Bindu Chamarthi

Features and prognosis of exertional syncope in light-chain associated AL cardiac amyloidosis

Syncope is common in AL amyloid heart disease and in almost 1/3 of our patients who experienced syncope, it was precipitated by physiologic stress. Stress-precipitated syncope was associated with a poor prognosis in such patients, both in terms of their median survival of 2 months and was frequently a precursor of sudden cardiac death.

Preoperative A1C and clinical outcomes in patients with diabetes undergoing major noncardiac surgical procedures.

OBJECTIVE To evaluate the relationship between preoperative A1C and clinical outcomes in individuals with diabetes mellitus undergoing noncardiac surgery. RESEARCH DESIGN AND METHODS Data were obtained from the National Surgical Quality Improvement Program database and the Research Patient Data Registry of the Brigham and Women’s Hospital. Patients admitted to the hospital for ≥1 day after undergoing noncardiac surgery from 2005 to 2010 were included in the study. RESULTS Of 1,775 patients with diabetes, 622 patients (35%) had an A1C value available within 3 months before surgery. After excluding same-day surgeries, patients with diabetes were divided into four groups (A1C ≤6.5% [N = 109]; >6.5–8% [N = 202]; >8–10% [N = 91]; >10% [N = 47]) and compared with age-, sex-, and BMI-matched nondiabetic control subjects (N = 888). Individuals with A1C values between 6.5 and 8% had a hospital length of stay (LOS) similar to the matched control group (P = 0.5). However, in individuals with A1C values ≤6.5 or >8%, the hospital LOS was significantly longer compared with the control group (P < 0.05). Multivariate regression analysis demonstrated that a higher A1C value was associated with increased hospital LOS after adjustments for age, sex, BMI, race, type of surgery, Charlson Comordity Index, smoking status, and glucose level on the day of surgery (P = 0.02). There were too few events to meaningfully evaluate for death, infections, or readmission rate. CONCLUSIONS Our study suggests that chronic hyperglycemia (A1C >8%) is associated with poor surgical outcomes (longer hospital LOS). Providing a preoperative intervention to improve glycemic control in individuals with A1C values >8% may improve surgical outcomes, but prospective studies are needed.

Inflammation and Hypertension: The Interplay of Interleukin-6, Dietary Sodium, and the Renin–Angiotensin System in Humans

BACKGROUND Prior evidence suggests a link between inflammation and hypertension. Interleukin-6 (IL-6) has been implicated in animal studies to play an important role in angiotensin II (ANGII)-mediated hypertension. The aim of this study was to examine the relationship of IL-6 and renin-angiotensin system (RAS) activity in human hypertension. METHODS Data from 385 hypertensives and 196 normotensives are included in this report. Blood pressure and laboratory evaluation were performed on liberal and low sodium diets. IL-6 response to an ANGII infusion was evaluated to assess the effect of acute RAS activation. RESULTS Hypertensives had higher baseline IL-6 and C-reactive protein (CRP) compared with normotensives on both diets. IL-6 increased in response to ANGII in hypertensives and normotensives (28% in hypertensives, 31% in normotensives, P ≤ 0.001 for change from baseline). In the setting of RAS activation by a low salt diet, multivariate regression analysis adjusted for age, body mass index (BMI), gender, race, and hypertension status demonstrated an independent positive association of plasma renin activity (PRA) with CRP (β = 0.199, P < 0.001). There was no significant difference in IL-6 or CRP levels between liberal and low sodium diets. CONCLUSION These findings confirm an association between hypertension and inflammation and provide human data supporting previous evidence from animal studies that IL-6 plays a role in ANGII-mediated hypertension. Notably, compared to levels on a liberal sodium diet, neither IL-6 nor CRP were higher with activation of the RAS by a low salt diet indicating that a low sodium diet is not inflammatory despite increased RAS activity.

A MECHANISM FOR SALT SENSITIVE HYPERTENSION: ABNORMAL DIETARY SODIUM MEDIATED VASCULAR RESPONSE TO ANGIOTENSIN II

Objectives Several mechanisms have been proposed for salt-sensitive hypertension, with most focusing on impaired renal sodium handling. We tested the hypothesis that abnormalities in peripheral vascular responsiveness to angiotensin-II (ANGII) might also exist in salt-sensitive hypertension because of the interplay of the renin–angiotensin system and dietary sodium. Methods Blood pressure (BP) response to ANGII infusion was studied in 295 hypertensive and 165 normotensive individuals after 7 days of high (200 mEq/day) and low (10 mEq/day) dietary sodium. Results Normotensive individuals demonstrated higher BP response to ANGII on high-salt than low-salt diet, whereas hypertensive individuals had similar responses on both diets; that is, the high-salt response was not enhanced as compared with low-salt response. Additionally, hypertensive individuals had a significantly greater high-salt BP response to norepinephrine than to ANGII. There was no correlation between the high-salt hormone levels and the difference in BP response to ANGII between the two diets. When stratified by BP response to dietary salt restriction, individuals with salt sensitivity of BP demonstrated abnormal high-salt BP responsiveness to ANGII. To assess if this represented increased tissue renin–angiotensin system activity in the vasculature, BP responses to angiotensin were compared before and after captopril in 20 hypertensive individuals on a high-salt diet. Individuals with the greatest BP-lowering effect to captopril had similar high and low-salt BP responses to ANGII at baseline and a significant increase in the high-salt response after captopril. Conclusion Hypertensive individuals have an abnormal vascular response to ANGII infusion on a high-salt diet. Dysregulated tissue renin–angiotensin system activity may play a role in this abnormal response. These findings raise an intriguing novel possibility for the pathophysiologic mechanism of salt-sensitive hypertension.

