Scott Akers

Spectrum of Pulmonary Neuroendocrine Cell Proliferation: Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia, Tumorlet, and Carcinoids

OBJECTIVE The objectives of this article are to review the radiologic, pathologic, and clinical features of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, tumorlet, and carcinoids and to discuss the possible role of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and tumorlet in the development of carcinoids. CONCLUSION Given the potential significant morbidity of diffuse idiopathic pulmonary neuroendocrine cell hyperplasia and its neoplastic counterparts, it is important to understand and recognize these disease entities. A conceptual continuum of these neuroendocrine entities is suggested.

Effective Arterial Elastance Is Insensitive to Pulsatile Arterial Load

Effective arterial elastance (EA) was proposed as a lumped parameter that incorporates pulsatile and resistive afterload and is increasingly being used in clinical studies. Theoretical modeling studies suggest that EA is minimally affected by pulsatile load, but little human data are available. We assessed the relationship between EA and arterial load determined noninvasively from central pressure–flow analyses among middle-aged adults in the general population (n=2367) and a diverse clinical population of older adults (n=193). In a separate study, we investigated the sensitivity of EA to changes in pulsatile load induced by isometric exercise (n=73). The combination of systemic vascular resistance and heart rate predicted 95.6% and 97.8% of the variability in EA among middle-aged and older adults, respectively. EA demonstrated a quasi-perfect linear relationship with the ratio of systemic vascular resistance/heart period (middle-aged adults, R=0.972; older adults, R=0.99; P<0.0001). Aortic characteristic impedance, total arterial compliance, reflection magnitude, and timing accounted together for <1% of the variability in EA in either middle-aged or older adults. Despite pronounced changes in pulsatile load induced by isometric exercise, changes in EA were not independently associated with changes pulsatile load but were rather a nearly perfect linear function of the ratio of systemic vascular resistance/heart period (R=0.99; P<0.0001). Our findings demonstrate that EA is simply a function of systemic vascular resistance and heart rate and is negligibly influenced by (and insensitive to) changes in pulsatile afterload in humans. Its current interpretation as a lumped parameter of pulsatile and resistive afterload should thus be reassessed.

Low kVp imaging for dose reduction in dual-source cardiac CT

With the widespread application of cardiac CT has come increasing concern over the effects of radiation dose associated with this exam. Dual source CT provides a number of methods for dose reduction in helical ECG-gated cardiac CT studies. This article discusses several of these methods, with a particular emphasis on low kVp scanning, which can be applied in a large percentage of patients.

Aging is Associated With an Earlier Arrival of Reflected Waves Without a Distal Shift in Reflection Sites

Background Despite pronounced increases in central pulse wave velocity (PWV) with aging, reflected wave transit time (RWTT), traditionally defined as the timing of the inflection point (TINF) in the central pressure waveform, does not appreciably decrease, leading to the controversial proposition of a “distal‐shift” of reflection sites. TINF, however, is exceptionally prone to measurement error and is also affected by ejection pattern and not only by wave reflection. We assessed whether RWTT, assessed by advanced pressure‐flow analysis, demonstrates the expected decline with aging. Methods and Results We studied a sample of unselected adults without cardiovascular disease (n=48; median age 48 years) and a clinical population of older adults with suspected/established cardiovascular disease (n=164; 61 years). We measured central pressure and flow with carotid tonometry and phase‐contrast MRI, respectively. We assessed RWTT using wave‐separation analysis (RWTTWSA) and partially distributed tube‐load (TL) modeling (RWTTTL). Consistent with previous reports, TINF did not appreciably decrease with age despite pronounced increases in PWV in both populations. However, aging was associated with pronounced decreases in RWTTWSA (general population −15.0 ms/decade, P<0.001; clinical population −9.07 ms/decade, P=0.003) and RWTTTL (general −15.8 ms/decade, P<0.001; clinical −11.8 ms/decade, P<0.001). There was no evidence of an increased effective reflecting distance by either method. TINF was shown to reliably represent RWTT only under highly unrealistic assumptions about input impedance. Conclusions RWTT declines with age in parallel with increased PWV, with earlier effects of wave reflections and without a distal shift in reflecting sites. These findings have important implications for our understanding of the role of wave reflections with aging.

Isosorbide Dinitrate, With or Without Hydralazine, Does Not Reduce Wave Reflections, Left Ventricular Hypertrophy, or Myocardial Fibrosis in Patients With Heart Failure With Preserved Ejection Fraction

