HIV-related Pulmonary Hypertension Research Articles

The Differentiation of Etiologies of Pulmonary Arterial Hypertension amongst Males and Females

There are limited studies which have studied the etiological differentiation of pulmonary arterial hypertension in large patient sample. To understand the association pattern of etiologies of pulmonary arterial hypertension. The National Inpatient Sample (NIS) was used to identify all patients 18 years and older hospitalized in 2016 with primary or secondary diagnosis of pulmonary arterial hypertension (PAH) by ICD-10 code I270. We then sought to differentiate etiologies of PAH among males and females. We looked for difference in relative risk profile, geographical distribution and outcomes including length of stay (LOS), mortality, Elixhauser mortality score and readmission score. Categorical variables were assessed with Chi square testing and continuous variables with two sample t-tests. Analyses were conducted using SAS v 9.4. A total of 10,300 patients with primary or secondary diagnosis of pulmonary arterial hypertension were identified, of which 31% were males and 69% females. This distribution was observed across the US (Figure 1A). In terms of prevalence, men were primarily in the Mountain states, whereas women were primarily in the Pacific states (Figure 1B/C). Males were more likely to have HIV related pulmonary hypertension (0.78% vs 0.14%, p=0.0208), whereas females were more likely to have scleroderma related pulmonary hypertension (1.1% vs 4.08%, p=0.0003). Males were likely to have atrial fibrillation (37.25% vs 32.29%, p=0.0316), coronary artery disease (43.51% vs 27.25%, p < 0.0001), smoking (35.68% vs 25.85%, p < 0.0001), and sleep apnea (26.29% vs 21.55%, p=0.0181), relative to females. There were no significant differences in relation to LOS, total hospital charges, mortality or readmission. Pulmonary arterial hypertension in males was more likely to be associated with HIV, coronary artery disease, atrial fibrillation, sleep apnea and smoking whereas among females, it was more likely to be associated with scleroderma.

Drug abuse and HIV-related pulmonary hypertension

: Improved survival among HIV-1-infected individuals with the advent of antiretroviral therapy has clearly led to a greater prevalence of noninfectious complications. One of the most devastating sequelae in these individuals is the development of pulmonary arterial hypertension (PAH). Various epidemiological studies suggest worse survival of HIV-PAH patients when compared with other forms of PAH. Given that only a subset and not all HIV-infected individuals develop HIV-PAH, it is suggested that an additional second-hit of genetic or environmental trigger is needed for the development of PAH. In this context, it has been well documented that HIV patients who abuse illicit drugs such as stimulants, opioids, and the like, are more susceptible to develop PAH. In this review, we highlight the studies that support the significance of a double hit of HIV and drug abuse in the incidence of PAH and focus on the research that has been undertaken to unravel the pathobiology and vascular remodeling mechanisms underlying the deleterious synergy between HIV infection and drugs of abuse in orchestrating the development of PAH.

Abstract 17190: Dual Hit of HIV-1 and Opioids Promote Oxidative Stress Mediated Pulmonary Endothelial Dysfunction

Introduction: HIV related pulmonary hypertension is one of the serious non-infectious cardiovascular complications in HIV infected individuals, especially among intravenous drug users. We previously demonstrated that opioids in combination with viral protein(s) result in reactive oxygen species (ROS) mediated induction of autophagy in pulmonary endothelial cells leading to shift in the cells from apoptosis to apoptosis resistant proliferative status associated with angio-proliferative remodeling observed in PAH. Here, we delineate the major sources of HIV-1 and morphine induced oxidative burst and its role in development of PAH using in-vivo model. Methods: Human pulmonary microvascular endothelial cells (HPMECs) were treated with morphine and HIV-Tat in the presence or absence of ROS scavengers followed by measurement of ROS. Mitochondrial specific superoxide radicals were measured with MitoSOX dye and ratio of mitochondrial DNA to nuclear DNA was determined by real-time PCR. To assess the in-vivo effect of HIV-1 and morphine on pulmonary vascular dysfunction, male HIV-Tg/WT Fischer rats (n=7-13per group) were subcutaneously administered 10 mg/kg body wt. morphine or saline daily IP for 21 days. Right ventricle systolic pressure (RVSP) and fulton Index were measured along with immunohistochemistry analysis of lungs. Result: Increased oxidative stress in HPMECs in response to combined treatment of morphine and tat (M+T) was noted to be contributed by mitochondria, NADPH oxidase and xanthine oxidase as observed by the decrease in ROS production of M+T treated cells on pre-treatment with ROS scavenger viz., Mitotempo (mitochondria), VAS3947 (NADPH oxidase) and allopurinol (Xanthine oxidase). However, M+T mediated early apoptosis and late hyperproliferation of HPMECs was prevented in presence of NADPH oxidase inhibitor. In parallel we observed elevated mitochondrial specific ROS at 2 hr and increased mitophagy at 3h followed by increase in total mitochondrial mass at 4-6h of MT treatment. Further, we observed significant increase in RVSP and RV hypertrophy in HIV-Tg rats exposed to morphine compared to WT rats. Immunohistochemical analysis also showed significant pulmonary vascular remodelling including endothelial proliferation in lung sections from HIV+morphine rats. Conclusion: Our findings suggest NADPH oxidase specific ROS role in autophagy-dependent increased proliferation of M+T treated HPMECs. Further our in-vivo findings provide evidence of potentiation of PAH development with the dual hit HIV-1 and opioids.

