Phosphorylation of cardiac sodium channel at Ser571 anticipates manifestations of the aging myopathy.

Diastolic dysfunction and delayed ventricular repolarization are typically observed in the elderly, but whether these defects are intimately associated with the progressive manifestation of the aging myopathy remains to be determined. In this regard, aging in experimental animals is coupled with increased late Na+ current (INa,L) in cardiomyocytes, raising the possibility that INa,L conditions the modality of electrical recovery and myocardial relaxation of the aged heart. For this purpose, aging male and female wild-type (WT) C57Bl/6 mice were studied together with genetically engineered mice with phosphomimetic (gain of function, GoF) or ablated (loss of function, LoF) mutations of the sodium channel Nav1.5 at Ser571 associated with, respectively, increased and stabilized INa,L. At ∼18 mo of age, WT mice developed prolonged duration of the QT interval of the electrocardiogram and impaired diastolic left ventricular (LV) filling, defects that were reversed by INa,L inhibition. Prolonged repolarization and impaired LV filling occurred prematurely in adult (∼5 mo) GoF mutant mice, whereas these alterations were largely attenuated in aging LoF mutant animals. Ca2+ transient decay and kinetics of myocyte shortening/relengthening were delayed in aged (∼24 mo) WT myocytes, with respect to adult cells. In contrast, delayed Ca2+ transients and contractile dynamics occurred at adult stage in GoF myocytes and further deteriorated in old age. Conversely, myocyte mechanics were minimally affected in aging LoF cells. Collectively, these results document that Nav1.5 phosphorylation at Ser571 and the late Na+ current modulate the modality of myocyte relaxation, constituting the mechanism linking delayed ventricular repolarization and diastolic dysfunction.NEW & NOTEWORTHY We have investigated the impact of the late Na current (INa,L) on cardiac and myocyte function with aging by using genetically engineered animals with enhanced or stabilized INa,L, due to phosphomimetic or phosphoablated mutations of Nav1.5. Our findings support the notion that phosphorylation of Nav1.5 at Ser571 prolongs myocardial repolarization and impairs diastolic function, contributing to the manifestations of the aging myopathy.

Scn1b expression in the adult mouse heart modulates Na+ influx in myocytes and reveals a mechanistic link between Na+ entry and diastolic function.

Voltage-gated sodium channels (VGSCs) are macromolecular assemblies composed of a number of proteins regulating channel conductance and properties. VGSCs generate Na+ current (INa) in myocytes and play fundamental roles in excitability and impulse conduction in the heart. Moreover, VGSCs condition mechanical properties of the myocardium, a process that appears to involve the late component of INa. Variants in the gene SCN1B, encoding the VGSC ß1- and ß1B-subunits, result in inherited neurological disorders and cardiac arrhythmias. But the precise contributions of ß1/ß1B-subunits and VGSC integrity to the overall function of the adult heart remain to be clarified. For this purpose, adult mice with cardiac-restricted, inducible deletion of Scn1b (conditional knockout, cKO) were studied. Myocytes from cKO mice had increased densities of fast (+20%)- and slow (+140%)-inactivating components of INa, with respect to control cells. By echocardiography and invasive hemodynamics, systolic function was preserved in cKO mice, but diastolic properties and ventricular compliance were compromised, with respect to control animals. Importantly, inhibition of late INa with GS967 normalized left ventricular filling pattern and isovolumic relaxation time in cKO mice. At the cellular level, cKO myocytes presented delayed kinetics of Ca2+ transients and cell mechanics, defects that were corrected by inhibition of INa. Collectively, these results document that VGSC ß1/ß1B-subunits modulate electrical and mechanical function of the heart by regulating, at least in part, Na+ influx in cardiomyocytes.NEW & NOTEWORTHY We have investigated the consequences of deletion of Scn1b, the gene encoding voltage-gated sodium channel ß1-subunits, on myocyte and cardiac function. Our findings support the notion that Scn1b expression controls properties of Na+ influx and Ca2+ cycling in cardiomyocytes affecting the modality of cell contraction and relaxation. These effects at the cellular level condition electrical recovery and diastolic function in vivo, substantiating the multifunctional role of ß1-subunits in the physiology of the heart.

Coronary circulatory function with increasing obesity: A complex U-turn.

