Overview of Methamphetamine-Associated Pulmonary Arterial Hypertension.

TOPIC IMPORTANCE: The global surge in methamphetamine use is a critical public health concern, particularly due to its robust correlation with methamphetamine-associated pulmonary arterial hypertension (MA-PAH). This association raises urgent alarms about the potential escalation of MA-PAH incidence, posing a significant and imminent challenge to global public health. REVIEW FINDINGS: This comprehensive review meticulously explores MA-PAH, offering insights into its epidemiology, pathophysiology, clinical presentation, diagnostic intricacies, and management strategies. The pathogenesis, yet to be fully described, involves complex molecular interactions, including alterations in serotonin signaling, reduced activity of carboxylesterase 1, oxidative stress, and dysregulation of pulmonary vasoconstrictors and vasodilators. These processes culminate in the structural remodeling of the pulmonary vasculature, resulting in pulmonary arterial hypertension. MA-PAH exhibits a more severe clinical profile in functional class and hemodynamics compared with idiopathic pulmonary arterial hypertension. Management involves a multifaceted approach, integrating pulmonary vasodilators, cessation of methamphetamine use, and implementing social and rehabilitation programs. These measures aim to enhance patient outcomes and detect potential relapses for timely intervention. SUMMARY: This review consolidates our understanding of MA-PAH, pinpointing knowledge gaps for future studies. Addressing these gaps is crucial for advancing diagnostic accuracy, unraveling mechanisms, and optimizing treatment for MA-PAH, thereby addressing the evolving landscape of this complex health concern.

Eosinophil and T cell markers predict functional decline in COPD patients.

BACKGROUND: The major marker utilized to monitor COPD patients is forced expiratory volume in one second (FEV1). However, a single measurement of FEV1 cannot reliably predict subsequent decline. Recent studies indicate that T lymphocytes and eosinophils are important determinants of disease stability in COPD. We therefore measured cytokine levels in the lung lavage fluid and plasma of COPD patients in order to determine if the levels of T cell or eosinophil related cytokines were predictive of the future course of the disease. METHODS: Baseline lung lavage and plasma samples were collected from COPD subjects with moderately severe airway obstruction and emphysematous changes on chest CT. The study participants were former smokers who had not had a disease exacerbation within the past six months or used steroids within the past two months. Those subjects who demonstrated stable disease over the following six months (DeltaFEV1 % predicted = 4.7 +/- 7.2; N = 34) were retrospectively compared with study participants who experienced a rapid decline in lung function (DeltaFEV1 % predicted = -16.0 +/- 6.0; N = 16) during the same time period and with normal controls (N = 11). Plasma and lung lavage cytokines were measured from clinical samples using the Luminex multiplex kit which enabled the simultaneous measurement of several T cell and eosinophil related cytokines. RESULTS AND DISCUSSION: Stable COPD participants had significantly higher plasma IL-2 levels compared to participants with rapidly progressive COPD (p = 0.04). In contrast, plasma eotaxin-1 levels were significantly lower in stable COPD subjects compared to normal controls (p < 0.03). In addition, lung lavage eotaxin-1 levels were significantly higher in rapidly progressive COPD participants compared to both normal controls (p < 0.02) and stable COPD participants (p < 0.05). CONCLUSION: These findings indicate that IL-2 and eotaxin-1 levels may be important markers of disease stability in advanced emphysema patients. Prospective studies will need to confirm whether measuring IL-2 or eotaxin-1 can identify patients at risk for rapid disease progression.

A genome-wide association study of pulmonary function measures in the Framingham Heart Study.

The ratio of forced expiratory volume in one second to forced vital capacity (FEV(1)/FVC) is a measure used to diagnose airflow obstruction and is highly heritable. We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated with the FEV(1)/FVC ratio, analyzed as a percent of the predicted value. Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction. Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV(1)/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09). One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham) was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV(1)/FVC (p-value = 2.0e-04). The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G) associated with higher FEV(1)/FVC ratio levels. Results from the Family Heart Study demonstrated that the association extended to FEV(1) and dichotomous airflow obstruction phenotypes, particularly among smokers. The SNP rs13147758 was associated with the percent predicted FEV(1)/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript. The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP) gene and several expressed sequence tags cloned from fetal lung. Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation.

Relation of smoking status to a panel of inflammatory markers: the framingham offspring.

