Publications

Most Recent Papers

Randomized Placebo Controlled Trial to Evaluate Effects of Eplerenone on Myocardial Perfusion and Function among Persons with HIV-Results from the MIRACLE HIV Study.

Srinivasa S, Walpert AR, Thomas TS, Huck DM, Jerosch-Herold M, Islam S, Lu MT, Burdo TH, deFilippi CR, Dunderdale CN, Feldpausch M, Iyengar S, Shen G, Baak S, Torriani M, Robbins GK, Lee H, Kwong R, Dicarli M, Adler GK, Grinspoon SK. 

Clin Infect Dis. 2023 May 27:ciad310. doi: 10.1093/cid/ciad310. Online ahead of print. PMID: 37243345 

Abstract 

Background: Increased renin angiotensin aldosterone system(RAAS) activity may contribute to excess cardiovascular disease in people with HIV(PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury and function among well-treated PWH. 

Methods: 40 PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID(n=20) or identical placebo(n=20) for 12 months. The primary endpoints were: 1) myocardial perfusion assessed by coronary flow reserve(CFR) on cardiac PET or stress myocardial blood flow(sMBF) on cardiac MRI or 2) myocardial inflammation by extracellular mass index(ECMi) on cardiac MRI. 

Results: Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI[mean(SD) 0.09(0.56) vs. -0.53(0.68)mL/min/g, P=.03], but not CFR by cardiac PET[0.01(0.64) vs. -0.07(0.48), P=.72, eplerenone vs. placebo]. Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume[-13(28) vs. 10(26)mL, P=.03] and global circumferential strain[median (GCS, median(interquartile range 25th-75th), -1.3(-2.9-1.0) vs. 2.3(-0.4-4.1)%, P=.03], eplerenone vs. placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in GCS(ρ=-0.65, P=.057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion(CFR<2.5 and/or sMBF<1.8), there was a treatment effect of eplerenone vs. placebo to improve CFR[0.28(0.27) vs. -0.05(0.36), P=.04]. Eplerenone prevented a small increase in troponin[0.00(-0.13-0.00) vs. 0.00(0.00-0.74)ng/L, P=.03] without effects on ECMi[0.9(-2.3-4.3) vs. -0.7(-2.2--0.1)g/m2, P=.38). CD4+ T cell count[127(-38-286) vs. -6(-168-53)cells/μL, P=.02] increased in the eplerenone vs. placebo-treated groups. 

Conclusions: RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury and function among PWH with subclinical cardiac disease when compared to placebo. 

Keywords: HIV; coronary flow reserve; eplerenone; global strain; mineralocorticoid receptor antagonist; myocardial blood flow; myocardial dysfunction; renin-angiotensin-aldosterone system. 

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Use and Side Effects of Sodium Glucose Transporter 2 Inhibitors among U.S. People with HIV with Clinical Indications.

Sise ME, Katz-Agranov N, Strohbehn IA, Harden D, Moreno D, Durbin C, Toribio M, Neilan TG, Zanni MV

J Acquir Immune Defic Syndr.2023 May 24. doi: 10.1097/QAI.0000000000003227. Online ahead of print. PMID: 37229530 

Abstract 

Background: Sodium glucose transporter inhibitors have been approved for treatment of diabetes mellitus (DM), chronic kidney disease (CKD), and heart failure (HF), but little is known about prescription levels and safety profiles among PWH. 

Methods: We leveraged data from the U.S. Mass General Brigham (MGB) electronic healthcare database to determine the use/uptake of SGLT2 inhibitors among PWH with DM2 (with or without CKD, proteinuria, or HF) and to assess rates of adverse events among PWH with DM2 taking SGLT2 inhibitors. 

Results: Among eligible PWH with DM2 receiving care at MGB (N=907), SGLT2 inhibitors were prescribed to 8.8%. SGLT2 inhibitors were prescribed to a fraction of eligible PWH with DM2 and a concomitant diagnosis of either CKD (3.8%), proteinuria (13.2%), or HF (8.2%). PWH with DM2 on SGLT2 inhibitors experienced side effects (urinary tract infection, diabetic ketoacidosis, acute kidney injury) at rates comparable to PWH with DM2 prescribed GLP-1 agonists. Rates of mycotic genitourinary infections were higher among those prescribed SGLT2 inhibitors (5% vs. 1%, P = 0.17), but no cases of necrotizing fasciitis ensued. 

Conclusions: Additional studies are needed to characterize population-specific salutary and adverse effects of SGLT2 inhibitors among PWH and potentially augment prescription rates when guideline indicated. 

