Omar A. Minai

Comorbidities in Chronic Obstructive Pulmonary Disease

Comorbidities such as cardiac disease, diabetes mellitus, hypertension, osteoporosis, and psychological disorders are commonly reported in patients with chronic obstructive pulmonary disease (COPD) but with great variability in reported prevalence. Tobacco smoking is a risk factor for many of these comorbidities as well as for COPD, making it difficult to draw conclusions about the relationship between COPD and these comorbidities. However, recent large epidemiologic studies have confirmed the independent detrimental effects of these comorbidities on patients with COPD. On the other hand, many of these comorbidities are now considered to be part of the commonly prevalent nonpulmonary sequelae of COPD that are relevant not only to the understanding of the real burden of COPD but also to the development of effective management strategies.

Estimating pulmonary artery pressures by echocardiography in patients with emphysema

In patients with emphysema being evaluated for lung volume reduction surgery, Doppler echocardiography has been used to screen for pulmonary hypertension as an indicator of increased peri-operative risk. To determine the accuracy of this test, the present authors compared the results of right heart catheterisations and Doppler echocardiograms in 163 patients participating in the cardiovascular substudy of the National Emphysema Treatment Trial. Substudy patients had both catheterisation and Doppler echocardiography performed before and after randomisation. In 74 paired catheterisations and echocardiograms carried out on 63 patients, the mean values of invasively measured pulmonary artery systolic pressures and the estimated right ventricular systolic pressures were similar. However, using the World Health Organizations definitions of pulmonary hypertension, echocardiography had a sensitivity of 60%, specificity of 74%, positive predictive value of 68% and a negative predictive value of 67% compared with the invasive measurement. Bland–Altman analysis revealed a bias of 0.37 kPa with 95% limits of agreement from -2.5–3.2 kPa. In patients with severe emphysema, echocardiographic estimates of pulmonary artery pressures correlate very weakly with right heart catheterisations, and the test characteristics (e.g. sensitivity, specificity, etc.) of echocardiographic assessments are poor.

Pulmonary Hypertension in COPD: Epidemiology, Significance, and Management: Pulmonary Vascular Disease: The Global Perspective

Pulmonary hypertension (PH) associated with parenchymal lung diseases is one of the most common forms of PH. Studies in patients with advanced COPD and hypoxemia have shown a very high prevalence of PH; however, prevalence in mild and moderate COPD is not known. Typical hemodynamic abnormalities include mild-to-moderate elevations in pulmonary artery pressure (PAP) and pulmonary vascular resistance with a preserved cardiac output. A small proportion (< 5%) of patients may have significant elevations in PAP (mean PAP > 35-40 mm Hg) in the presence of mild airflow limitation and are believed to have disproportionate PH. COPD-associated PH has significant clinical implications because it can produce functional limitation and has a negative impact on prognosis. Doppler echocardiography is the best noninvasive test, but noninvasive methods used for diagnosis are prone to error and cannot be relied on when making or refuting the diagnosis of PH. All patients require right-sided heart catheterization if treatment with PH-specific medications is contemplated. The most important steps in managing these patients are: (1) confirm the diagnosis; (2) optimize COPD management; (3) rule out comorbidities; (4) assess and treat hypoxemia; and (5) enroll the patient in pulmonary rehabilitation, if indicated. In patients with PH and advanced airflow limitation, lung transplantation offers the best opportunity for long-term benefit. The role of PH-specific medications remains poorly defined and requires further study but may be considered in patients with disproportionate PH.

Cardiac disease in chronic obstructive pulmonary disease.

