Michael J. Cuttica

Hemodynamic Predictors of Mortality in Adults with Sickle Cell Disease

BACKGROUND Pulmonary hypertension (PH) in adults with sickle cell disease (SCD) is associated with early mortality, but no prior studies have evaluated quantitative relationships of mortality to physiological measures of pre- and postcapillary PH. OBJECTIVES To identify risk factors associated with mortality and to estimate the expected survival in a cohort of patients with SCD with PH documented by right heart catheterization. METHODS Nine-year follow-up data (median, 4.7 yr) from the National Institutes of Health SCD PH screening study are reported. A total of 529 adults with SCD were screened by echocardiography between 2001 and 2010 with no exclusion criteria. Hemodynamic data were collected from 84 patients. PH was defined as mean pulmonary artery pressure (PAP) ≥ 25 mm Hg. Survival rates were estimated by the Kaplan-Meier method, and mortality risk factors were analyzed by the Cox proportional hazards regression. MEASUREMENTS AND MAIN RESULTS Specific hemodynamic variables were independently related to mortality: mean PAP (hazard ratio [HR], 1.61; 95% confidence interval [CI], 1.05-2.45 per 10 mm Hg increase; P = 0.027), diastolic PAP (HR, 1.83; 95% CI, 1.09-3.08 per 10 mm Hg increase; P = 0.022), diastolic PAP - pulmonary capillary wedge pressure (HR, 2.19; 95% CI, 1.23-3.89 per 10 mm Hg increase; P = 0.008), transpulmonary gradient (HR, 1.78; 95% CI, 1.14-2.79 per 10 mm Hg increase; P = 0.011), and pulmonary vascular resistance (HR, 1.44; 95% CI, 1.09-1.89 per Wood unit increase; P = 0.009) as risk factors for mortality. CONCLUSIONS Mortality in adults with SCD and PH is proportional to the physiological severity of precapillary PH, demonstrating its prognostic and clinical relevance despite anemia-induced high cardiac output and less severely elevated pulmonary vascular resistance.

Loss of lung health from young adulthood and cardiac phenotypes in middle age

RATIONALE Chronic lung diseases are associated with cardiovascular disease. How these associations evolve from young adulthood forward is unknown. Understanding the preclinical history of these associations could inform prevention strategies for common heart-lung conditions. OBJECTIVES To use the Coronary Artery Risk Development in Young Adults (CARDIA) study to explore the development of heart-lung interactions. METHODS We analyzed cardiac structural and functional measurements determined by echocardiography at Year 25 of CARDIA and measures of pulmonary function over 20 years in 3,000 participants. MEASUREMENTS AND MAIN RESULTS Decline in FVC from peak was associated with larger left ventricular mass (β = 6.05 g per SD of FVC decline; P < 0.0001) and greater cardiac output (β = 0.109 L/min per SD of FVC decline; P = 0.001). Decline in FEV1/FVC ratio was associated with smaller left atrial internal dimension (β = -0.038 cm per SD FEV1/FVC decline; P < 0.0001) and lower cardiac output (β = -0.070 L/min per SD of FEV1/FVC decline; P = 0.03). Decline in FVC was associated with diastolic dysfunction (odds ratio, 3.39; 95% confidence interval, 1.37-8.36; P = 0.006). CONCLUSIONS Patterns of loss of lung health are associated with specific cardiovascular phenotypes in middle age. Decline in FEV1/FVC ratio is associated with underfilling of the left heart and low cardiac output. Decline in FVC with preserved FEV1/FVC ratio is associated with left ventricular hypertrophy and diastolic dysfunction. Cardiopulmonary interactions apparent with common complex heart and lung diseases evolve concurrently from early adulthood forward.

Time-resolved magnetic resonance angiography: Evaluation of intrapulmonary circulation parameters in pulmonary arterial hypertension

To determine whether pulmonary arterial and venous transit times measured by time‐resolved magnetic resonance angiography (MRA) can be used as a diagnostic tool for pulmonary arterial hypertension (PAH).