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Early Detection of Adrenal Insufficiency: The Impact of Newborn Screening for Adrenoleukodystrophy.

Ramirez Alcantara J, Grant NR, Sethuram S, Nagy A, Becker C, Sahai I, Stanley T, Halper A, Eichler FS.J Clin Endocrinol Metab. 2023 May 23:dgad286. doi: 10.1210/clinem/dgad286. Online ahead of print. PMID: 37220095 

Abstract 

Context: Males with adrenoleukodystrophy (ALD) have an 80% lifetime risk of developing adrenal insufficiency (AI), which can be life-threatening when undetected. Newborn screening (NBS) for ALD has been implemented in 29 states, yet the impact of NBS upon clinical management has not been reported. 

Objective: To investigate whether the implementation of NBS has altered the time to diagnosis of AI in children with ALD. 

Design: We conducted a retrospective medical chart review of pediatric patients with ALD. 

Setting: All patients were seen in a leukodystrophy clinic in an academic medical center. 

Patients: We included all pediatric patients with ALD who were seen between May 2006 and January 2022. We identified 116 patients (94% boys). 

Main outcome measures: We extracted information about ALD diagnosis in all patients and AI surveillance, diagnosis, and treatment in boys with ALD. 

Results: Thirty-one (27%) patients were diagnosed with ALD by NBS and 85 (73%) were diagnosed outside the newborn period. The prevalence of AI among boys in our patient population was 74%. AI diagnosis was made significantly earlier in boys diagnosed with ALD by NBS than in boys diagnosed outside the newborn period (median [IQR] age of diagnosis = 6.7 [3.9,12.12] months vs 6.05 [3.74,8.35] years) (p<0.001). When maintenance dose of glucocorticoids were initiated, there were significant differences in ACTH and peak cortisol levels in patients diagnosed by NBS and outside the newborn period. 

Conclusions: Our results suggest that implementing NBS for ALD leads to significantly earlier detection of AI and earlier initiation of glucocorticoid supplementation in boys affected by ALD. 

Keywords: adrenal insufficiency; adrenoleukodystrophy; newborn screening. 

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Osteopontin is an integral mediator of cardiac interstitial fibrosis in models of HIV infection.

Robinson JA, Mahmud FJ, Greif E, Toribio M, Zanni MV, Brown AM, Burdo TH. 

J Infect Dis. 2023 May 10:jiad149. doi: 10.1093/infdis/jiad149. Online ahead of print. PMID: 37162508 

Abstract 

Background: People with human immunodeficiency virus (HIV) (PWH) have heightened incidence/risk of diastolic dysfunction and heart failure. Women with HIV (WWH) have elevated cardiac fibrosis, and plasma osteopontin (Opn) correlated to cardiac pathology. Therefore, this study provides mechanistic insight into the relationship between osteopontin and cardiac fibrosis during HIV infection. 

Methods: Mouse embryonic fibroblasts (MEFs) modeled cardiac fibroblasts in vitro. Simian immunodeficiency virus (SIV)-infected macaques with/without antiretroviral therapy (ART) and HIV-infected humanized mice modelled HIV-associated cardiac fibrosis. 

Results: LPS-stimulated MEFs were myofibroblast-like, secreted cytokines, and produced Opn transcripts. SIV-infected animals had elevated plasma Opn at necropsy, full-length Opn in the ventricle, and ventricular interstitial fibrosis. Regression modelling identified growth differentiation factor (GDF)-15, CD14+CD16+ monocytes, and CD163 expression on CD14+ CD16+ monocytes as independent predictors of plasma Opn during SIV infection. HIV-infected humanized mice showed increased interstitial fibrosis compared to uninfected/untreated animals, and systemic inhibition of osteopontin by RNA aptamer reduced left ventricle fibrosis in HIV-infected humanized mice. 

Discussion: Since Opn is elevated in the plasma and left ventricle during SIV infection and systemic inhibition of Opn reduced cardiac fibrosis in HIV-infected mice, Opn may be a potential target for adjunctive therapies to reduced cardiac fibrosis in PWH. 

Keywords: HIV; SIV; cardiac fibrosis; humanized mice; monocyte activation; osteopontin. 

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The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets: A Report from the 23rd Annual Harvard Nutrition Obesity Symposium.

Becetti I, Bwenyi EL, de Araujo IE, Ard J, Cryan JF, Farooqi IS, Ferrario CR, Gluck ME, Holsen LM, Kenny PJ, Lawson EA, Lowell BB, Schur EA, Stanley TL, Tavakkoli A, Grinspoon SK, Singhal V. 