The cardiac manifestations of chronic obstructive pulmonary disease (COPD) are numerous. Impairments of right ventricular dysfunction and pulmonary vascular disease are well known to complicate the clinical course of COPD and correlate inversely with survival. The pathogenesis of pulmonary vascular disease in COPD is likely multifactorial and related to alterations in gas exchange and vascular biology, as well as structural changes of the pulmonary vasculature and mechanical factors. Several modalities currently exist for the assessment of pulmonary vascular disease in COPD, but right heart catheterization remains the gold standard. Although no specific therapy other than oxygen has been generally accepted for the treatment of pulmonary hypertension in this population, there has been renewed interest in specific pulmonary vasodilators. The coexistence of COPD and coronary artery disease occurs frequently. This association is likely related to shared risk factors as well as similar pathogenic mechanisms, such as systemic inflammation. Management strategies for the care of patients with COPD and coronary artery disease are similar to those without COPD, but care must be given to address their respiratory limitations. Arrhythmias occur frequently in patients with COPD, but are rarely fatal and can generally be treated medically. Use of beta-blockers in the management of cardiac disease, while a theoretical concern in patients with increased airway resistance, is generally safe with the use of cardioselective agents.

Causes and Circumstances of Death in Pulmonary Arterial Hypertension

RATIONALE The causes and circumstances surrounding death are understudied in patients with pulmonary arterial hypertension (PAH). OBJECTIVES We sought to determine the specific reasons and characteristics surrounding the death of patients with PAH. METHODS All deaths of patients with pulmonary hypertension (PH) followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the PH team. A total of 84 patients with PAH (age 58 ± 14 yr; 73% females) who died between June 2008 and May 2012 were included. MEASUREMENTS AND MAIN RESULTS PH was determined to be the direct cause of death (right heart failure or sudden death) in 37 (44%) patients; PH contributed to but did not directly cause death in 37 (44%) patients; and the death was not related to PH in the remaining cases (n = 7; 8.3%). In three (3.6%) patients the final cause of death could not be adequately assessed. Most patients died in a healthcare environment and most received PH-specific therapies. In our cohort, 50% of all patients with PAH and 75.7% of those who died of right heart failure received parenteral prostanoid therapy. Less than half of patients had advanced healthcare directives. CONCLUSIONS Most patients with PAH in our cohort died of their disease; however, right ventricular failure or sudden death was the sole cause of death in less than half of patients.

MANIFESTATIONS OF SCLERODERMA PULMONARY DISEASE

Scleroderma is a multisystem disease of unknown cause characterized by synthesis and deposition of excessive extracellular matrix and vascular anti-GBM antibodies, leading to pulmonary hemorrhage and glomerulonephritis with rapidly progressive renal insufficiency. Recent advances in the understanding of disease pathogenesis and diagnosis and treatment have significantly improved our ability to recognize the syndrome, distinguish it from other similar disorders, and offer successful treatment. This article focuses on the pathogenetic features, clinical manifestations, diagnostic strategies, and therapeutic principles of anti-GBM disease.

Frequency and Impact of Pulmonary Hypertension in Patients With Obstructive Sleep Apnea Syndrome

The correlates and consequences of pulmonary hypertension (PH) associated with obstructive sleep apnea (OSA) are poorly understood. Patients undergoing pulmonary artery catheterization within 6 months of an overnight polysomnography showing OSA were included in the present analysis. A total of 83 patients with complete data were analyzed (no PH, n = 25 [30%]; PH, 58 [70%]; of these, 18 had a pulmonary capillary wedge pressure of <15 mm Hg). No significant differences were observed between the PH and no PH groups regarding age or apnea-hypopnea index. The correlates of PH were elevated right ventricular systolic pressure (p <0.001), body mass index (p = 0.026), female gender (p = 0.01), nocturnal desaturation (82% vs 18%), and forced vital capacity <70% (p = 0.04) on univariate analysis and female gender (p = 0.03), age <49 years (p = 0.02), body mass index of > or =26 kg/m(2) (p = 0.08), and right ventricular systolic pressure of > or =30 mm Hg (p <0.001) on multivariate analysis. Patients with PH had a lower 6-minute walk distance (285.5 +/- 122 m vs 343 +/- 213 m, p = 0.4). The survival rate at 1, 4, and 8 years for patients with PH was 93%, 75%, and 43% compared to 100%, 90%, and 76% for patients without PH, respectively. Patients with severe PH (n = 27; 33%) had more nocturnal desaturation (p = 0.045), worse pulmonary hemodynamics, and greater mortality (37%) than the groups with mild or moderate PH (16%) or no PH (16%). In conclusion, our results have shown that, although generally mild to moderate, severe PH can occur in patients with OSA. Female gender, younger age, obesity, and nocturnal desaturation were associated with PH. PH can cause functional limitations and increased mortality in patients with OSA.