Response to a Dolutegravir-based Regimen in an HIV-Infected Woman with Multiple Comorbidities and a Highly Resistant Strain

HIV-infected patients have a higher burden of comorbidities than the general population and drug-drug interactions limit the choice of antiretroviral compounds, also limiting the possibility of drug sequencing in case of toxicity or failure. In our patient, affected by HIV-related pulmonary hypertension (HIV-PAH), the use of sildenafil and ambrisentan excluded the possibility of using two of the main classes of antiretrovirals, protease inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Having failed a combination regimen based on raltegravir, while awaiting the results of genotypic testing for drug resistance she was switched to dolutegravir, a brand new integrase strand transfer inhibitor (INSTI) with high genetic barrier, and in one month her HIV-1 viremia dramatically dropped to undetectable levels. The genotypic test revealed resistance to all the drugs she was taking including dolutegravir. The backbone was changed to a dual regimen including rilpivirine and viral suppression was maintained at three months. Unprecedented pharmacokinetic data are provided for the two antiviral drugs in combination with sildenafil and ambrisentan.

Bosentan and Sildenafil in the Treatment of HIV-Associated Pulmonary Hypertension

We present the case of an HIV/HCV-coinfected patient with HIV-related pulmonary hypertension (HRPH) who experienced a good clinical and functional response to bosentan, with a subsequent switch to oral sildenafil due to increased transaminase levels. Bosentan resulted less handy in this case, probably due to both side effects and co-morbidities.

The World of Pulmonary Vascular Disease

The world of pulmonary vascular disease (PVD) is lopsided in this sense: those nations that have the highest numbers of PVD researchers have the lowest number of PVD patients. We ran a PubMed search for PVD researchers and found that, of all the authors of published articles on PVD, 90.3% were from the United States, Canada, the United Kingdom, France, Germany and Japan, while those from all the rest of the world totaled only 9.7% (Fig. 1). Meanwhile, schistosomiasis is very rare in North America, but is the most common cause of pulmonary hypertension worldwide.[1] In addition, the burden of HIV-related pulmonary hypertension is likely to be far greater in Africa.[2] The global distribution of researchers studying pulmonary vascular disease. (a) Intensity map depicting the number of researchers in different countries represented by relative color intensity. (b) The number of papers published on pulmonary vascular disease each year since 1990. (c) The regional distribution of researchers. The data were compiled from a PubMed-wide search by Abigail Drennan and Amy Zeifman in the University of Illinois at Chicago. The world's 193 nations protect their borders, and the movement of people between nations is carefully controlled. But diseases ignore borders and nationalities, and “view” the world in their own terms. Idiopathic pulmonary hypertension (IPAH), for example, ignores nationality and focuses on gender, predominantly affecting young women. Happily, knowledge is just like disease in that sense, that it ignores national boundaries, makes a graveyard of ignorance, and improves public health. Global distribution of researchers studying pulmonary vascular disease Perhaps the most basic lesson from the whole history of Medicine is that diseases thrive in a “climate” of ignorance, and are defeated by knowledge. Yellow fever decimated the world until Cuban doctor Carlos Finlay proposed, in 1881, that its vector was the female of the mosquito species Aedes aegypti, which American doctor Walter Reed confirmed in 1900. Likewise, pulmonary vascular disease is flourishing today in some parts of the world (and indeed in some parts of the so-called “developed” world) in part because of the ignorance that still surrounds it. But, again happily, that ignorance is being reduced by what can be called “the Voice of the World of PVD.” This journal, Pulmonary Circulation, was the first-ever peer-reviewed journal dedicated to PVD, and at present it remains the only journal devoted to the field of pulmonary circulation publishing original research articles, review articles, case reports and perspectives in PVD. But we are only part of “the Voice,” which is also being expressed around the world in various ways, notably at the annual meetings of professional associations. For example, just in 2011 so far, there have been PVD conferences in Panama and in Dubai, as well as two in China and two in India, all hosted by the Pulmonary Vascular Research Institute, the PVRI, publisher of Pulmonary Circulation-over and above important meetings that have been held throughout North America and Europe.[3] Meanwhile, educational efforts for the general public are also a critical part of the Voice of PVD, notably those being undertaken by the Pulmonary Hypertension Association, whose former board member, Gail Boyer Hayes, recently wrote, “If a village is required to raise a child, surely the whole world is needed to cure PH.”[4] Pulmonary Circulation is therefore not merely a repository of research findings. In sharing important knowledge among the world's physicians, physician scientists, investigators, and even patients–both in print and online–this journal is slowly but surely helping to reduce the ignorance that PVD needs in order to keep killing people. As its editors, we keep “the big picture” firmly in mind. The goal is not merely to produce a medical periodical. The goal is to empower our profession by facilitating the information exchange that will lead to new therapies, new strategies, and ultimately even cures. Our goal is not merely a world-class publication, but nothing less than a world without PVD. When vascular and cardiopulmonary diseases no longer exist, this journal will have achieved its purpose. Until that day, we welcome the addition of your voice to ours, through your submission of manuscripts describing your best work, which will then help the work of others throughout the lopsided World of PVD.