Background Wave reflections, which are increased in patients with heart failure with preserved ejection fraction, impair diastolic function and promote pathologic myocardial remodeling. Organic nitrates reduce wave reflections acutely, but whether this is sustained chronically or affected by hydralazine coadministration is unknown. Methods and Results We randomized 44 patients with heart failure with preserved ejection fraction in a double‐blinded fashion to isosorbide dinitrate (ISDN; n=13), ISDN+hydralazine (ISDN+hydral; n=15), or placebo (n=16) for 6 months. The primary end point was the change in reflection magnitude (RM; assessed with arterial tonometry and Doppler echocardiography). Secondary end points included change in left ventricular mass and fibrosis, measured with cardiac magnetic resonance imaging, and the 6‐minute walk distance. ISDN reduced aortic characteristic impedance (mean baseline=0.15 [95% CI, 0.14–0.17], 3 months=0.11 [95% CI, 0.10–0.13], 6 months=0.10 [95% CI, 0.08–0.12] mm Hg/mL per second; P=0.003) and forward wave amplitude (Pf, mean baseline=54.8 [95% CI, 47.6–62.0], 3 months=42.2 [95% CI, 33.2–51.3]; 6 months=37.0 [95% CI, 27.2–46.8] mm Hg, P=0.04), but had no effect on RM (P=0.64), left ventricular mass (P=0.33), or fibrosis (P=0.63). ISDN+hydral increased RM (mean baseline=0.39 [95% CI, 0.35–0.43]; 3 months=0.31 [95% CI, 0.25–0.36]; 6 months=0.44 [95% CI, 0.37–0.51], P=0.03), reduced 6‐minute walk distance (mean baseline=343.3 [95% CI, 319.2–367.4]; 6 months=277.0 [95% CI, 242.7–311.4] meters, P=0.022), and increased native myocardial T1 (mean baseline=1016.2 [95% CI, 1002.7–1029.7]; 6 months=1054.5 [95% CI, 1036.5–1072.3], P=0.021). A high proportion of patients experienced adverse events with active therapy (ISDN=61.5%, ISDN+hydral=60.0%; placebo=12.5%; P=0.007). Conclusions ISDN, with or without hydralazine, does not exert beneficial effects on RM, left ventricular remodeling, or submaximal exercise and is poorly tolerated. ISDN+hydral appears to have deleterious effects on RM, myocardial remodeling, and submaximal exercise. Our findings do not support the routine use of these vasodilators in patients with heart failure with preserved ejection fraction. Clinical Trial Registration URL: www.clinicaltrials.gov. Unique identifier: NCT01516346.

Heart Failure, Left Ventricular Remodeling, and Circulating Nitric Oxide Metabolites.

Background Stable plasma nitric oxide (NO) metabolites (NOM), composed predominantly of nitrate and nitrite, are attractive biomarkers of NO bioavailability. NOM levels integrate the influence of NO‐synthase‐derived NO production/metabolism, dietary intake of inorganic nitrate/nitrite, and clearance of NOM. Furthermore, nitrate and nitrite, the most abundant NOM, can be reduced to NO via the nitrate‐nitrite‐NO pathway. Methods and Results We compared serum NOM among subjects without heart failure (n=126), subjects with heart failure and preserved ejection fraction (HFpEF; n=43), and subjects with heart failure and reduced ejection fraction (HFrEF; n=32). LV mass and extracellular volume fraction were measured with cardiac MRI. Plasma NOM levels were measured after reduction to NO via reaction with vanadium (III)/hydrochloric acid. Subjects with HFpEF demonstrated significantly lower unadjusted levels of NOM (8.0 μmol/L; 95% CI 6.2–10.4 μmol/L; ANOVA P=0.013) than subjects without HF (12.0 μmol/L; 95% CI 10.4–13.9 μmol/L) or those with HFrEF (13.5 μmol/L; 95% CI 9.7–18.9 μmol/L). There were no significant differences in NOM between subjects with HFrEF and subjects without HF. In a multivariable model that adjusted for age, sex, race, diabetes mellitus, body mass index, current smoking, systolic blood pressure, and glomerular filtration rate, HFpEF remained a predictor of lower NOM (β=−0.43; P=0.013). NOM did not correlate with LV mass, or LV diffuse fibrosis. Conclusions HFpEF, but not HFrEF, is associated with reduced plasma NOM, suggesting greater endothelial dysfunction, enhanced clearance, or deficient dietary ingestion of inorganic nitrate. Our findings may underlie the salutary effects of inorganic nitrate supplementation demonstrated in recent clinical trials in HFpEF.

Late Systolic Myocardial Loading Is Associated With Left Atrial Dysfunction in HypertensionCLINICAL PERSPECTIVE

Background— Late systolic load has been shown to cause diastolic dysfunction in animal models. Although the systolic loading sequence of the ventricular myocardium likely affects its coupling with the left atrium (LA), this issue has not been investigated in humans. We aimed to assess the relationship between the myocardial loading sequence and LA function in human hypertension. Methods and Results— We studied 260 subjects with hypertension and 19 normotensive age- and sex-matched controls. Time-resolved central pressure and left ventricular geometry were measured with carotid tonometry and cardiac magnetic resonance imaging, respectively, for computation of time-resolved ejection-phase myocardial wall stress (MWS). The ratio of late/early ejection-phase MWS time integrals was computed as an index of late systolic myocardial load. Atrial mechanics were measured with cine-steady-state free-precession magnetic resonance imaging using feature-tracking algorithms. Compared with normotensive controls, hypertensive participants demonstrated increased late/early ejection-phase MWS and reduced LA function. Greater levels of late/early ejection-phase MWS were associated with reduced LA conduit, reservoir, and booster pump LA function. In models that included early and late ejection-phase MWS as independent correlates of LA function, late systolic MWS was associated with lower, whereas early systolic MWS was associated with greater LA function, indicating an effect of the relative loading sequence (late versus early MWS) on LA function. These relationships persisted after adjustment for multiple potential confounders. Conclusions— A myocardial loading sequence characterized by prominent late systolic MWS was independently associated with atrial dysfunction. In the context of available experimental data, our findings support the deleterious effects of late systolic loading on ventricular–atrial coupling.

