Farbod N. Rahaghi

Blood Glucose Dynamics

Measurement of blood glucose concentration is central to the diagnosis and treatment of diabetes. Although there are large numbers of historic glucose measurements in individuals with diabetes, until recently there have been very few data sets that were recorded continuously or sampled frequently enough to reveal intrinsic blood glucose dynamics, or the change in blood glucose with time. There have even fewer such recordings from individuals not having diabetes to serve as a therapeutic target. As a result, blood glucose dynamics have generally not been used in the diagnosis or treatment of the disease. Although present blood glucose monitoring is based largely on discrete measurements, future monitoring will likely focus on analysis of blood glucose excursions. New measurements are now being obtained, and there is a need for new methods of analysis to extract the maximal information from the data. Several approaches are demonstrated here for characterization of blood glucose dynamics, and a patient profiling system is proposed. An example of new insights is the observation that there are four time scales of blood glucose variations in individuals without diabetes, and these time scales are modified or lost in diabetes.

Pulmonary artery enlargement is associated with right ventricular dysfunction and loss of blood volume in small pulmonary vessels in chronic obstructive pulmonary disease.

Background—Chronic obstructive pulmonary disease causes significant morbidity and concomitant pulmonary vascular disease and cardiac dysfunction are associated with poor prognosis. Computed tomography–detected relative pulmonary artery (PA) enlargement defined as a PA to ascending aorta diameter ratio >1 (PA:A>1) is a marker for pulmonary hypertension and predicts chronic obstructive pulmonary disease exacerbations. However, little is known about the relationship between the PA:A ratio, pulmonary blood volume, and cardiac function. Methods and Results—A single-center prospective cohort study of patients with chronic obstructive pulmonary disease was conducted. Clinical characteristics and computed tomography metrics, including the PA:A and pulmonary blood vessel volume, were measured. Ventricular functions, volumes, and dimensions were measured by cine cardiac MRI with 3-dimensional analysis. Linear regression examined the relationships between clinical characteristics, computed tomography and cardiac MRI metrics, and 6-minute walk distance. Twenty-four patients were evaluated and those with PA:A>1 had higher right ventricular (RV) end-diastolic and end-systolic volume indices accompanied by lower RV ejection fraction (52±7% versus 60±9%; P=0.04). The PA:A correlated inversely with total intraparenchymal pulmonary blood vessel volume and the volume of distal vessels with a cross-sectional area of <5 mm2. Lower forced expiratory volume, PA:A>1, and hyperinflation correlated with reduced RV ejection fraction. Both PA diameter and reduced RV ejection fraction were independently associated with reduced 6-minute walk distance. Conclusions—The loss of blood volume in distal pulmonary vessels is associated with PA enlargement on computed tomography. Cardiac MRI detects early RV dysfunction and remodeling in nonsevere chronic obstructive pulmonary disease patients with a PA:A>1. Both RV dysfunction and PA enlargement are independently associated with reduced walk distance. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00608764.

Understanding the contribution of native tracheobronchial structure to lung function: CT assessment of airway morphology in never smokers

BackgroundComputed tomographic (CT) airway lumen narrowing is associated with lower lung function. Although volumetric CT measures of airways (wall volume [WV] and lumen volume [LV]) compared to cross sectional measures can more accurately reflect bronchial morphology, data of their use in never smokers is scarce. We hypothesize that native tracheobronchial tree morphology as assessed by volumetric CT metrics play a significant role in determining lung function in normal subjects. We aimed to assess the relationships between airway size, the projected branching generation number (BGN) to reach airways of <2mm lumen diameter –the site for airflow obstruction in smokers- and measures of lung function including forced expiratory volume in 1 second (FEV1) and forced expiratory flow between 25% and 75% of vital capacity (FEF 25–75).MethodsWe assessed WV and LV of segmental and subsegmental airways from six bronchial paths as well as lung volume on CT scans from 106 never smokers. We calculated the lumen area ratio of the subsegmental to segmental airways and estimated the projected BGN to reach a <2mm-lumen-diameter airway assuming a dichotomized tracheobronchial tree model. Regression analysis was used to assess the relationships between airway size, BGN, FEF 25–75, and FEV1.ResultsWe found that in models adjusted for demographics, LV and WV of segmental and subsegmental airways were directly related to FEV1 (P <0.05 for all the models). In adjusted models for age, sex, race, LV and lung volume or height, the projected BGN was directly associated with FEF 25–75 and FEV1 (P = 0.001) where subjects with lower FEV1 had fewer calculated branch generations between the subsegmental bronchus and small airways. There was no association between airway lumen area ratio and lung volume.ConclusionWe conclude that in never smokers, those with smaller central airways had lower airflow and those with lower airflow had less parallel airway pathways independent of lung size. These findings suggest that variability in the structure of the tracheobronchial tree may influence the risk of developing clinically relevant smoking related airway obstruction.

