The metabolic cost of lowering blood pressure with hydrochlorothiazide

Abstract Background The 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. Methods This 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. Results Hepatic 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. Conclusions Our 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

Proton magnetic resonance spectroscopy in skeletal muscle: Experts' consensus recommendations

H-1-MR spectroscopy of skeletal muscle provides insight into metabolism that is not available noninvasively by other methods. The recommendations given in this article are intended to guide those who have basic experience in general MRS to the special application of H-1-MRS in skeletal muscle. The highly organized structure of skeletal muscle leads to effects that change spectral features far beyond simple peak heights, depending on the type and orientation of the muscle. Specific recommendations are given for the acquisition of three particular metabolites (intramyocellular lipids, carnosine and acetylcarnitine) and for preconditioning of experiments and instructions to study volunteers.Peer reviewe

Measurement of pancreatic volume by abdominal MRI: a validation study.

To develop abdominal magnetic resonance imaging (MRI) protocol to measure pancreatic volume in humans and to validate it in large animals.We performed abdominal MRI in eight mini-pigs using a clinical 3T MRI system. We used consecutive parallel abdominal slices, covering the entire pancreas to calculate pancreatic volume. Following MRI, animals were sacrificed, the pancreas was removed, and the volume of the pancreas was measured by water displacement. We used the same MRI protocol to measure pancreatic volume in 21 humans. To assess reproducibility of in vivo measurement we repeated MRI pancreas volume evaluation within 24 hours in additional five humans.In mini-pigs the measurements of pancreatic volume by MRI and by water displacement were almost identical (R(2) = 0.9867; p<0.0001). In humans the average pancreas volume was 72.7+/-4.5 ml, range from 35.0 to 105.5 ml. This result is in strong agreement with results of previous large postmortem and computed tomography (CT) studies. Repeated measurements of pancreatic volume in humans were highly reproducible. Pancreatic volume measured in vivo was negatively correlated with age, body fat mass, pancreatic TG levels, and visceral fat mass.These initial results are highly encouraging and our protocol for pancreatic volume estimation in vivo may prove useful in obesity research to follow in vivo changes of pancreatic volume and structure during time course of obesity and type 2 diabetes development

General characteristics, metabolic variables, and abdominal and pancreatic fat distribution of study subjects.

<p>BMI- body mass index, AIR_g – acute insulin response to glucose, LDL – low density lipoprotein, HDL – high density lipoprotein, SBP – systolic blood pressure, DBP – diastolic blood pressure).</p

Human pancreas imaging.

<p>A. Representative, human abdominal image with pancreas highlighted in yellow. In average 47 slices were needed to cover entire human pancreas. The slice orientation is oblique relative to human body but it is axial relative to pancreas. B. High reproducibility of pancreatic volume measurement by abdominal MRI in 4 human subjects with the average pancreas size within 24 hours. The filled circles represent measurement at visit 1 and open circles represent measurement at visit 2, 24 hours later.</p

Pancreas volume measurements.

<p>A. In vivo – Representative abdominal image with highlighted pig pancreas. In average 20 abdominal slices were needed to cover entire mini-pig pancreas. B. Ex vivo - the extracted mini-pig pancreas.</p

The histogram of pancreatic volume in studied population.

<p>The histogram of pancreatic volume in studied population.</p

The strong correlation of pancreatic volumes measured by MRI and ex vivo.

<p>The correlation remains strong even without the point from an animal with an exceptionally large pancreatic volume. The dashed line indicates identity line.</p

Myocardial steatosis across the spectrum of human health and disease

Abstract Preclinical data strongly suggest that myocardial steatosis leads to adverse cardiac remodelling and left ventricular dysfunction. Using 1H cardiac magnetic resonance spectroscopy, similar observations have been made across the spectrum of health and disease. The purpose of this brief review is to summarize these recent observations. We provide a brief overview of the determinants of myocardial triglyceride accumulation, summarize the current evidence that myocardial steatosis contributes to cardiac dysfunction, and identify opportunities for further research