Perioperative Risk and Management in Patients With Pulmonary Hypertension

Pulmonary hypertension (PH) is a known risk factor for perioperative complications. Unlike in the case of cardiac surgery, PH is currently not listed as an independent risk factor for postoperative complications in guidelines for the management of noncardiac surgery. Despite the paucity of data, though, patients with PH are often counseled against having elective procedures because early and sudden postoperative deaths have been reported. Patients with PH are unable to accommodate alterations in right ventricular (RV) preload or afterload induced by fluid shifts, medications, or changes in the autonomic nervous system precipitated by hypoxia or hypercapnia. These factors become magnified in situations of added stress such as surgical intervention. Systemic hypotension and arrhythmias may precipitate RV ischemia, further worsening RV function. Patient and surgical characteristics and choice of anesthetic technique are crucial factors in perioperative management. The two main principles of perioperative management are the prevention of systemic hypotension (risk of RV ischemia) and the prevention of acute elevations in pulmonary arterial pressure (risk of RV failure). Close monitoring, optimization of systemic BP, pain control, oxygenation and ventilation, avoidance of exacerbating factors, and use of vasopressors and pulmonary vasodilators as necessary are essential elements of management. Understanding the pathophysiology, cause, and severity of PH in the individual perioperative patient allows accurate risk assessment, optimization of PH and RV function prior to surgery, and appropriate intraoperative and postoperative management.

Heart Rate Recovery Predicts Clinical Worsening in Patients with Pulmonary Arterial Hypertension

RATIONALE Reduced heart rate recovery after exercise is associated with increased mortality in cardiopulmonary diseases. OBJECTIVES We sought to evaluate the association between heart rate recovery at 1 minute of rest (HRR1) after 6-min walk test (6MW test) and clinical worsening in patients with idiopathic pulmonary arterial hypertension (IPAH). METHODS HRR1 was defined as the difference in heart rate at the end of 6MW test and at 1 minute after completion of the 6MW test. Between August 1, 2009 and March 30, 2010, 75 consecutive patients with IPAH underwent 6MW test and were included in the analysis. MEASUREMENTS AND MAIN RESULTS Compared with patients with HRR1 ≥ 16 (n = 45 [60%]), those with HRR1 less than 16 (n = 30 [40%]) were more likely to have clinical worsening (odds ratio, 9.7; 95% confidence interval [CI], 3-30; P < 0.001) and shorter time to first clinical worsening event (TCW) (6.7 mo vs. 13 mo; P < 0.001) during follow-up. By multivariable analysis, the best predictors of clinical worsening were HRR1 less than 16 (hazard ratio, 5.2; 95% CI, 1.8-14.8; P = 0.002) and mean pulmonary arterial pressure (hazard ratio, 1.04; 95% CI, 1.007-1.08; P = 0.02). Compared with the distance walked during the 6MW test (6MWD), HRR1 less than 16 was a better predictor of clinical worsening (C statistic 0.757 vs. 0.703) and TCW (C index 0.730 vs. 0.696). The addition of HRR1 increased the ability of 6MWD to predict clinical worsening events. CONCLUSIONS HRR1 after 6MW test is a strong predictor of clinical worsening and TCW in patients with IPAH. The addition of HRR1 to 6MWD increases the capacity of 6MWD to predict clinical worsening and TCW in patients with IPAH.

Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension

BACKGROUND Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH. METHODS In this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints. RESULTS At 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05). CONCLUSIONS Up-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).