Cardiopulmonary coupling in chronic obstructive pulmonary disease: the role of imaging.

Chronic obstructive pulmonary disorder (COPD) is a systemic disease that affects the cardiovascular system through multiple pathways. Pulmonary hypertension, ventricular dysfunction, and atherosclerosis are associated with smoking and COPD, causing significant morbidity and poor prognosis. Coupling between the pulmonary and cardiovascular system involves mechanical interdependence and inflammatory pathways that potentially affect the entire circulation. Although treatments specific for COPD-related cardiovascular and pulmonary vascular disease are limited, early diagnosis, study of pathophysiology, and monitoring the effects of treatment are enhanced with improved imaging techniques. In this article, we review recent advancements in the imaging of the vasculature and the heart in patients with COPD. We also explore the potential mechanism of coupling between the progression of COPD and vascular disease. Imaging methods reviewed include specific implementations of computed tomography, magnetic resonance imaging, dual-energy computed tomography, positron emission tomography, and echocardiography. Specific applications to the proximal and distal pulmonary vasculature, as well as to the heart and systemic circulation, are also discussed.

Pulmonary vascular morphology as an imaging biomarker in chronic thromboembolic pulmonary hypertension.

Patients with chronic thromboembolic pulmonary hypertension (CTEPH) have morphologic changes to the pulmonary vasculature. These include pruning of the distal vessels, dilation of the proximal vessels, and increased vascular tortuosity. Advances in image processing and computer vision enable objective detection and quantification of these processes in clinically acquired computed tomographic (CT) scans. Three-dimensional reconstructions of the pulmonary vasculature were created from the CT angiograms of 18 patients with CTEPH diagnosed using imaging and hemodynamics as well as 15 control patients referred to our Dyspnea Clinic and found to have no evidence of pulmonary vascular disease. Compared to controls, CTEPH patients exhibited greater pruning of the distal vasculature (median density of small-vessel volume: 2.7 [interquartile range (IQR): 2.5–3.0] vs. 3.2 [3.0–3.8]; P = 0.008), greater dilation of proximal arteries (median fraction of blood in large arteries: 0.35 [IQR: 0.30–0.41] vs. 0.23 [0.21–0.31]; P = 0.0005), and increased tortuosity in the pulmonary arterial tree (median: 4.92% [IQR: 4.85%–5.21%] vs. 4.63% [4.39%–4.92%]; P = 0.004). CTEPH was not associated with dilation of proximal veins or increased tortuosity in the venous system. Distal pruning of the vasculature was correlated with the cardiac index (R = 0.51, P = 0.04). Quantitative models derived from CT scans can be used to measure changes in vascular morphology previously described subjectively in CTEPH. These measurements are also correlated with invasive metrics of pulmonary hemodynamics, suggesting that they may be used to assess disease severity. Further work in a larger cohort may enable the use of such measures as a biomarker for diagnostic, phenotyping, and prognostic purposes.

