Angela Price

Noninvasive Quantification of Pancreatic Fat in Humans

OBJECTIVE To validate magnetic resonance spectroscopy (MRS) as a tool for non-invasive quantification of pancreatic triglyceride (TG) content and to measure the pancreatic TG content in a diverse human population with a wide range of body mass index (BMI) and glucose control. METHODS To validate the MRS method, we measured TG content in the pancreatic tissue of 12 lean and 12 fatty ZDF rats (ages 5-14 weeks) both by MRS and the gold standard biochemical assay. We used MRS to measure pancreatic TG content in vivo in 79 human volunteers. Additionally, to assess the reproducibility of the method, in 33 volunteers we obtained duplicate MRS measurements 1-2 weeks apart. RESULTS MRS quantifies pancreatic TG content with high reproducibility and concordance to the biochemical measurement (Spearmans rank correlation coefficient = 0.91). In humans, median pancreatic TG content was as follows: (1) normal weight and normoglycemic group 0.46 f/w%, (2) overweight or obese but normoglycemic group 3.16 f/w%, (3) impaired fasting glucose or impaired glucose tolerance group (BMI matched with group 2) 5.64 f/w%, and (4) untreated type 2 diabetes group (BMI matched with group 2) 5.54 f/w% (Jonckheere-Terpstra trend test across groups p < 0.001). CONCLUSIONS Human pancreatic steatosis, as measured by MRS, increases with BMI and with impaired glycemia. MRS is a quantitative and reproducible non-invasive clinical research tool which will enable systematic studies of the relationship between ectopic fat accumulation in the pancreas and development of type 2 diabetes.

Appropriate Use and Clinical Impact of Transthoracic Echocardiography

IMPORTANCE Transthoracic echocardiography (TTE) accounts for almost half of all cardiac imaging services and is a widely available and versatile tool. Appropriate use criteria (AUC) for echocardiography were developed to improve patient care and health outcomes. Prior studies have shown that most TTEs are appropriate by AUC. However, the associations among TTE, AUC, and their clinical impact have not been well explored. OBJECTIVES To describe the proportion of TTEs that affect clinical care in an academic medical center overall and in subgroups defined as appropriate and inappropriate by AUC. DESIGN AND SETTING Retrospective review of medical records from 535 consecutive TTEs at an academic medical center was performed. The TTEs were classified according to 2011 AUC by 2 cardiologists blinded to clinical impact and were assessed for clinical impact by 2 cardiologists blinded to AUC. Clinical impact was assigned to 1 of the following 3 categories: (1) active change in care, (2) continuation of current care, or (3) no change in care. PARTICIPANTS Five hundred thirty-five patients undergoing TTE. EXPOSURE Transthoracic echocardiography. MAIN OUTCOMES AND MEASURES Prevalence of appropriate, inappropriate, and uncertain TTEs and prevalence of clinical impact subcategories. RESULTS Overall, 31.8% of TTEs resulted in an active change in care; 46.9%, continuation of current care; and 21.3%, no change in care. By 2011 AUC, 91.8% of TTEs were appropriate; 4.3%, inappropriate; and 3.9%, uncertain. We detected no statistically significant difference between appropriate and inappropriate TTEs in the proportion of TTEs that led to active change in care (32.2% vs 21.7%; P= .29). CONCLUSIONS AND RELEVANCE Although 9 in 10 TTEs were appropriate by 2011 AUC, fewer than 1 in 3 TTEs resulted in an active change in care, nearly half resulted in continuation of current care, and slightly more than 1 in 5 resulted in no change in care. The low rate of active change in care (31.8%) among TTEs mostly classified as appropriate (91.8%) highlights the need for a better method to optimize TTE utilization to use limited health care resources efficiently while providing high-quality care.