Perivascular T-Cell Infiltration Leads to Sustained Pulmonary Artery Remodeling after Endothelial Cell Damage

Pulmonary hypertension is a vascular proliferative disease characterized by pulmonary artery remodeling because of dysregulated endothelial and smooth muscle cell proliferation. Although the role of inflammation in the development of the disease is not well-defined, plexogenic lesions in human disease are characterized by perivascular inflammation composed, in part, of T cells. We explored the role of T-cell infiltration on pulmonary vascular remodeling after endothelial cell damage. We induced endothelial cell damage using monocrotaline and isolated the role of T cells by using Rag1(tm1Mom) mice and performing adoptive T-cell transfer. We found that monocrotaline causes pulmonary vascular endothelial cell injury followed by a perivascular inflammatory response. The infiltration of inflammatory cells primarily involves CD4(+) T cells and leads to the progressive muscularization of small (<30 μm) arterioles. Pulmonary vascular proliferative changes were accompanied by progressive and persistent elevations in right ventricular pressure and right ventricular hypertrophy. Supporting the central role of CD4(+) T cells in the inflammatory response, Rag1(tm1Mom) (Rag1(-/-)) mice, which are devoid of T and B cells, were protected from the development of vascular injury when exposed to monocrotaline. The introduction of T cells from control mice into Rag1(-/-) mice reproduced the vascular injury phenotype. These data indicate that after endothelial cell damage, CD4(+) T-cell infiltration participates in pulmonary vascular remodeling. This finding suggests that a CD4(+) T-cell immune response may contribute to the pathogenesis of inflammatory vascular lesions seen in some forms of pulmonary hypertension.

Pulmonary hypertension in advanced chronic obstructive pulmonary disease.

Purpose of review Pulmonary hypertension is a common complication seen in patients with advanced chronic obstructive pulmonary disease (COPD). Information related to the true prevalence, implications for functional outcomes, pathogenesis, and therapeutic options available has been lacking. The purpose of this review is to summarize some exciting findings from the last several years that address these holes in our knowledge. Recent findings Several recent studies have explored the prevalence and the functional implications of pulmonary hypertension for patients with COPD. These highlight the importance of clearly defining pulmonary hypertension that can be quite heterogeneous in this patient population. Furthermore, the concept that pulmonary hypertension in COPD is merely driven by hypoxic vasoconstriction has been called into question by several lines of investigation that suggest a much more complex pathogenesis potentially occurring independently of hypoxemia. Finally, there has been much interest in exploring pulmonary hypertension-specific therapies in patients with COPD, but available data to support their use are limited. Summary The recent findings summarized here have expanded our knowledge regarding this important comorbidity in patients with advanced COPD. We now know that pulmonary hypertension is common, has clear effects on both morbidity and mortality, and has a complex pathophysiology that we are only beginning to understand.

Esophageal dilatation and interstitial lung disease in systemic sclerosis: A cross-sectional study ☆

OBJECTIVE A patulous esophagus on high-resolution computed tomography (HRCT) of the thorax is frequently observed in patients with systemic sclerosis (SSc). Microaspiration has been purported to play a role in the development and progression of SSc interstitial lung disease (ILD), but studies examining the role of microaspiration in SSc ILD have yielded conflicting results. This study was conducted to determine the association between esophageal diameter and SSc ILD. METHODS A cross-sectional study of Northwestern Scleroderma Registry patients with available HRCT exams was conducted. The predictor variable was the widest esophageal diameter (WED) on HRCT, and the primary and secondary outcome variables were radiographic ILD and pulmonary function tests respectively. The degree of radiographic ILD was assessed using a semi-quantitative score adapted from published methods. Estimated regression coefficients adjusted for age, sex, race, body mass index, smoking; SSc disease subtype, serum autoantibodies, and disease duration; modified Rodnan skin score, proton pump inhibitor, and immune suppressant medication use and erythrocyte sedimentation rate were calculated. RESULTS A total of 270 subjects were studied. In the adjusted analyses, there were positive associations between WED and total ILD score (β = 0.27; 95% CI: 0.09-0.41), fibrosis (β = 0.15; 95% CI: 0.07-0.23), and ground glass opacities (β = 0.12; 95% CI: 0.04-0.20); there were negative associations between WED and FVC % predicted (β = -0.42; 95% CI: -0.69 to -0.13), and adjusted DLCO % predicted (β = -0.45; 95% CI: -0.80 to -0.09) after adjusting for potential confounders. CONCLUSIONS Increasing esophageal diameter on HRCT in patients with SSc is associated with more severe radiographic ILD, lower lung volumes, and lower DLCO % predicted. Longitudinal studies are needed to determine if esophageal dilatation is associated with the incidence and/or progression of ILD in patients with SSc.