Pruning of the Pulmonary Vasculature in Asthma. The Severe Asthma Research Program (SARP) Cohort

&NA; Rationale: Loss of the peripheral pulmonary vasculature, termed vascular pruning, is associated with disease severity in patients with chronic obstructive pulmonary disease. Objectives: To determine if pulmonary vascular pruning is associated with asthma severity and exacerbations. Methods: We measured the total pulmonary blood vessel volume (TBV) and the blood vessel volume of vessels less than 5 mm2 in cross‐sectional area (BV5) and of vessels less than 10 mm2 (BV10) in cross‐sectional area on noncontrast computed tomographic scans of participants from the Severe Asthma Research Program. Lower values of the BV5 to TBV ratio (BV5/TBV) and the BV10 to TBV ratio (BV10/TBV) represented vascular pruning (loss of the peripheral pulmonary vasculature). Measurements and Main Results: Compared with healthy control subjects, patients with severe asthma had more pulmonary vascular pruning. Among those with asthma, those with poor asthma control had more pruning than those with well‐controlled disease. Pruning of the pulmonary vasculature was also associated with lower percent predicted FEV1 and FVC, greater peripheral and sputum eosinophilia, and higher BAL serum amyloid A/lipoxin A4 ratio but not with low‐attenuation area or with sputum neutrophilia. Compared with individuals with less pruning, individuals with the most vascular pruning had 150% greater odds of reporting an asthma exacerbation (odds ratio, 2.50; confidence interval, 1.05‐5.98; P = 0.039 for BV10/TBV) and reported 45% more asthma exacerbations during follow‐up (incidence rate ratio, 1.45; confidence interval, 1.02‐2.06; P = 0.036 for BV10/TBV). Conclusions: Pruning of the peripheral pulmonary vasculature is associated with asthma severity, control, and exacerbations, and with lung function and eosinophilia.

Ventricular geometry from non-contrast non-ECG-gated CT scans: An imaging marker of cardiopulmonary disease in smokers

RATIONALE AND OBJECTIVES Imaging-based assessment of cardiovascular structure and function provides clinically relevant information in smokers. Non-cardiac-gated thoracic computed tomographic (CT) scanning is increasingly leveraged for clinical care and lung cancer screening. We sought to determine if more comprehensive measures of ventricular geometry could be obtained from CT using an atlas-based surface model of the heart. MATERIALS AND METHODS Subcohorts of 24 subjects with cardiac magnetic resonance imaging (MRI) and 262 subjects with echocardiography were identified from COPDGene, a longitudinal observational study of smokers. A surface model of the heart was manually initialized, and then automatically optimized to fit the epicardium for each CT. Estimates of right and left ventricular (RV and LV) volume and free-wall curvature were then calculated and compared to structural and functional metrics obtained from MRI and echocardiograms. RESULTS CT measures of RV dimension and curvature correlated with similar measures obtained using MRI. RV and LV volume obtained from CT inversely correlated with echocardiogram-based estimates of RV systolic pressure using tricuspid regurgitation jet velocity and LV ejection fraction respectively. Patients with evidence of RV or LV dysfunction on echocardiogram had larger RV and LV dimensions on CT. Logistic regression models based on demographics and ventricular measures from CT had an area under the curve of >0.7 for the prediction of elevated right ventricular systolic pressure and ventricular failure. CONCLUSIONS These data suggest that non-cardiac-gated, non-contrast-enhanced thoracic CT scanning may provide insight into cardiac structure and function in smokers.

Arterial and Venous Pulmonary Vascular Morphology and Their Relationship to Findings in Cardiac Magnetic Resonance Imaging in Smokers.

Objective Prior work has described the relationship between pulmonary vascular pruning on computed tomography (CT) scans and metrics of right-sided heart dysfunction in smokers. In this analysis, we sought to look at pruning on a lobar level, as well as examine the effect of the arterial and venous circulation on this association. Methods Automated vessel segmentation applied to noncontrast CT scans from the COPDGene Study in 24 subjects with cardiac magnetic resonance imaging scans was used to create a blood volume distribution profile. These vessels were then manually tracked to their origin and characterized as artery or vein. Results Assessment of pruning on a lobar level revealed associations between pruning and right ventricular function previously not observed on a global level. The right ventricular mass index, the right ventricular end-systolic volume index, and pulmonary arterial-to-aorta ratio were associated with both arterial and venous pruning, whereas right ventricular ejection fraction was associated with only arterial pruning. Conclusions Lobar assessment and segmentation of the parenchymal vasculature into arterial and venous components provide additional information about the relationship between loss of vasculature on CT scans and right ventricular dysfunction.