Improvement of HIV-related pulmonary hypertension after the introduction of an antiretroviral therapy

To the Editors: The potential impact of combination antiretroviral therapy (CART) on HIV-related pulmonary arterial hypertension (PAH) remains controversial 1–4. We herein report the case of a dramatic improvement in PAH at the time of the inception of CART in a 19-yr-old female with HIV-1 infection due to mother-to-child transmission. HIV-related PAH was diagnosed in January 2006, when she was stable in stage A2 of the US Centers for Disease Control and Prevention classification without any antiretroviral therapy (table 1⇓). Specific PAH therapy with bosentan was started in January 2006, in combination with oral anticoagulant and diuretic therapy. CART was indicated at that time, but not prescribed owing to patient …

Pulmonary arterial hypertension in HIV-infected patients

In recent years, much more insight is given to the pathogenic role of HIV and to the clinical manifestations of HIV-related pulmonary hypertension (HRPH), that currently represents one of the most severe events during the HIV disease. HRPH occurs in early and late stages of HIV infection and does not seem to be related to the degree of immune deficiency. Many of the symptoms in HRPH result from right ventricular dysfunction: the first clinical manifestation is effort intolerance and exertional dyspnoea that will progress to the point of breathlessness at rest. Echocardiography has been proved to be an extremely useful tool for the diagnosis of HRPH, and Doppler echocardiography may be used to estimate systolic pulmonary artery pressure, and to monitor the effects of therapy. Assessment of hemodynamic measures by catheterization remains, however, the best test for evaluating the response to therapy. Cardiac catheterization is mandatory to characterize the disease and exclude an underlying cardiac shunt as etiology. Vasodilators have been extensively used in the treatment of pulmonary hypertension, since vasoconstriction is a determinant characteristic of this disease. More recently, more effective therapies for pulmonary arterial hypertension have been available, including prostanoids, endothelin-receptor antagonists, and phosphodiesterase-5 inhibitors, allowing an amelioration of symptoms and a better prognosis. However, HRPH remains a progressive disease for which treatment is often unsatisfactory and there is no cure. As new efficient antiretroviral treatment will be introduced, clinicians should expect to encounter an increasing number of cases of pulmonary hypertension in HIV-infected patients in the future.