Effects of ranolazine on exercise capacity, right ventricular indices, and hemodynamic characteristics in pulmonary arterial hypertension: a pilot study.

Ranolazine, a late inward sodium current and fatty acid oxidation inhibitor, may improve right ventricular (RV) function in pulmonary arterial hypertension (PAH); however, the safety and efficacy of ranolazine in humans with PAH is unknown. Therefore, we sought to (1) determine whether ranolazine is safe and well tolerated in PAH and (2) explore ranolazines effect on symptoms, exercise capacity, RV structure and function, and hemodynamic characteristics. We therefore conducted a 3-month, prospective, open-label pilot study involving patients with symptomatic PAH (n = 11) and echocardiographic evidence of RV dysfunction. We evaluated the safety and tolerability of ranolazine and compared symptoms, exercise capacity, exercise bicycle echocardiographic parameters, and invasive hemodynamic parameters between baseline and 3 months of ranolazine therapy using paired t tests. Of the 11 patients enrolled, one discontinued ranolazine therapy due to a drug-drug interaction after 3 days of therapy. All 10 of the remaining patients continued therapy for 3 months, and 8 (80%) of 10 completed all study tests. After 3 months, ranolazine administration was safe and associated with improvement in functional class (P = 0.0013), reduction in RV size (P = 0.015), improved RV function (improvement in RV strain during exercise at 3 months; P = 0.037), and a trend toward improved exercise time and exercise watts on bicycle echocardiography (P = 0.06 and 0.01, respectively). Ranolazine was not associated with improvement in invasive hemodynamic parameters. In conclusion, in a pilot study involving PAH, ranolazine therapy was safe and well tolerated, and it resulted in improvement in symptoms and echocardiographic parameters of RV structure and function but did not alter invasive hemodynamic parameters.

MDCT bolus tracking data as an adjunct for predicting the diagnosis of pulmonary hypertension and concomitant right-heart failure.

OBJECTIVE The purpose of this study was to investigate the utility of bolus-triggering data from pulmonary CT angiography for predicting the diagnosis of pulmonary hypertension (PH) and right ventricular dysfunction (RVD) and to test its performance against previously established CT signs of PH. MATERIALS AND METHODS Automated bolus-triggering data from pulmonary CT angiograms of 101 patients were correlated with echocardiographic findings and a variety of CT-derived indexes of PH and RVD, including right and left ventricular minor axis diameter; pulmonary artery (PA), aortic, and superior vena caval diameters; right ventricular thickness; contrast reflux; and configuration of the interventricular septum. For bolus triggering, a region of interest was placed in the main PA. Time to threshold, defined as the time from the beginning of contrast injection to the time attenuation exceeded the threshold (100 HU), was measured. On the basis of results of two consecutive echocardiographic studies, subjects were divided into control and PH groups. The latter group was subdivided into PH without RVD and PH with RVD. Time to threshold values were compared between groups and correlated with standard CT-derived parameters. RESULTS Significant differences between groups were found in time to threshold, PA and right ventricular diameters, and PA-to-aorta and right ventricular-to-left ventricular ratios. Time to threshold had an incremental pattern from the control group (6.6 ± 1.0 seconds) to PH without RVD (9.2 ± 2.4 seconds) and PH with RVD (12.1 ± 3.4 seconds) (p < 0.001). The optimal diagnostic performance of time to threshold for revealing the presence of PH and RVD was at cutoff values of 7.75 and 8.75 seconds, respectively. Time to threshold had a strong direct correlation with PA diameter. In multivariable analyses, time to threshold was identified as a significant predictor of PH and RVD. The specificity of time to threshold and PA diameter together was higher than that of PA diameter alone. CONCLUSION Measurement of time to threshold of contrast enhancement derived from bolus-timing data at MDCT may be a useful adjunctive tool for diagnosing PH and consequent RVD.