Am J Clin Nutr. 2023 May 4:S0002-9165(23)48896-X. doi: 10.1016/j.ajcnut.2023.05.003. Online ahead of print. PMID: 37149092 

Abstract 

Obesity is increasing at an alarming rate. The effectiveness of currently available strategies for the treatment of obesity (including pharmacologic, surgical, and behavioral interventions) is limited. Understanding the neurobiology of appetite and the important drivers of energy intake (EI) can lead to the development of more effective strategies for the prevention and treatment of obesity. Appetite regulation is complex and is influenced by genetic, social, and environmental factors. It is intricately regulated by a complex interplay of endocrine, gastrointestinal, and neural systems. Hormonal and neural signals generated in response to the energy state of the organism and the quality of food eaten are communicated by paracrine, endocrine, and gastrointestinal signals to the nervous system. The central nervous system integrates homeostatic and hedonic signals to regulate appetite. Although there has been an enormous amount of research over many decades regarding the regulation of EI and body weight, research is only now yielding potentially effective treatment strategies for obesity. The purpose of this article is to summarize the key findings presented in June 2022 at the 23rd annual Harvard Nutrition Obesity Symposium entitled "The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets." Findings presented at the symposium, sponsored by NIH P30 Nutrition Obesity Research Center at Harvard, enhance our current understanding of appetite biology, including innovative techniques used to assess and systematically manipulate critical hedonic processes, which will shape future research and the development of therapeutics for obesity prevention and treatment. 

Keywords: GLP-1; appetite; brain; endocrine; genetics; neurobiology; obesity. 

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Most Cited Publications

Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease 

Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007 Jul;92(7):2506-12. doi: 10.1210/jc.2006-2190. Epub 2007 Apr 24. PMID: 17456578; PMCID: PMC2763385.

Abstract

Context: Metabolic changes and smoking are common among HIV patients and may confer increased cardiovascular risk.

Objective: The aim of the study was to determine acute myocardial infarction (AMI) rates and cardiovascular risk factors in HIV compared with non-HIV patients in two tertiary care hospitals.

Design, setting, and participants: We conducted a health care system-based cohort study using a large data registry with 3,851 HIV and 1,044,589 non-HIV patients. AMI rates were determined among patients receiving longitudinal care between October 1, 1996, and June 30, 2004.

Main outcome measures: The primary outcome was myocardial infarction, identified by International Classification of Diseases coding criteria.

Results: AMI was identified in 189 HIV and 26,142 non-HIV patients. AMI rates per 1000 person-years were increased in HIV vs. non-HIV patients [11.13 (95% confidence interval [CI] 9.58-12.68) vs. 6.98 (95% CI 6.89-7.06)]. The HIV cohort had significantly higher proportions of hypertension (21.2 vs. 15.9%), diabetes (11.5 vs. 6.6%), and dyslipidemia (23.3 vs. 17.6%) than the non-HIV cohort (P < 0.0001 for each comparison). The difference in AMI rates between HIV and non-HIV patients was significant, with a relative risk (RR) of 1.75 (95% CI 1.51-2.02; P < 0.0001), adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. In gender-stratified models, the unadjusted AMI rates per 1000 person-years were higher for HIV patients among women (12.71 vs. 4.88 for HIV compared with non-HIV women), but not among men (10.48 vs. 11.44 for HIV compared with non-HIV men). The RRs (for HIV vs. non-HIV) were 2.98 (95% CI 2.33-3.75; P < 0.0001) for women and 1.40 (95% CI 1.16-1.67; P = 0.0003) for men, adjusting for age, gender, race, hypertension, diabetes, and dyslipidemia. A limitation of this database is that it contains incomplete data on smoking. Smoking could not be included in the overall regression model, and some of the increased risk may be accounted for by differences in smoking rates.

Conclusions: AMI rates and cardiovascular risk factors were increased in HIV compared with non-HIV patients, particularly among women. Cardiac risk modification strategies are important for the long-term care of HIV patients.

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Adipose-derived circulating miRNAs regulate gene expression in other tissues 

Thomou T, Mori MA, Dreyfuss JM, Konishi M, Sakaguchi M, Wolfrum C, Rao TN, Winnay JN, Garcia-Martin R, Grinspoon SK, Gorden P, Kahn CR. Adipose-derived circulating miRNAs regulate gene expression in other tissues. Nature. 2017 Feb 23;542(7642):450-455. doi: 10.1038/nature21365. Epub 2017 Feb 15. Erratum in: Nature. 2017 May 10;545(7653):252. PMID: 28199304; PMCID: PMC5330251.