Preoperative pulmonary vascular morphology and its relationship to postpneumonectomy hemodynamics.

RATIONALE AND OBJECTIVES Pulmonary edema and pulmonary hypertension are postsurgical complications of pneumonectomy that may represent the remaining pulmonary vasculatures inability to accommodate the entirety of the cardiac output. Quantification of the aggregate pulmonary vascular cross-sectional area (CSA) has been used to study the development of pulmonary vascular disease in smokers. In this study, we applied this technique to demonstrate the potential utility of pulmonary vascular quantification in surgical risk assessment. Our hypothesis was that those subjects with the lowest aggregate vascular CSA in the nonoperative lung would be most likely to have elevated pulmonary vascular pressures in the postoperative period. MATERIALS AND METHODS A total of 61 subjects with postoperative hemodynamics and adequate imaging were identified from 159 patients undergoing pneumonectomies for mesothelioma. The total CSA of blood vessels perpendicular to the plane of computed tomographic (CT) scan slices was computed for blood vessels <5 mm(2) (CSA 5 mm). This measurement expressed as a percentage of lung parenchyma area (CSA 5%) was compared to postoperative hemodynamic measurements obtained by right heart catheterization. RESULTS In patients where a contrasted CT scan was used (n = 26), CSA 5% was correlated with postoperative day 0 minimum cardiac index (R = 0.37, P = .03) but not with the maximum pulmonary arterial pressures. In patients with noncontrast CT scans (n = 35), CSA 5% was inversely correlated with postoperative day 0 maximum pulmonary arterial pressures (R = 0.43, P = .03) but not with the minimum cardiac index. The preoperative perfusion fraction of the nonsurgical lung did not correlate with postoperative hemodynamics. CONCLUSIONS CSA of pulmonary vasculature with an area ≤5 mm(2) has potential in estimating the ability of pulmonary vascular bed to accommodate postsurgical changes in pneumonectomy.

Interstitial Features at Chest CT Enhance the Deleterious Effects of Emphysema in the COPDGene Cohort

Purpose To determine if interstitial features at chest CT enhance the effect of emphysema on clinical disease severity in smokers without clinical pulmonary fibrosis. Materials and Methods In this retrospective cohort study, an objective CT analysis tool was used to measure interstitial features (reticular changes, honeycombing, centrilobular nodules, linear scar, nodular changes, subpleural lines, and ground-glass opacities) and emphysema in 8266 participants in a study of chronic obstructive pulmonary disease (COPD) called COPDGene (recruited between October 2006 and January 2011). Additive differences in patients with emphysema with interstitial features and in those without interstitial features were analyzed by using t tests, multivariable linear regression, and Kaplan-Meier analysis. Multivariable linear and Cox regression were used to determine if interstitial features modified the effect of continuously measured emphysema on clinical measures of disease severity and mortality. Results Compared with individuals with emphysema alone, those with emphysema and interstitial features had a higher percentage predicted forced expiratory volume in 1 second (absolute difference, 6.4%; P < .001), a lower percentage predicted diffusing capacity of lung for carbon monoxide (DLCO) (absolute difference, 7.4%; P = .034), a 0.019 higher right ventricular-to-left ventricular (RVLV) volume ratio (P = .029), a 43.2-m shorter 6-minute walk distance (6MWD) (P < .001), a 5.9-point higher St Georges Respiratory Questionnaire (SGRQ) score (P < .001), and 82% higher mortality (P < .001). In addition, interstitial features modified the effect of emphysema on percentage predicted DLCO, RVLV volume ratio, 6WMD, SGRQ score, and mortality (P for interaction < .05 for all). Conclusion In smokers, the combined presence of interstitial features and emphysema was associated with worse clinical disease severity and higher mortality than was emphysema alone. In addition, interstitial features enhanced the deleterious effects of emphysema on clinical disease severity and mortality.