Effects of HIV‐1 on Endothelial Gene Expression

Recent data suggest that HIV‐infected persons are at a heightened risk of developing non‐infectious lung disorders. HIV‐related pulmonary hypertension (HIV‐PH), a disorder characterized by increased pulmonary vessel tone and vascular remodeling, is one such example. HIV‐PH is estimated to occur 2500 times more frequently than primary PH in the general population. HIV‐PH is also found to progress more rapidly than primary PH with no association between CD4+ count and disease severity. These observations suggest a correlation between HIV infection and HIV‐PH unrelated to immune dysfunction. However, the cause of HIV‐PH is unknown. We hypothesize that HIV infection plays a critical role in HIV‐PH development by upregulating genes that modulate vasoconstriction and remodeling. To test this hypothesis, we employed co‐cultures of human pulmonary artery endothelial cells (HPAEC) and/or PBMC, either alone or exposed to HIV‐1. Gene array results showed a marked upregulation in the gelatinase, matrix metalloproteinase‐2 (MMP2) in the HPAEC, PBMC and HIV‐1 group as compared to other groups. RT‐PCR confirmed these results and also showed increased expression of angiotensinogen and angiotensin converting enzyme, precursors of the potent vasoconstrictor, angiotensin II. Altogether, our data suggest that HIV‐1‐induced gene alterations may contribute to the increased risk of HIV‐1 patients to develop PH.

127 Gender differences in HIV-related pulmonary hypertension - results from the HIV-HEART Study

127 Gender differences in HIV-related pulmonary hypertension - results from the HIV-HEART Study

1154 Sildenafil: a therapeutical option of HIV-related pulmonary hypertension

1154 Sildenafil: a therapeutical option of HIV-related pulmonary hypertension

Occult lymphadenopathic Kaposi's sarcoma associated with severe pulmonary hypertension: A clinical hint about the potential role of HHV-8 in HIV-related pulmonary hypertension?

Severe pulmonary hypertension (PH) mimicking idiopathic PH is an increasingly recognized complication of human immunodeficiency virus (HIV) infection. PH shares several histopathologic features with Kaposi's sarcoma (KS), the most common malignancy in AIDS patients, and molecular evidence of the vasculotropic Kaposi's sarcoma-associated herpesvirus or human herpesvirus 8 (HHV-8) has been found in the lung tissue of patients with the disease. Although the prevalence of HHV-8 infection is increased among HIV-infected patients, no clinical association between KS and PH has ever been reported. Herein, we described a 30-year-old HIV-infected female co-infected with HHV-8 who developed severe PH coincident with occult KS. The clinical presentation of KS was unusual and remained masqueraded for years as an indolent cervical lymphadenopathy, without the typical cutaneous lesions. This is the first ever-reported case of PH associated with KS. Although the co-occurrence of both diseases in this patient could have been just a coincidence, the observation may also indicate that a relationship between HHV-8 infection and HIV-associated PH exists. Coinfection with HHV-8 and occult lymphadenopatic KS should be considered in HIV-infected patients developing PH.

HIV-1 Nef Is Associated with Complex Pulmonary Vascular Lesions in SHIV-nef–infected Macaques

HIV-infected patients with pulmonary arterial hypertension have histologic manifestations that are indistinguishable from those found in patients with idiopathic pulmonary arterial hypertension. In addition, the role of pleiotropic viral proteins in the development of plexiform lesions in HIV-related pulmonary hypertension (HRPH) has not been explored. Simian immunodeficiency virus (SIV) infection of macaques has been found to closely recapitulate many of the characteristic features of HIV infection, and thus hallmarks of pulmonary arterial hypertension should also be found in this nonhuman primate model of HIV. To determine whether pulmonary arterial lesions were present in archived SIV-infected macaque lung tissues from Johns Hopkins University and two National Primate Research Centers. Archived macaque and human lung sections were examined via immunohistochemistry for evidence of complex vascular lesions. Complex plexiform-like lesions characterized by lumenal obliteration, intimal disruption, medial hypertrophy, thrombosis, and recanalized lumena were found exclusively in animals infected with SHIV-nef (a chimeric viral construct containing the HIV nef gene in an SIV backbone), but not in animals infected with SIV. The mass of cells in the lesions were factor VIII positive, and contained cells positive for muscle-specific and smooth muscle actins. Lung mononuclear cells were positive for HIV Nef, suggesting viral replication. Endothelial cells in both the SHIV-nef macaques and patients with HRPH, but not in patients with idiopathic pulmonary arterial hypertension, were also Nef positive. The discovery of complex vascular lesions in SHIV-nef- but not SIV-infected animals, and the presence of Nef in the vascular cells of patients with HRPH, suggest that Nef plays a key role in the development of severe pulmonary arterial disease.

Long-term survival and interruption of HAART in HIV-related pulmonary hypertension

Reported here is a case of a patient with pulmonary arterial hypertension related to HIV (PAHRH) in which lipodystrophy necessitated interruption of highly active antiretroviral therapy (HAART) and long-term survival was the outcome. Although previous studies have suggested antiretroviral therapy may benefit patients with this rare complication of HIV infection, no worsening of PAHRH was observed when HAART was interrupted. Clinical and echocardiographic parameters remained stable during 7 months of follow up. In cases in which HAART is associated with relevant toxicity, interruption of HAART in patients with PAHRH can be considered, but should be used only if no alternatives are available. Close follow-up is warranted.