Branched chain and aromatic amino acids change acutely following two medical therapies for type 2 diabetes mellitus

OBJECTIVE Elevated circulating levels of branched chain and aromatic amino acids (BCAA/AAAs) are associated with insulin resistance and incident type 2 diabetes (T2D). BCAA/AAAs decrease acutely during an oral glucose tolerance test (OGTT), a diagnostic test for T2D. It is unknown whether changes in BCAA/AAAs also signal an early response to commonly used medical therapies for T2D. MATERIALS AND METHODS A liquid chromatography-mass spectrometry approach was used to measure BCAA/AAAs in 30 insulin sensitive (IS) and 30 insulin resistant (IR) subjects before and after: (1) one dose of a sulfonylurea medication, glipizide, 5 mg orally; (2) two days of twice daily metformin 500 mg orally; and (3) a 75-g OGTT. Percent change in BCAA/AAAs was determined after each intervention. RESULTS Following glipizide, which increased insulin and decreased glucose in both subject groups, BCAA/AAAs decreased in the IS subjects only (all P<0.05). Following metformin, which decreased glucose and insulin in only the IR subjects, 4 BCAA/AAAs increased in the IR subjects at or below P=0.05, and none changed in the IS subjects. Following OGTT, which increased glucose and insulin in all subjects, BCAA/AAAs decreased in all subjects (P<0.05). CONCLUSIONS BCAA/AAAs changed acutely during glipizide and metformin administration, and the magnitude and direction of change differed by the insulin resistance status of the individual and the intervention. These results indicate that BCAA/AAAs may be useful biomarkers for monitoring the early response to therapeutic interventions for T2D.

Lysine-specific demethylase 1: an epigenetic regulator of salt-sensitive hypertension.

BACKGROUND Hypertension (HTN) represents a complex heritable disease in which environmental factors may directly affect gene function via epigenetic mechanisms. The aim of this study was to test the hypothesis that dietary salt influences the activity of a histone-modifying enzyme, lysine-specific demethylase 1 (LSD-1), which in turn is associated with salt-sensitivity of blood pressure (BP). METHODS Animal and human studies were performed. Salt-sensitivity of LSD-1 expression was assessed in wild-type (WT) and LSD-1 heterozygote knockout (LSD-1(+/-)) mice. Clinical relevance was tested by multivariate associations between single-nuclear polymorphisms (SNPs) in the LSD-1 gene and salt-sensitivity of BP, with control of dietary sodium, in a primary African-American hypertensive cohort and two replication hypertensive cohorts (Caucasian and Mexican-American). RESULTS LSD-1 expression was modified by dietary salt in WT mice with lower levels associated with liberal salt intake. LSD-1(+/-) mice expressed lower LSD-1 protein levels than WT mice in kidney tissue. Similar to LSD-1(+/-) mice, African-American minor allele carriers of two LSD-1 SNPs displayed greater change in systolic BP (SBP) in response to change from low to liberal salt diet (rs671357, P = 0.01; rs587168, P = 0.005). This association was replicated in the Hispanic (rs587168, P = 0.04) but not the Caucasian cohort. Exploratory analyses demonstrated decreased serum aldosterone concentrations in African-American minor allele carriers similar to findings in the LSD-1(+/-) mice, decreased α-EnaC expression in LSD-1(+/-) mice, and impaired renovascular responsiveness to salt loading in minor allele carriers. CONCLUSION The results of this translational research study support a role for LSD-1 in the pathogenesis of salt-sensitive HTN.

Renin gene polymorphism: its relationship to hypertension, renin levels and vascular responses.

The renin gene has been previously reported to be associated with essential hypertension in a variety of ethnic groups. However, no studies have systematically evaluated the relationship between single nucleotide polymorphisms (SNPs) representing coverage of the entire renin gene and hypertension risk. To evaluate the association between renin gene variation and hypertension we investigated data on HyperPATH cohort with 570 hypertensive and 222 normotensive Caucasian subjects. Six tagging SNPs and resultant haplotypes were tested for associations with hypertension risk, followed by mean arterial pressure (MAP), plasma renin activity (PRA) and the change in MAP in response to angiotensin II (AngII) infusion (AngII ΔMAP). The A allele of SNP rs6693954 and the haplotype containing rs6696954A were significantly associated with higher risk for hypertension (OR = 1.98, p = 0.0001; OR = 1.63 p = 0.0005, respectively). The same haplotype block was also associated with altered PRA levels and blunted AngII ΔMAP (global p-value = 0.02, 0.047, respectively). Our results confirm that polymorphisms in the renin gene are associated with increased risk for hypertension in an independent cohort, and that the underlying mechanism may reside in the interaction of renin activity and vascular responsiveness to angiotensin II.

