrane toxin, intermedilysin (ILY), exclusively lyses the erythrocytes of transgenically expressing human CD59 mice (ThCD59RBC), thereby inducing ILY-dose–dependent massive hemolysis. Using this murine hemolysis model, we found that the acute increase in pulmonary arterial pressure leading to right ventricle failure caused sudden death. Reduced NO bioavailability and massive platelet activation/aggregation leading to the formation of massive thrombosis specifically in the pulmonary microvasculature played the critical roles in pathogenesis of acute hemolysis-associated fatal PAH. Therapeutic interventions enhancing NO bioactivity or inhibiting platelet activation prevented sudden death or prolonged survival time via the suppression of the acute increase in pulmonary arterial pressure and improvement of right ventricle function. These findings further highlight the importance of the inhibition of platelet activation and the enhancement of NO bioavailability for the treatment and prevention of hemolysis-associated (fatal) PAH.

Long-term incidence of death due to thromboembolic disease among patients with unprovoked pulmonary embolism

To summarize recent studies that have quantified the incidence of death due to late thromboembolic disease among patients initially diagnosed with acute unprovoked pulmonary embolism. These findings will aid clinicians who must weigh the risk versus the benefits of long-term anticoagulant therapy. The incidence of death due to fatal acute recurrent pulmonary embolism following 3-6 months of anticoagulant therapy is approximately 0.2-0.4% per year, depending in part on the presence or absence of chronic comorbidity. In addition, up to 1-3% of all patients with pulmonary embolism are diagnosed with chronic thromboembolic pulmonary hypertension within 3 years of the index event. Patients with acute pulmonary embolism who develop acute pulmonary hypertension greater than 50 mmHg that does not resolve in the first few weeks are at highest risk for progression, particularly if the event is recurrent pulmonary embolism. The incidence of death due to recurrent pulmonary embolism or significantly debilitating or fatal thromboembolic pulmonary hypertension in the first 3 years after anticoagulant treatment is discontinued is approximately 1-3%. In patients in whom the risk of fatal or disabling hemorrhage is lower, the benefits of chronic anticoagulation may outweigh the risks.

Pulmonary hypertension in sarcoidosis, caused by extrinsic compression of major pulmonary vessels

Pulmonary hypertension is an increasingly recognised complication of sarcoidosis that arises from a variety of physiological mechanisms, including pulmonary fibrosis, granulomatous vasculitis, and circulating vasoactive mediators. We present the case of a young man with sarcoidosis complicated by fatal pulmonary hypertension due to extrinsic compression of the major pulmonary vessels by mediastinal granulomatous inflammation and lymphadenopathy.

MRI: One-Stop Shop for the Comprehensive Assessment of Pulmonary Arterial Hypertension?

Pulmonary arterial hypertension (PAH) is a complex disease that affects the right-sided circulation, including the right ventricle (RV) and the pulmonary vasculature. An obliterative remodeling in the vascular wall, characterized by increased cellular proliferation and suppressed apoptosis, 1 Michelakis ED Spatio-temporal diversity of apoptosis within the vascular wall in pulmonary arterial hypertension: heterogeneous BMP signaling may have therapeutic implications. Circ Res. 2006; 98: 172-175 Crossref PubMed Scopus (60) Google Scholar leads to occlusion of pulmonary arteries (PAs), increased RV afterload, RV failure, and premature death. Emerging therapies target the proliferation/apoptosis of vascular cells, rather than vascular tone, that characterized PAH therapeutics during the past 50 years. 2 Zhao YD Courtman DW Deng Y et al. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res. 2005; 96: 442-450 Crossref PubMed Scopus (406) Google Scholar 3 Cowan KN Heilbut A Humpl T et al. Complete reversal of fatal pulmonary hypertension in rats by a serine elastase inhibitor. Nat Med. 2000; 6: 698-702 Crossref PubMed Scopus (326) Google Scholar 4 McMurtry MS Archer SL Altieri DC et al. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest. 2005; 115: 1479-1491 Crossref PubMed Scopus (318) Google Scholar 5 McMurtry MS Bonnet S Wu X et al. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res. 2004; 95: 830-840 Crossref PubMed Scopus (380) Google Scholar Despite the progress in the vascular biology of PAH, there is an impressive relative lack of studies of the RV in both animals and humans. This is despite the recognition that both the morbidity and mortality of PAH patients are largely driven by the function of the RV. 6 Voelkel NF Quaife RA Leinwand LA et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation. 2006; 114: 1883-1891 Crossref PubMed Scopus (969) Google Scholar Traditionally, studies of the heart focus on the systemic circulation and the left ventricle (LV), and effects on the RV are merely extrapolated from the LV. However, there is recent recognition that there are several fundamental differences between the RV and LV, including their responses to increased afterload and their perfusion, among others. 6 Voelkel NF Quaife RA Leinwand LA et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation. 2006; 114: 1883-1891 Crossref PubMed Scopus (969) Google Scholar Intriguingly, the two ventricles have a different embryologic origin. 7 Zaffran S Kelly RG Meilhac SM et al. Right ventricular myocardium derives from the anterior heart field. Circ Res. 2004; 95: 261-268 Crossref PubMed Scopus (297) Google Scholar Accordingly, there is now a call for further research regarding the RV with an RV-specific request for proposal by the National Institutes of Health (NIH) as well as an NIH subcommittee taskforce for the promotion of research and understanding of RV biology. 6 Voelkel NF Quaife RA Leinwand LA et al. Right ventricular function and failure: report of a National Heart, Lung, and Blood Institute working group on cellular and molecular mechanisms of right heart failure. Circulation. 2006; 114: 1883-1891 Crossref PubMed Scopus (969) Google Scholar