Spironolactone Prevents Chlorthalidone-Induced Sympathetic Activation and Insulin Resistance in Hypertensive Patients

Recent studies from our laboratory indicate that chlorthalidone triggers persistent activation of the sympathetic nervous system and promotes insulin resistance in hypertensive patients, independent of serum potassium. Mechanisms underlying these adverse effects of chlorthalidone remain unknown, but increasing evidence in rodents suggests the role of angiotensin and aldosterone excess in inducing both sympathetic overactivity and insulin resistance. Accordingly, we conducted studies in 17 subjects with untreated stage 1 hypertension, measuring sympathetic nerve activity at baseline and after 12 weeks of chlorthalidone alone (25 mg/d), chlorthalidone plus spironolactone, and chlorthalidone plus irbesartan, using randomized crossover design. We found that chlorthalidone alone decreased 24-hour ambulatory blood pressure from 135±3/84±2 to 124±2/78±2 mm Hg and significantly increased sympathetic nerve activity from baseline (from 41±3 versus 49±4 bursts per minute; P<0.01). The addition of spironolactone to chlorthalidone returned sympathetic nerve activity value to baseline (42±3 bursts per minute; P>0.05), whereas the addition of irbesartan failed to alter the sympathetic nerve activity response to chlorthalidone in the same subjects (52±2 bursts per minute; P<0.01) despite a similar reduction in ambulatory blood pressure (121±2/75±2 and 121±2/75±2 mm Hg, respectively). Chlorthalidone alone also increased indices of insulin resistance, which was not observed when used in combination with spironolactone. In conclusion, our study demonstrates beneficial effects of spironolactone in attenuating both chlorthalidone-induced sympathetic activation and insulin resistance in humans, independent of blood pressure reduction. Because sympathetic overactivity and insulin resistance contribute to the poor prognosis in patients with cardiovascular disease, combination therapy of chlorthalidone with mineralocorticoid receptor antagonists may constitute a preferable regimen than chlorthalidone alone in hypertensive patients.

Differential Effects of Nebivolol Versus Metoprolol on Functional Sympatholysis in Hypertensive Humans

&NA; In young healthy humans, sympathetic vasoconstriction is markedly blunted during exercise to optimize blood flow to the metabolically active muscle. This phenomenon known as functional sympatholysis is impaired in hypertensive humans and rats by angiotensin II–dependent mechanisms, involving oxidative stress and inactivation of nitric oxide (NO). Nebivolol is a &bgr;1-adrenergic receptor blocker that has NO-dependent vasodilatory and antioxidant properties. We therefore asked whether nebivolol would restore functional sympatholysis in hypertensive humans. In 21 subjects with stage 1 hypertension, we measured muscle oxygenation and forearm blood flow responses to reflex increases in sympathetic nerve activity evoked by lower body negative pressure at rest, and during rhythmic handgrip exercise at baseline, after 12 weeks of nebivolol (5–20 mg/d) or metoprolol (100–300 mg/d), using a double-blind crossover design. We found that nebivolol had no effect on lower body negative pressure–induced decreases in oxygenation and forearm blood flow in resting forearm (from −29±5% to −30±5% and from −29±3% to −29±3%, respectively; P=NS). However, nebivolol attenuated the lower body negative pressure–induced reduction in oxygenation and forearm blood flow in exercising forearm (from −14±4% to −1±5% and from −15±2% to −6±2%, respectively; both P<0.05). This effect of nebivolol on oxygenation and forearm blood flow in exercising forearm was not observed with metoprolol in the same subjects, despite a similar reduction in blood pressure. Nebivolol had no effect on sympathetic nerve activity at rest or during handgrip, suggesting a direct effect on vascular function. Thus, our data demonstrate that nebivolol restored functional sympatholysis in hypertensive humans by a mechanism that does not involve &bgr;1-adrenergic receptors. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01502787.