Association between Cardiorespiratory Fitness and Lung Health from Young Adulthood to Middle Age

Rationale: Beyond the risks of smoking, there are limited data on factors associated with change in lung function over time. Objectives: To determine whether cardiorespiratory fitness was longitudinally associated with preservation of lung health. Methods: Prospective data were collected from 3,332 participants in the Coronary Artery Risk Development in Young Adults study aged 18‐30 in 1985 who underwent treadmill exercise testing at baseline visit, and 2,735 participants with a second treadmill test 20 years later. The association between cardiorespiratory fitness and covariate adjusted decline in lung function was evaluated. Measurements and Main Results: Higher baseline fitness was associated with less decline in lung function. When adjusted for age, height, race‐sex group, peak lung function, and years from peak lung function, each additional minute of treadmill duration was associated with 1.00 ml/yr less decline in FEV1 (P < 0.001) and 1.55 ml/yr less decline in FVC (P < 0.001). Greater decline in fitness was associated with greater annual decline in lung function. Each 1‐minute decline in treadmill duration between baseline and Year 20 was associated with 2.54 ml/yr greater decline in FEV1 (P < 0.001) and 3.27 ml/yr greater decline in FVC (P < 0.001). Both sustaining higher and achieving relatively increased levels of fitness over 20 years were associated with preservation of lung health. Conclusions: Greater cardiopulmonary fitness in young adulthood, less decline in fitness from young adulthood to middle age, and achieving increased fitness from young adulthood to middle age are associated with less decline in lung health over time. Clinical trial registered with www.clinicaltrials.gov (NCT 00005130).

Infrared imaging of nitric oxide-mediated blood flow in human sickle cell disease

Vascular dysfunction is an important pathophysiologic manifestation of sickle cell disease (SCD), a condition that increases risk of pulmonary hypertension and stroke. We hypothesized that infrared (IR) imaging would detect changes in cutaneous bloodflow reflective of vascular function. We performed IR imaging and conventional strain gauge plethysmography in twenty-five adults with SCD at baseline and during intra-arterial infusions of an endothelium-dependent vasodilator acetylcholine (ACh), an endothelium-independent vasodilator sodium nitroprusside (SNP), and a NOS inhibitor L-NMMA. Skin temperature measured by IR imaging increased in a dose-dependent manner to graded infusions of ACh (+1.1°C, p<0.0001) and SNP (+0.9°C, p<0.0001), and correlated with dose-dependent increases in forearm blood flow (ACh: +19.9 mL/min/100 mL, p<0.0001; r(s)=0.57, p=0.003; SNP: +8.6 mL/min/100 mL, p<0.0001; r=0.70, p=0.0002). Although IR measurement of skin temperature accurately reflected agonist-induced increases in blood flow, it was less sensitive to decreases in blood flow caused by NOS inhibition. Baseline forearm skin temperature measured by IR imaging correlated significantly with baseline forearm blood flow (31.8±0.2°C, 6.0±0.4 mL/min/100 mL; r=0.58, p=0.003), and appeared to represent a novel biomarker of vascular function. It predicted a blunted blood flow response to SNP (r=-0.61, p=0.002), and was independently associated with a marker of pulmonary artery pressure, as well as hemoglobin level, diastolic blood pressure, homocysteine, and cholesterol (R(2)=0.84, p<0.0001 for the model). IR imaging of agonist-stimulated cutaneous blood flow represents a less cumbersome alternative to plethysmography methodology. Measurement of baseline skin temperature by IR imaging may be a useful new marker of vascular risk in adults with SCD.