The health effects of exposure to household air pollution are gaining international attention. While the bulk of the known mortality estimates due to these exposures are derived from respiratory conditions, there is growing evidence of adverse cardiovascular health effects. Pulmonary hypertension and right heart failure are common conditions in low- and middle-income countries whose etiology may be related to common exposures in these regions such as schistosomiasis, human immunodeficiency virus, tuberculosis infections and other causes. While little is known of the interplay between exposure to household air pollution, right heart function and such conditions, the large burden of pulmonary hypertension and right heart failure in regions where there is significant exposure to household air pollution raises the possibility of a linkage. This review is presented in three parts. First, we explore what is known about pulmonary hypertension and right heart failure in low- and middle-income countries by focusing on eight common causes thereof. We then review what is known of the impact of household air pollution on pulmonary hypertension and posit that when individuals with one of these eight common comorbidities are exposed to household air pollution they may be predisposed to develop pulmonary hypertension or right heart failure. Lastly, we posit that there may be a direct link between exposure to household air pollution and right heart failure independent of pre-existing conditions which merits further investigation. Our overall aim is to highlight the multifactorial nature of these complex relationships and offer avenues for research in this expanding field of study.

Adults with chronic medical conditions are more likely to report unmet health care needs. Whether unmet health care needs are associated with an increased risk of adverse health outcomes is unclear.Adults with at least one self-reported chronic condition (arthritis, chronic obstructive pulmonary disease, diabetes mellitus, heart disease, hypertension, mood disorder, stroke) from the 2001 and 2003 cycles of the Canadian Community Health Survey were linked to national hospitalization data. Participants were followed from the date of their survey until March 31, 2005, for the primary outcomes of all-cause and cause-specific admission to hospital. Secondary outcomes included length of stay, 30-day and 1-year all-cause readmission to hospital, and in-hospital death. Negative binomial regression models were used to estimate the association between unmet health care needs, admission to hospital, and length of stay, with adjustment for socio-demographic variables, health behaviours, and health status. Logistic regression was used to estimate the association between unmet needs, readmission, and in-hospital death. Further analyses were conducted by type of unmet need.Of the 51 932 adults with self-reported chronic disease, 15.5% reported an unmet health care need. Participants with unmet health care needs had a risk of all-cause admission to hospital similar to that of patients with no unmet needs (adjusted rate ratio [RR] 1.04, 95% confidence interval [CI] 0.94-1.15). When stratified by type of need, participants who reported issues of limited resource availability had a slightly higher risk of hospital admission (RR 1.18, 95% CI 1.09-1.28). There was no association between unmet needs and length of stay, readmission, or in-hospital death.Overall, unmet health care needs were not associated with an increased risk of admission to hospital among those with chronic conditions. However, certain types of unmet needs may be associated with higher or lower risk. Whether unmet needs are associated with other measures of resource use remains to be determined.

OBJECTIVE:

Earlier detection of pulmonary arterial hypertension (PAH), a leading cause of death in systemic sclerosis (SSc), facilitates earlier treatment. The objective of this study was to develop the first evidence-based detection algorithm for PAH in SSc.

METHODS:

In this cross-sectional, international study conducted in 62 experienced centres from North America, Europe and Asia, adults with SSc at increased risk of PAH (SSc for >3 years and predicted pulmonary diffusing capacity for carbon monoxide <60%) underwent a broad panel of non-invasive assessments followed by diagnostic right heart catheterisation (RHC). Univariable and multivariable analyses selected the best discriminatory variables for identifying PAH. After assessment for clinical plausibility and feasibility, these were incorporated into a two-step, internally validated detection algorithm. Nomograms for clinical practice use were developed.

RESULTS:

Of 466 SSc patients at increased risk of PAH, 87 (19%) had RHC-confirmed PAH. PAH was mild (64% in WHO functional class I/II). Six simple assessments in Step 1 of the algorithm determined referral to echocardiography. In Step 2, the Step 1 prediction score and two echocardiographic variables determined referral to RHC. The DETECT algorithm recommended RHC in 62% of patients (referral rate) and missed 4% of PAH patients (false negatives). By comparison, applying European Society of Cardiology/European Respiratory Society guidelines to these patients, 29% of diagnoses were missed while requiring an RHC referral rate of 40%.

CONCLUSIONS:

The novel, evidence-based DETECT algorithm for PAH detection in SSc is a sensitive, non-invasive tool which minimises missed diagnoses, identifies milder disease and addresses resource usage.