Abstract

Adipose tissue is a major site of energy storage and has a role in the regulation of metabolism through the release of adipokines. Here we show that mice with an adipose-tissue-specific knockout of the microRNA (miRNA)-processing enzyme Dicer (ADicerKO), as well as humans with lipodystrophy, exhibit a substantial decrease in levels of circulating exosomal miRNAs. Transplantation of both white and brown adipose tissue-brown especially-into ADicerKO mice restores the level of numerous circulating miRNAs that are associated with an improvement in glucose tolerance and a reduction in hepatic Fgf21 mRNA and circulating FGF21. This gene regulation can be mimicked by the administration of normal, but not ADicerKO, serum exosomes. Expression of a human-specific miRNA in the brown adipose tissue of one mouse in vivo can also regulate its 3' UTR reporter in the liver of another mouse through serum exosomal transfer. Thus, adipose tissue constitutes an important source of circulating exosomal miRNAs, which can regulate gene expression in distant tissues and thereby serve as a previously undescribed form of adipokine.

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Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients 

Burdo TH, Lo J, Abbara S, Wei J, DeLelys ME, Preffer F, Rosenberg ES, Williams KC, Grinspoon S. Soluble CD163, a novel marker of activated macrophages, is elevated and associated with noncalcified coronary plaque in HIV-infected patients. J Infect Dis. 2011 Oct 15;204(8):1227-36. doi: 10.1093/infdis/jir520. PMID: 21917896; PMCID: PMC3203384.

Abstract

Background: Pro-inflammatory monocytes/macrophages may contribute to increased atherosclerosis in human immunodeficiency virus (HIV)-infected patients. We investigate--to our knowledge, for the first time--sCD163 and other markers of monocyte activation in relationship to atherosclerotic plaque in HIV-infected patients.

Methods: One hundred two HIV-infected and 41 HIV-seronegative men with equivalent cardiovascular risk factors and without history of coronary artery disease were prospectively recruited and underwent computed tomography coronary angiography.

Results: sCD163 levels and presence of plaque were significantly higher among antiretroviral-treated subjects with undetectable HIV RNA levels, compared with seronegative controls (1172 ± 646 vs. 883 ± 561 ng/mL [P = .02] for sCD163 and 61% vs. 39% [P = .03] for presence of plaque). After adjusting for age, race, lipids, blood pressure, glucose, smoking, sCD14, and HIV infection, sCD163 remained independently associated with noncalcified plaque (P = .008). Among HIV-infected patients, sCD163 was associated with coronary segments with noncalcified plaque (r = 0.21; P = .04), but not with calcium score. In contrast, markers of generalized inflammation, including C-reactive protein level, and D-dimer were not associated with sCD163 or plaque among HIV-infected patients.

Conclusions: sCD163, a monocyte/macrophage activation marker, is increased in association with noncalcified coronary plaque in men with chronic HIV infection and low or undetectable viremia. These data suggest a potentially important role of chronic monocyte/macrophage activation in the development of noncalcified vulnerable plaque.

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Arterial inflammation in patients with HIV 

Subramanian S, Tawakol A, Burdo TH, Abbara S, Wei J, Vijayakumar J, Corsini E, Abdelbaky A, Zanni MV, Hoffmann U, Williams KC, Lo JGrinspoon SK. Arterial inflammation in patients with HIV. JAMA. 2012 Jul 25;308(4):379-86. doi: 10.1001/jama.2012.6698. PMID: 22820791; PMCID: PMC3724172.

Abstract

Context: Cardiovascular disease is increased in patients with human immunodeficiency virus (HIV), but the specific mechanisms are unknown.

Objective: To assess arterial wall inflammation in HIV, using 18fluorine-2-deoxy-D-glucose positron emission tomography (18F-FDG-PET), in relationship to traditional and nontraditional risk markers, including soluble CD163 (sCD163), a marker of monocyte and macrophage activation.

Design, setting, and participants: A cross-sectional study of 81 participants investigated between November 2009 and July 2011 at the Massachusetts General Hospital. Twenty-seven participants with HIV without known cardiac disease underwent cardiac 18F-FDG-PET for assessment of arterial wall inflammation and coronary computed tomography scanning for coronary artery calcium. The HIV group was compared with 2 separate non-HIV control groups. One control group (n = 27) was matched to the HIV group for age, sex, and Framingham risk score (FRS) and had no known atherosclerotic disease (non-HIV FRS-matched controls). The second control group (n = 27) was matched on sex and selected based on the presence of known atherosclerotic disease (non-HIV atherosclerotic controls).

Main outcome measure: Arterial inflammation was prospectively determined as the ratio of FDG uptake in the arterial wall of the ascending aorta to venous background as the target-to-background ratio (TBR).