Replication and Meta-analysis of the Gene-Environment Interaction between Body Mass Index and the Interleukin-6 Promoter Polymorphism with Higher Insulin Resistance

Insulin resistance (IR) is a complex disorder caused by an interplay of both genetic and environmental factors. Recent studies identified a significant interaction between body mass index (BMI) and the rs1800795 polymorphism of the interleukin-6 gene that influences both IR and onset of type 2 diabetes mellitus, with obese individuals homozygous for the C allele demonstrating the highest level of IR and greatest risk for type 2 diabetes mellitus. Replication of a gene-environment interaction is important to confirm the validity of the initial finding and extend the generalizability of the results to other populations. Thus, the objective of this study was to replicate this gene-environment interaction on IR in a hypertensive population and perform a meta-analysis with prior published results. The replication analysis was performed using white individuals with hypertension from the Hypertensive Pathotype cohort (N = 311), genotyped for rs1800795. Phenotype studies were conducted after participants consumed 2 diets--high sodium (200 mmol/d) and low sodium (10 mmol/d)--for 7 days each. Measurements for plasma glucose, insulin, and interleukin-6 were obtained after 8 hours of fasting. Insulin resistance was characterized by the homeostatic model assessment (HOMA-IR). In Hypertensive Pathotype, BMI was a significant effect modifier of the relationship between rs1800795 and HOMA-IR; higher BMI was associated with higher HOMA-IR among homozygote CC individuals when compared with major allele G carriers (P = .003). Furthermore, the meta-analysis in 1028 individuals confirmed the result, demonstrating the same significant interaction between rs1800795 and BMI on HOMA-IR (P = 1.05 × 10(-6)). This rare replication of a gene-environment interaction extends the generalizability of the results to hypertension while highlighting this polymorphism as a marker of IR in obese individuals.

Early Identification of Individuals with Poorly Controlled Diabetes Undergoing Elective Surgery: Improving A1C Testing in the Preoperative Period.

OBJECTIVE To describe a process improvement strategy that increased the identification of individuals with poorly controlled diabetes (glycated hemoglobin [A1C] ≥8%) undergoing elective surgery at a major academic medical center and increased their access to specialist care. METHODS An algorithm was developed to ensure A1C measurements were obtained as per the American Association of Clinical Endocrinologists/American Diabetes Association (AACE/ADA) guidelines. The diabetes management team worked collaboratively with anesthesiologists, surgeons, and preoperative nurse practitioners to improve the glycemic control of patients with an A1C ≥8%. RESULTS Before implementing the program, A1C testing was recorded in 854 out of 2,335 (37%) patients with diabetes seen in the preoperative clinic from January 1, 2011 to December 31, 2012. The program was instituted in February 2013. From February 2013 to February 2014, A1C testing occurred in 1,236 out of 1,334 (93%) patients with diabetes. After excluding those scheduled for same day surgery, 228 patients were considered high risk with A1C ≥8%, and 175 were available for endocrine preoperative consultation. The program led to significant blood glucose level improvements on the day of surgery. CONCLUSION A process improvement strategy to evaluate and treat diabetes in the preoperative period of elective surgery patients was implemented by a multidisciplinary team (endocrinologists, nurse practitioners, anesthesiologists, and surgeons) and resulted in a substantial improvements in obtaining A1C tests, access to specialist diabetes care, and glycemic control on the day of surgery. The impact of improved glycemic control on hospital and surgical outcomes needs further evaluation.

Predictors of plasma and urinary catecholamine levels in normotensive and hypertensive men and women

Age, sex, hypertension and dietary sodium are proposed to affect plasma and urinary catecholamines. Yet no prior study has examined the simultaneous effects of these factors within the same study population. So results may have been confounded by factors not determined. We investigate, for the first time, the impact of simultaneously determined predictors of plasma and urinary catecholamines and the relationship of catecholamines with the diagnosis of hypertension. Hypertensive and normotensive subjects (n=308) were studied off antihypertensives in liberal and low sodium balance. 24 h urinary catecholamines (norepinephrine and epinephrine) were measured. Plasma catecholamines were measured supine after overnight fast. Repeated measures multivariate linear regression models examined the effect of sex, race, age, body mass index (BMI), dietary salt (liberal salt vs low salt), hypertension status and mean arterial pressure (MAP) on plasma and urinary catecholamines. Logistic regression determined the relationship of catecholamines with diagnosis of hypertension. Dietary sodium restriction and increasing age predicted increased plasma and urinary norepinephrine, with sodium restriction having the greatest effect. Female sex predicted lower urinary and plasma epinephrine. Neither plasma nor urinary catecholamines predicted the diagnosis of hypertension. In summary, specific demographic factors variably impact catecholamines and should be considered when assessing catecholamines in research and clinical settings.