Hypoxic pulmonary hypertension (HPH) is characterized by pulmonary vasoconstriction and vascular remodeling, which are mediated by pulmonary artery smooth muscle cell (PASMC) contraction and proliferation, respectively. An increase in cytosolic Ca(2+) concentration [Ca(2+)]cyt is a major trigger for pulmonary vasoconstriction and an important stimulus for PASMC proliferation. Ca(2+) influx, through voltage-dependent Ca(2+) channels (VDCC), is an important pathway for the regulation of [Ca(2+)]cyt. The potential role for L- and T-type VDCC in HPH is still unclear. Using a HPH mouse model, we undertook this study to identify if VDCC in pulmonary artery (PA) are functionally upregulated, and determine which type of VDCC are altered in HPH. Mice subjected to chronic hypoxia developed pulmonary hypertension within 4 weeks, and high K(+)- and U-46619-induced contraction of PA was greater in chronic hypoxic mice than that in normoxic control mice. Additionally, we demonstrate that high K(+)- and U-46619-induced Ca(2+) influx in PASMC is significantly increased in the hypoxic group. The VDCC activator, Bay K8864, induced greater contraction of the PA of hypoxic mice than in that of normoxic mice in isometric force measurements. L-type and T-type VDCC blockers significantly attenuated absolute contraction of the PA in hypoxic mice. Chronic hypoxia did not increase high K(+)- and U-46619-induced contraction of mesenteric artery. Compared with MA, PA displayed higher expression of Cav1.2 and Cav3.2 upon exposure to chronic hypoxia. In conclusion, both L-type and T-type VDCC were functionally upregulated in PA, but not MA, in HPH mice, which could result from selectively increased expression of Cav1.2 and Cav3.2.

Chronic hypoxia is one of the main causes of pulmonary hypertension (PH) associated with reactive oxygen species (ROS) production. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is known to be an endothelial receptor of oxidized low-density lipoprotein (oxLDL), which is assumed to play a role in the initiation of ROS generation. We investigated the role of LOX-1 and ROS generation in pulmonary hypertension and vascular remodeling in LOX-1 transgenic (Tg) mice. We maintained 8- to 10-week-old male LOX-1 Tg mice and wild-type (WT) mice in normoxic (room air) or hypoxic (10% O2 chambers) for 3 weeks. The right ventricular systolic pressure (RVSP) was comparable between the 2 groups under normoxic condition; however, chronic hypoxia significantly increased the RVSP and right ventricular hypertrophy in LOX-1 Tg mice as compared to that in WT mice. The medial wall thickness of the pulmonary arteries was significantly greater in LOX-1 Tg mice than in WT mice. Further, hypoxia enhanced ROS production and nitrotyrosine expression in LOX-1 Tg mice, supporting the observed pathological changes. Administration of the NADPH oxidase inhibitor apocynin caused a significant reduction in the PH and vascular remodeling in LOX-1 Tg mice. Our results suggest that LOX-1-ROS generation induces development and progression of PH.

This study analysed the relationship between pulmonary vascular resistance (PVR) and compliance (Ca) in patients with idiopathic pulmonary arterial hypertension (IPAH) and proximal chronic thromboembolic pulmonary hypertension (CTEPH). It has recently been shown that the time constant of the pulmonary circulation (RC-time), or PVR x Ca, remains unaltered in various forms and severities of PH, with the exception of left heart failure. We reasoned that increased wave reflection in proximal CTEPH would be another cause of decreased RC-time. We conducted a retrospective analysis of invasive pulmonary hemodynamic measurements in IPAH (n=78), proximal CTEPH (n=91) before and after pulmonary endarterectomy (PEA) and distal CTEPH (n=53). Proximal CTEPH was defined by a postoperative mean pulmonary artery pressure (mPAP) ≤ 25 mmHg. Outcome measures were the RC-time, PVR, Ca and the relationship between systolic and mean pulmonary artery pressures. The RC time for Pre-PEA CTEPH was 0.49 ± 0.11s compared with Post PEA-CTEPH 0.37 ± 0.11s (p<0.0001), IPAH 0.63 ± 0.14s (p<0.001) and Distal CTEPH 0.55 ± 0.12s (p<0.05). A shorter RC-time was associated with a disproportionate decrease in systolic PAP with respect to mPAP. We concluded that the pulmonary RC-time is decreased in proximal CTEPH compared to IPAH, before and after PEA, which may be explained by increased wave reflection but also importantly by persistent structural changes after removal of proximal obstructions. A reduced RC-time in CTEPH is in accord with a wider pulse pressure and hence greater RV work for a given mean PA pressure.