AIMS: We sought to investigate the hypothesis that smoking is accompanied by systemic inflammation. METHODS AND RESULTS: We examined the relation of smoking to 11 systemic inflammatory markers in Framingham Study participants (n=2944, mean age 60 years, 55% women, 12% ethnic minorities) examined from 1998-2001. The cohort was divided into never (n=1149), former (n=1424), and current smokers with last cigarette >6h (n=134) or < or =6h (n=237) prior to phlebotomy. In multivariable-adjusted models there were significant overall between-smoking group differences (defined as p<0.0045 to account for multiple testing) for every inflammatory marker tested, except for serum CD40 ligand (CD40L), myeloperoxidase (MPO) and tumor necrosis factor receptor-2 (TNFR2). With multivariable-adjustment, pair-wise comparisons with never smokers revealed that former smokers had significantly lower concentrations of plasma CD40L (p<0.0001) and higher concentrations of (CRP) C-reactive protein (p=0.002). CONCLUSIONS: As opposed to never smokers, those with acute cigarette smoke exposure (< or =6h) had significantly higher concentrations of all markers (p<0.0001) except serum CD40L, MPO, and TNFR2; plasma CD40L were significantly lower. Compared with never smokers, cigarette smokers have significantly elevated concentrations of most circulating inflammatory markers, consistent with the hypothesis that smoking is associated with a systemic inflammatory state.

Systemic inflammation and COPD: the Framingham Heart Study.

BACKGROUND: The current paradigm for the pathogenesis of COPD includes an ultimately maladaptive local inflammatory response to environmental stimuli. We examined the hypothesis that systemic inflammatory biomarkers are associated with impaired lung function, particularly among those with extensive cigarette smoking. METHODS: Using data from the Framingham Heart Study, we examined cross-sectional associations of systemic inflammatory biomarkers (CD40 ligand [CD40L], intercellular adhesion molecule [ICAM]-1, interleukin [IL]-6, monocyte chemoattractant protein-1, P-selectin, and myeloperoxidase, in addition to C-reactive protein) to impaired lung function. RESULTS: IL-6 was consistently associated with impaired lung function; a 1-SD higher concentration of IL-6 was associated with a 41-mL lower FEV(1) (95% confidence interval [CI], - 61 to - 20) and a borderline 15% higher odds of COPD (odds ratio, 1.15; 95% CI, 0.99 to 1.34). Additionally, P-selectin was associated with lower FEV(1) levels; after adjusting for the other biomarkers, a 1-SD higher concentration of P-selectin predicted an FEV(1) that was on average 19 mL lower (95% CI, - 37 to 0). Including the biomarkers individually as sole exposures in the models generally strengthened the impaired lung function/biomarker association; the relations of ICAM-1 to FEV(1), and ICAM and CD40L to COPD became significant. The observed associations did not vary significantly with smoking history, except that the association between CD40L and COPD appeared greater in individuals with more extensive smoking histories. CONCLUSIONS: Among participants in the Framingham Heart Study, systemic inflammation was associated with lower levels of pulmonary function. Further research into the role of systemic inflammation in the development of pulmonary dysfunction is merited.

Framingham Heart Study genome-wide association: results for pulmonary function measures.

BACKGROUND: Pulmonary function measures obtained by spirometry are used to diagnose chronic obstructive pulmonary disease (COPD) and are highly heritable. We conducted genome-wide association (GWA) analyses (Affymetrix 100K SNP GeneChip) for measures of lung function in the Framingham Heart Study. METHODS: Ten spirometry phenotypes including percent of predicted measures, mean spirometry measures over two examinations, and rates of change based on forced expiratory volume in one second (FEV1), forced vital capacity (FVC), forced expiratory flow from the 25th to 75th percentile (FEF25-75), the FEV1/FVC ratio, and the FEF25-75/FVC ratio were examined. Percent predicted phenotypes were created using each participant's latest exam with spirometry. Predicted lung function was estimated using models defined in the set of healthy never-smokers, and standardized residuals of percent predicted measures were created adjusting for smoking status, pack-years, and body mass index (BMI). All modeling was performed stratified by sex and cohort. Mean spirometry phenotypes were created using data from two examinations and adjusting for age, BMI, height, smoking and pack-years. Change in pulmonary function over time was studied using two to four examinations with spirometry to calculate slopes, which were then adjusted for age, height, smoking and pack-years. RESULTS: Analyses were restricted to 70,987 autosomal SNPs with minor allele frequency > or = 10%, genotype call rate > or = 80%, and Hardy-Weinberg equilibrium p-value > or = 0.001. A SNP in the interleukin 6 receptor (IL6R) on chromosome 1 was among the best results for percent predicted FEF25-75. A non-synonymous coding SNP in glutathione S-transferase omega 2 (GSTO2) on chromosome 10 had top-ranked results studying the mean FEV1 and FVC measurements from two examinations. SNPs nearby the SOD3 and vitamin D binding protein genes, candidate genes for COPD, exhibited association to percent predicted phenotypes. CONCLUSION: GSTO2 and IL6R are credible candidate genes for association to pulmonary function identified by GWA. These and other observed associations warrant replication studies. This resource of GWA results for pulmonary function measures is publicly available at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.