Results: Participants with HIV demonstrated well-controlled HIV disease (mean [SD] CD4 cell count, 641 [288] cells/μL; median [interquartile range] HIV-RNA level, <48 [<48 to <48] copies/mL). All were receiving antiretroviral therapy (mean [SD] duration, 12.3 [4.3] years). The mean FRS was low in both HIV and non-HIV FRS-matched control participants (6.4; 95% CI, 4.8-8.0 vs 6.6; 95% CI, 4.9-8.2; P = .87). Arterial inflammation in the aorta (aortic TBR) was higher in the HIV group vs the non-HIV FRS-matched control group (2.23; 95% CI, 2.07-2.40 vs 1.89; 95% CI, 1.80-1.97; P < .001), but was similar compared with the non-HIV atherosclerotic control group (2.23; 95% CI, 2.07-2.40 vs 2.13; 95% CI, 2.03-2.23; P = .29). Aortic TBR remained significantly higher in the HIV group vs the non-HIV FRS-matched control group after adjusting for traditional cardiovascular risk factors (P = .002) and in stratified analyses among participants with undetectable viral load, zero calcium, FRS of less than 10, a low-density lipoprotein cholesterol level of less than 100 mg/dL (<2.59 mmol/L), no statin use, and no smoking (all P ≤ .01). Aortic TBR was associated with sCD163 level (P = .04) but not with C-reactive protein (P = .65) or D-dimer (P = .08) among patients with HIV.

Conclusion: Participants infected with HIV vs noninfected control participants with similar cardiac risk factors had signs of increased arterial inflammation, which was associated with a circulating marker of monocyte and macrophage activation.

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Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system 

Triant VA, Brown TT, Lee H, Grinspoon SK. Fracture prevalence among human immunodeficiency virus (HIV)-infected versus non-HIV-infected patients in a large U.S. healthcare system. J Clin Endocrinol Metab. 2008 Sep;93(9):3499-504. doi: 10.1210/jc.2008-0828. Epub 2008 Jul 1. PMID: 18593764; PMCID: PMC2567857.

Abstract

Context: Reduced bone mineral density has been demonstrated among HIV-infected patients, but fracture prevalence is unknown.

Objective: The objective of the study was to compare fracture prevalence in HIV-infected and non-HIV-infected patients.

Design: This was a population-based study.

Setting: The study was conducted at a large U.S. health care system.

Patients: A total of 8525 HIV-infected and 2,208,792 non-HIV-infected patients with at least one inpatient or outpatient encounter between October 1, 1996, and March 21, 2008, was compared.

Main outcome measure: Fracture prevalence using specific International Classification of Diseases, Ninth Revision, Clinical Modification fracture codes was measured.

Results: The overall fracture prevalence was 2.87 vs. 1.77 patients with fractures per 100 persons in HIV-infected, compared with non-HIV-infected patients (P < 0.0001). Among females, the overall fracture prevalence was 2.49 vs. 1.72 per 100 persons in HIV-infected vs. non-HIV-infected patients (P = 0.002). HIV-infected females had a higher prevalence of vertebral (0.81 vs. 0.45; P = 0.01) and wrist (1.31 vs. 0.83; P = 0.01) fractures per 100 persons, compared with non-HIV-infected females but had a similar prevalence of hip fractures (0.47 vs. 0.56; P = 0.53). Among males, the fracture prevalence per 100 persons was higher in HIV-infected vs. non-HIV-infected patients for any fracture (3.08 vs. 1.83; P < 0.0001), vertebral fractures (1.03 vs. 0.49; P < 0.0001), hip fractures (0.79 vs. 0.45; P = 0.001), and wrist fractures (1.46 vs. 0.99; P = 0.001). Fracture prevalence was higher relative to non-HIV-infected patients among African-American and Caucasian females and Caucasian males.

Conclusions: Fracture prevalence is increased in HIV-infected compared with non-HIV-infected patients.

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Patents

GHRH or analogues thereof for use in treatment of hepatic disease

Patent Number: 10,799,562

Abstract

The present application relates to novel methods for preventing, slowing the progression of, or treating nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and/or liver fibrosis, and/or reducing the risks of liver cancer in subjects, such as HIV-infected subjects, using a GHRH molecule, e.g., trans-3-hexenoyl-GHRH.sub.(1-44)-NH.sub.2, or a pharmaceutically acceptable salt thereof. The subjects may have particular pathological features such as liver fibrosis, a hepatic fat fraction (HFF) of at least about 10%, serum alanine aminotransferase (ALT) levels of at least about 30 U/L, and/or a NAFLD Activity Score (NAS) of at least 4 or 5.

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