Inactive Matrix Gla-Protein and Arterial Stiffness in Type 2 Diabetes Mellitus

BACKGROUND Large artery stiffness is increased in diabetes mellitus and causes an excessive pulsatile load to the heart and to the microvasculature. The identification of pathways related to arterial stiffness may provide novel therapeutic targets to ameliorate arterial stiffness in diabetes. Matrix Gla-Protein (MGP) is an inhibitor of vascular calcification. Activation of MGP is vitamin K dependent. We hypothesized that levels of inactive MGP (dephospho-uncarboxylated MGP; dp-ucMGP) are related to arterial stiffness in type 2 diabetes. METHODS We enrolled a multiethnic cohort of 66 participants with type 2 diabetes. Carotid-femoral pulse wave velocity (CF-PWV) was measured with high-fidelity arterial tonometry (Sphygmocor Device). Dp-ucMGP was measured with ELISA (VitaK; The Netherlands). RESULTS The majority of the participants were middle-aged (62 ± 12 years), male (91%), and had a history of hypertension (82%). Average hemoglobin A1C was 7.2% (55 mmol/mol). Mean dp-ucMGP was 624 ± 638 pmol/l and mean CF-PWV was 11 ± 4 m/sec. In multivariable analyses, dp-ucMGP was independently related to African American ethnicity (&bgr; = −0.24, P = 0.005), warfarin use (&bgr; = 0.56, P < 0.001), and estimated glomerular filtration rate (eGFR, &bgr; = −0.32, P < 0.001). Dp-ucMGP predicted CF-PWV (&bgr; = 0.40, P = 0.011), even after adjustment for age, gender, ethnicity, mean arterial pressure, eGFR, and warfarin use. CONCLUSIONS In our cross-sectional analysis, circulating dp-ucMGP was independently associated with CF-PWV in type 2 diabetes. This suggests that deficient vitamin K-dependent activation of MGP may lead to large artery stiffening and could be targeted with vitamin K supplementation in the patients with diabetes.

Differential Background Clearance of Fluorodeoxyglucose Activity in Normal Tissues and its Clinical Significance

The clearance of 2-deoxy-2-[18F]fluoro-D-glucose (FDG) activity in normal tissues varies significantly with extended distribution time. Although most tissues have lower standardized uptake value (SUV) on 2-hour/3-hour delayed images, others may have stable or higher FDG activity with longer distribution times. The continuously decreased SUV on delayed imaging in some tissues, especially in the liver, indicates that longer distribution time will decrease background activity, increase lesion-to-background ratio, and thus improve imaging quality, whereas the continuously increased SUV from 1 to 3 hours in the heart suggest that longer distribution time will improve detection of viable myocardium in a viability study.

Beta‐Blocker Use Is Associated With Impaired Left Atrial Function in Hypertension

Background Impaired left atrial (LA) mechanical function is present in hypertension and likely contributes to various complications, including atrial arrhythmias, stroke, and heart failure. Various antihypertensive drug classes exert differential effects on central hemodynamics and left ventricular function. However, little is known about their effects on LA function. Methods and Results We studied 212 subjects with hypertension and without heart failure or atrial fibrillation. LA strain was measured from cine steady‐state free‐precession cardiac MRI images using feature‐tracking algorithms. In multivariable models adjusted for age, sex, race, body mass index, blood pressure, diabetes mellitus, LA volume, left ventricular mass, and left ventricular ejection fraction, beta‐blocker use was associated with a lower total longitudinal strain (standardized β=−0.21; P=0.008), and lower LA expansion index (standardized β=−0.30; P<0.001), indicating impaired LA reservoir function. Beta‐blocker use was also associated with a lower positive strain (standardized β=−0.19; P=0.012) and early diastolic strain rate (standardized β=0.15; P=0.039), indicating impaired LA conduit function. Finally, beta‐blocker use was associated with a lower (less negative) late‐diastolic strain (standardized β=0.15; P=0.049), strain rate (standardized β=0.18; P=0.019), and a lower active LA emptying fraction (standardized β=−0.27; P<0.001), indicating impaired booster pump function. Use of other antihypertensive agents was not associated with LA function. Conclusions Beta‐blocker use is significantly associated with impaired LA function in hypertension. This association could underlie the increased risk of atrial fibrillation and stroke seen with the use of beta‐blockers (as opposed to other antihypertensive agents) demonstrated in recent trials.