HIV-related pulmonary hypertension. From pathogenesis to clinical aspects

HIV-related pulmonary hypertension (HIV-PH) is a cardiovascular complication of HIV infection that has been recognized in the last years with increasing frequency. HIV-related pulmonary hypertension is a clinical disorder which carries a bad prognosis. While a direct HIV infection of the pulmonary vessels in the pathogenesis of this disorder was not demonstrated, currently a multifactorial pathogenesis of this disease could be hypothesized. Echocardiography has been found to be the most useful screening imaging modality for the diagnosis of HIV-PH, with a high predictive negative value and a low positive predictive value. For this reason Doppler echocardiography is not the gold standard in the diagnosis of HIV-PH.The treatment of HIV-PH is complex and controversial. To date, no study determining the agent of choice for the treatment of this disease exists. Different studies have shown variable results in patiens with HIV-PH treated with highly active antiretroviral therapy (HAART) but only HAART seems not to be effective in lowering pulmonary hypertension in these patients, and in some patients, HIV-PH develops in spite of a previous HAART. It seems reasonable in HIV-PH patients that a treatment with oral vasodilator drugs can improve the adherence of a long-lasting and complex antiretroviral therapy.

Inhaled iloprost proved to be a potent acute pulmonary vasodilator in eight patients with HIV-related severe pulmonary hypertension,

Inhaled iloprost proved to be a potent acute pulmonary vasodilator in eight patients with HIV-related severe pulmonary hypertension,

Clinical manifestation of HIV-related pulmonary hypertension.

In recent years, much more thought has been given to the pathogenic role of HIV and to the clinical manifestations of HIV-related pulmonary hypertension (HRPH), which currently represents one of the most severe events during HIV disease. HRPH occurs in early and late stages of HIV infection and does not seem to be related to the degree of immune deficiency. Many of the symptoms in HRPH result from right ventricular dysfunction: the first clinical manifestation is effort intolerance and exertional dyspnea that will progress to the point of breathlessness at rest. The diagnosis of HRPH can be made only after all etiologies for pulmonary hypertension have been excluded. Echocardiography has been proven to be an extremely useful tool for diagnosing HRPH, and Doppler echocardiography can be used to estimate systolic pulmonary artery pressure and to monitor the effects of therapy. Assessment of hemodynamic measures by catheterization remains, however, the best test for evaluating response to therapy. Cardiac catheterization is mandatory to characterize the disease and exclude an underlying cardiac shunt as etiology. Vasodilators have been extensively used in the treatment of pulmonary hypertension, since vasoconstriction is a determinant characteristic of this disease. However, HRPH remains a progressive disease for which treatment is often unsatisfactory and there is no cure. As new, more efficient antiretroviral treatment are introduced, clinicians should expect to encounter an increasing number of cases of pulmonary hypertension in HIV+ patients in the future.

Primary Pulmonary Hypertension

Primary pulmonary hypertension (PPH), also referred to as unexplained or idiopathic, is a disease or constellation of diseases described at both clinical and pathologic levels. However, neither the clinical syndrome nor the pathologic changes independently define the population with this disease. The vast majority of patients with clinical PPH has a pulmonary arteriopathy, although a few patients will have pathologic evidence of other diseases or even normal lung vessels.1–4 Pulmonary arteriopathy is not pathognomonic for PPH, because similar changes are also characteristic of patients with congenital heart disease, pulmonary hypertension associated with portal hypertension, toxin-induced pulmonary hypertension, and HIV-related pulmonary hypertension.

Marked Pulmonary Function Abnormalities in a Case of HIV-Associated Pulmonary Hypertension

Recent reports have suggested an association between primary pulmonary hypertension and human immunodeficiency virus (HIV) infection. This appears to be an accelerated syndrome, associated with a relatively brief duration of symptoms, yet prominent right ventricular failure and severe pulmonary hypertension on presentation. We present a case of a primary pulmonary hypertension in a 35-year-old HIV-seropositive hemophiliac. His accelerated clinical course is consistent with previously reported cases of HIV-related pulmonary hypertension. However, this patient's pulmonary function tests revealed marked hyperinflation, a decreased diffusing capacity, and no airflow obstruction. To our knowledge, this very usual constellation of pulmonary function changes has not been described previously in this syndrome.