Feasibility of retinoids for the treatment of emphysema study.

BACKGROUND: Retinoids promote alveolar septation in the developing lung and stimulate alveolar repair in some animal models of emphysema. METHODS: One hundred forty-eight subjects with moderate-to-severe COPD and a primary component of emphysema, defined by diffusing capacity of the lung for carbon monoxide (Dlco) [37.1 +/- 12.0% of predicted] and CT density mask (38.5 +/- 12.8% of voxels <- 910 Hounsfield units) [mean +/- SD] were enrolled into a randomized, double-blind, feasibility study at five university hospitals. Participants received all-trans retinoic acid (ATRA) at either a low dose (LD) [1 mg/kg/d] or high dose (HD) [2 mg/kg/d], 13-cis retinoic acid (13-cRA) [1 mg/kg/d], or placebo for 6 months followed by a 3-month crossover period. RESULTS: No treatment was associated with an overall improvement in pulmonary function, CT density mask score, or health-related quality of life (QOL) at the end of 6 months. However, time-dependent changes in Dlco (initial decrease with delayed recovery) and St. George Respiratory Questionnaire (delayed improvement) were observed in the HD-ATRA cohort and correlated with plasma drug levels. In addition, 5 of 25 participants in the HD-ATRA group had delayed improvements in their CT scores that also related to ATRA levels. Retinoid-related side effects were common but generally mild. CONCLUSIONS: No definitive clinical benefits related to the administration of retinoids were observed in this feasibility study. However, time- and dose-dependent changes in Dlco, CT density mask score, and health-related QOL were observed in subjects treated with ATRA, suggesting the possibility of exposure-related biological activity that warrants further investigation.

Sarcoidosis-associated pulmonary hypertension: outcome with long-term epoprostenol treatment.

RATIONALE: Pulmonary hypertension is a known complication of sarcoidosis and is associated with increased mortality. Little is known about the outcome of sarcoidosis-associated pulmonary hypertension, including response to treatment. OBJECTIVE: To determine the characteristics and outcome of patients with sarcoidosis-associated pulmonary hypertension treated with IV epoprostenol. DESIGN: Retrospective chart review of all cases of pulmonary hypertension with a concomitant diagnosis of sarcoidosis evaluated in the Boston University Pulmonary Hypertension Center from 2000 to 2004. MEASUREMENTS: Data collected included patient demographics, sarcoidosis stage, pulmonary function, echocardiography results, treatment, baseline and posttreatment hemodynamic measurements, and clinical outcome. RESULTS: Eight patients were identified; four of the patients had stage IV pulmonary sarcoidosis. Pulmonary function test results were notable for severe diffusion impairment (mean diffusion capacity of the lung for carbon monoxide, 30% of predicted), with only mild-to-moderate restrictive physiology (mean FVC, 59% of predicted). Seventy-five percent of patients required supplemental oxygen at the time of presentation. All patients had moderate or severe pulmonary hypertension and were New York Heart Association (NYHA)/World Health Organization (WHO) class III or IV. A vasodilator trial with epoprostenol was performed in seven of the eight patients; six of the seven patients had a significant hemodynamic response (> 25% reduction in pulmonary vascular resistance). All but one of the responders (five of six patients) continued on therapy. Average clinical improvement was one to two NYHA/WHO classes at a mean follow-up of 29 months (range, 15 to 49 months). CONCLUSIONS: In patients with sarcoidosis-associated pulmonary hypertension, the severity of pulmonary vascular disease occurs out of proportion to lung function abnormalities. The majority of our patients responded to epoprostenol; survival may be improved in this group.

Association between glycemic state and lung function: the Framingham Heart Study.

Diabetes mellitus has been inconsistently associated with a reduced level of pulmonary function. To elucidate this association further, we analyzed the relationship of diabetes and of fasting blood glucose to the level of pulmonary function assessed by spirometry in the 3,254 members of the Framingham Offspring Cohort. Diabetes was defined as a fasting blood glucose of 126 mg/dl or more or pharmacologic treatment. Subjects were classified as current, former, or never smokers based on questionnaire responses. Predicted pulmonary function was determined from the coefficients of a regression of pulmonary function on age, sex, and body habitus in the 1,110 never smokers. Both the diagnosis of diabetes and a higher level of fasting blood glucose were associated with lower than predicted levels of pulmonary function. The adverse effect of diabetes and glycemic level on pulmonary function was stronger among ever smokers than never smokers, suggesting an interaction between the level of fasting glycemia and tobacco smoking.