The metabolic cost of lowering blood pressure with hydrochlorothiazide

BackgroundThe landmark Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) placed a new spotlight on thiazide diuretics as the first-line therapy for hypertension. This is concerning as thiazide-diuretics may contribute to comorbidities associated with the current epidemic of obesity. Previous randomized clinical trials have linked thiazide diuretic treatment to insulin resistance, metabolic syndrome, and increased incidence of type 2 diabetes.MethodsThis proof of concept, longitudinal, randomized, double–blind study evaluated the effects of the angiotensin II receptor blocker Valsartan and the specific thiazide diuretic Hydrochlorothiazide (HCTZ) on hepatic triglyceride level (primary outcome), as well as triglyceride levels within other organs including the heart, skeletal muscle, and pancreas. Additionally, we evaluated whether myocardial function, insulin sensitivity, and insulin secretion were affected by these treatments.ResultsHepatic TG levels increased by 57% post HCTZ treatment: ∆hTG HCTZ = 4.12% and remained unchanged post Valsartan treatment: ∆hTG V = 0.06%. The elevation of hepatic TG levels after HCTZ treatment was additionally accompanied by a reduction in insulin sensitivity: ∆SI HCTZ = -1.14. Treatment with Valsartan resulted in improved insulin sensitivity: ∆SI V = 1.24. Treatment-induced changes in hepatic TG levels and insulin sensitivity were statistically significant between groups (phTG = 0.0098 and pSI = 0.0345 respectively). Disposition index, DI, remained unchanged after HCTZ treatment: ∆DI HCTZ = -141 but it was increased by a factor of 2 after treatment with Valsartan: ∆DI V =1018). However, the change between groups was not statistically significant. Both therapies did not modify abdominal visceral and subcutaneous fat mass as well as myocardial structure and function. Additionally, myocardial, pancreatic, and skeletal muscle triglyceride deposits remained unchanged in both therapeutic arms.ConclusionsOur findings are two-fold and relate to hepatic steatosis and insulin sensitivity. HCTZ treatment worsened hepatic steatosis measured as hepatic triglyceride content and reduced insulin sensitivity. Valsartan treatment did not affect hepatic triglyceride levels and improved insulin sensitivity. The results of this study reinforce the message that in patients at risk for type 2 diabetes it is particularly important to choose an antihypertensive regimen that lowers blood pressure without exacerbating patient’s metabolic profile.

Differential effects of nebivolol vs. metoprolol on microvascular function in hypertensive humans.

Use of β-adrenergic receptor (AR) blocker is associated with increased risk of fatigue and exercise intolerance. Nebivolol is a newer generation β-blocker, which is thought to avoid this side effect via its vasodilating property. However, the effects of nebivolol on skeletal muscle perfusion during exercise have not been determined in hypertensive patients. Accordingly, we performed contrast-enhanced ultrasound perfusion imaging of the forearm muscles in 25 untreated stage I hypertensive patients at rest and during handgrip exercise at baseline or after 12 wk of treatment with nebivolol (5-20 mg/day) or metoprolol succinate (100-300 mg/day), with a subsequent double crossover for 12 wk. Metoprolol and nebivolol each induced a reduction in the resting blood pressure and heart rate (130.9 ± 2.6/81.7 ± 1.8 vs. 131.6 ± 2.7/80.8 ± 1.5 mmHg and 63 ± 2 vs. 64 ± 2 beats/min) compared with baseline (142.1 ± 2.0/88.7 ± 1.4 mmHg and 75 ± 2 beats/min, respectively, both P < 0.01). Metoprolol significantly attenuated the increase in microvascular blood volume (MBV) during handgrip at 12 and 20 repetitions/min by 50% compared with baseline (mixed-model P < 0.05), which was not observed with nebivolol. Neither metoprolol nor nebivolol affected microvascular flow velocity (MFV). Similarly, metoprolol and nebivolol had no effect on the increase in the conduit brachial artery flow as determined by duplex Doppler ultrasound. Thus our study demonstrated a first direct evidence for metoprolol-induced impairment in the recruitment of microvascular units during exercise in hypertensive humans, which was avoided by nebivolol. This selective reduction in MBV without alteration in MFV by metoprolol suggested impaired vasodilation at the precapillary arteriolar level.

Cost-Effectiveness of Therapeutic Drug Monitoring in Diagnosing Primary Aldosteronism in Patients With Resistant Hypertension.

Primary aldosteronism (PA) is present in up to 20% of patients with treatment‐resistant hypertension (TRH). Investigation for PA in patients with TRH is recommended by current guidelines after medication nonadherence is excluded. Studies using therapeutic drug monitoring (TDM) have shown that >50% of patients with TRH are nonadherent to their prescribed antihypertensive medications. However, the relationship between the prevalence of PA and medication adherence as confirmed by TDM has not been previously assessed. A retrospective analysis from a hypertension referral clinic showed that prevalence of PA in adherent patients with TRH by TDM was significantly higher than in nonadherent patients (28% vs 8%, P<.05). Furthermore, cost analysis showed that TDM‐guided PA screening was

Therapeutic Drug Monitoring Facilitates Blood Pressure Control in Resistant Hypertension

590.69 less expensive per patient, with minimal impact on the diagnostic accuracy. These data support a TDM‐guided PA screening approach as a cost‐saving strategy compared with routine PA screening for TRH.