Mixed connective tissue disease (MCTD) is rare in pediatric rheumatic diseases. Pulmonary arterial hypertension (PAH) associated with MCTD usually progresses gradually and is difficult to note at the asymptomatic phase. We report a 11-year-old girl with MCTD complicated with rapidly progressive PAH. Although PAH was not detected by echocardiogram or chest CT scan at the initial examination, it became clear in 1 year and suddenly came to cardiac arrest during an invasive procedure. She was successfully treated with extracorporeal assist and both vasodilative and immunosuppressive medication. A combination of echocardiogram and plasma BNP levels could be a useful marker for the follow-up of such cases. PAH could develop early in the course of pediatric MCTD and needs attention to unexpected acute exacerbation, especially under emotional stress.

Background:

 To investigate the possible role of sex hormones in the pathogenesis of pulmonary arterial hypertension (PAH), the effect of β-estradiol (E2) on bone morphogenetic protein (BMP) signaling, a key signaling pathway involved in PAH, was studied in human pulmonary arterial endothelial cells (HPAEC).

Methods and Results:

 BMP signaling molecules, including BMP receptor, Smad1/5/8 and Id1, were studied in HPAEC under 1% O2 (hypoxia) and 21% O2 (normoxia) as well as the effect of hypoxia-inducible factor (HIF)-1α expression in the presence of E2 on BMP signaling. The effects of an estrogen receptor (ER) antagonist (ICI 182,780) and cycloheximide, and the interaction of ER with Smad or HIF-1α were also studied. In the presence of E2, BMP signaling was augmented under normoxia but suppressed under hypoxia. HIF-1α accumulation suppressed BMP signaling, whereas HIF-1α inhibition augmented signaling. These effects were cancelled by ICI 182,780. Moreover, binding between ER, HIF-1α and phosphorylated (p)-Smad1/5/8 proteins occurred only under hypoxia. On inhibition of de novo synthesis with cycloheximide, however, p-Smad1/5/8 expression was suppressed only under normoxia.

Conclusions:

 The effects of E2 on BMP signaling in HPAEC altered depending on O2 concentration and different mechanisms may be involved. BMP and sex hormones may play an important role in PAH development.

The ligand-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), regulates metabolism, cell proliferation, and inflammation. Pulmonary hypertension (PH) is associated with reduced PPARγ expression, and hypoxia exposure regimens that cause PH reduce PPARγ expression. The current study examines mechanisms of hypoxia-induced PPARγ downregulation in vitro and in vivo. Hypoxia reduced PPARγ mRNA and protein levels, PPARγ activity, and the expression of PPARγ-regulated genes in human pulmonary artery smooth muscle cells (HPASMC) exposed to 1% oxygen for 72hours. Similarly, exposure of mice to hypoxia (10% O2) for 3 weeks reduced PPARγ mRNA and protein in mouse lung. Inhibiting ERK1/2 with PD98059 or treatment with siRNA directed against either NF-κB p65 or Nox4 attenuated hypoxic reductions in PPARγ expression and activity. Furthermore, degradation of H2O2 using PEG-catalase prevented hypoxia-induced ERK 1/2 phosphorylation and Nox4 expression suggesting sustained ERK 1/2-mediated signaling and Nox4 expression in this response. Mammalian two hybrid assays demonstrated that PPARγ and p65 bind directly to each other in a mutually repressive fashion. Taken together, we conclude that hypoxic regimens that promote PH pathogenesis and HPASMC proliferation reduce PPARγ expression and activity through ERK1/2-, p65-, and Nox4-dependent pathways. These findings provide novel insights into mechanisms by which pathophysiological stimuli such as hypoxia cause loss of PPARγ activity and pulmonary vascular cell proliferation, pulmonary vascular remodeling, and PH. These results also indicate that restoration of PPARγ activity with pharmacological ligands may provide a novel therapeutic approach in selected forms of PH.

Over the last decennium, myocardial structure, cardiomyocyte function and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) A high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease and salt sensitive hypertension induce a systemic proinflammatory state; 2) A systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) Coronary microvascular endothelial inflammation reduces nitric oxide (NO) bioavailability, cyclic guanosine monophosphate (cGMP) content and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) Low PKG activity favours hypertrophy development and raises resting tension because of hypophosphorylation of titin; 5) Both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and HF development. The new HFPEF paradigm shifts emphasis from left ventricular (LV) afterload excess to coronary microvascular inflammation. This shift is supported by a favourable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction (HFREF), where remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation or vascular hyperaemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity with NO-donors, phosphodiesterase 5 inhibitors and statins.