AIMS: The aim of this investigation was to explore and characterize alterations in coronary circulatory function in function of increasing body weight with medically controlled cardiovascular risk factors and, thus, "metabolically" unhealthy obesity. MATERIALS AND METHODS: We prospectively enrolled 106 patients with suspected CAD but with normal stress-rest myocardial perfusion on 13 N-ammonia PET/CT and with medically controlled or no cardiovascular risk factors. 13 N-ammonia PET/CT concurrently determined myocardial blood flow (MBF) during pharmacologically induced hyperaemia and at rest. Based on body mass index (BMI), patients were grouped into normal weight (BMI: 20.0-24.9 kg/m2 , n = 22), overweight (BMI: 25.0-29.9 kg/m2 , n = 27), obese (BMI: 30.0-39.9 kg/m2 , n = 31), and morbidly obese (BMI ≥ 40kg/m2 , n = 26). RESULTS: Resting MBF was comparable among groups (1.09 ± 0.18 vs. 1.00 ± 0.15 vs. 0.96 ± 0.18 vs.. 1.06 ± 0.31 ml/g/min; p = .279 by ANOVA). Compared to normal weight individuals, the hyperaemic MBF progressively decreased in in overweight and obese groups, respectively (2.54 ± 0.48 vs. 2.02 ± 0.27 and 1.75 ± 0.39 ml/g/min; p < .0001), while it increased again in the group of morbidly obese individuals comparable to normal weight (2.44 ± 0.41 vs. 2.54 ± 0.48 ml/g/min, p = .192). The BMI of the study population correlated with the hyperaemic MBF in a quadratic or U-turn fashion (r = .34, SEE = 0.46; p ≤ .002). CONCLUSIONS: The U-turn of hyperaemic MBF from obesity to morbid obesity is likely to reflect contrasting effects of abdominal versus subcutaneous adipose tissue on coronary circulatory function indicative of two different disease entities, but needing further investigations.

Comparative Host-Pathogen Interaction Analyses of SARS-CoV2 and Aspergillus fumigatus, and Pathogenesis of COVID-19-Associated Aspergillosis.

COVID-19 caused a global catastrophe with a large number of cases making it one of the major pandemics of the human history. The clinical presentations of the disease are continuously challenging healthcare workers with the variation of pandemic waves and viral variants. Recently, SARS-CoV2 patients have shown increased occurrence of invasive pulmonary aspergillosis infection even in the absence of traditional risk factors. The mechanism of COVID-19-associated aspergillosis is not completely understood and therefore, we performed this system biological study in order to identify mechanistic implications of aspergillosis susceptibility in COVID-19 patients and the important targets associated with this disease. We performed host-pathogen interaction (HPI) analysis of SARS-CoV2, and most common COVID-19-associated aspergillosis pathogen, Aspergillus fumigatus, using in silico approaches. The known host-pathogen interactions data of SARS-CoV2 was obtained from BIOGRID database. In addition, A. fumigatus host-pathogen interactions were predicted through homology modeling. The human targets interacting with both pathogens were separately analyzed for their involvement in aspergillosis. The aspergillosis human targets were screened from DisGeNet and GeneCards. The aspergillosis targets involved in both HPI were further analyzed for functional overrepresentation analysis using PANTHER. The results indicate that both pathogens interact with a number of aspergillosis targets and altogether they recruit more aspergillosis targets in host-pathogen interaction than alone. Common aspergillosis targets involved in HPI with both SARS-CoV2 and A. fumigatus can indicate strategies for the management of both conditions by modulating these common disease targets.

A holistic overview on corn cob biochar: A mini-review.

Corn cob is one of the agricultural waste materials subjected to improper burning, which creates pollution. It can be used for the production of green technologies for further applications. Carbonisation or slow pyrolysis could be promising alternative to burning. It has many applications, such as soil ameliorant, waste water treatment, carbon sequestration, composting, supercapacitor, fuel cell and biocomposites material. It motivated to investigate the suitability of corn cob as a potential material for biochar production and its application. The advanced form of analysis, such as thermogravimetric, scanning electron microscopy, surface area, Fourier transform infrared spectroscopy, nuclear magnetic resonance spectroscopy and Raman spectroscopy, is elaborated for in-depth knowledge of characteristics. The hypothesis is that if the available corn cob is used for biochar production, it will reduce the carbon dioxide (CO2) emission. On a global level, conversion of available corn cob into biochar is expected to reduce CO2 emission by 0.13 Gt per year. The reduction in CO2 emission also favours economy. If 1 tonne of biomass per year is converted into biochar, 0.82 tonnes of CO2 can be reduced per year and by considering the emission cost of Rs 1800 per tonne, the cost saving would be Rs 1476 per year. The presented mini-review article provides an outline of the state-of-art information on corn cob biochar and its novel application. It will be helpful to scientific domain to find new opportunities in biochar research and also the humanity will be benefitted due to reduction in greenhouse gases.

A polymorphism in intron I of the human angiotensinogen gene (hAGT) affects binding by HNF3 and hAGT expression and increases blood pressure in mice.

Angiotensinogen (AGT) is the precursor of one of the most potent vasoconstrictors, peptide angiotensin II. Genome-wide association studies have shown that two A/G polymorphisms (rs2493134 and rs2004776), located at +507 and +1164 in intron I of the human AGT (hAGT) gene, are associated with hypertension. Polymorphisms of the AGT gene result in two main haplotypes. Hap-I contains the variants -217A, -6A, +507G, and +1164A and is pro-hypertensive, whereas Hap-II contains the variants -217G, -6G, +507A, and +1164G and does not affect blood pressure. The nucleotide sequence of intron I of the hAGT gene containing the +1164A variant has a stronger homology with the hepatocyte nuclear factor 3 (HNF3)-binding site than +1164G. Here we found that an oligonucleotide containing +1164A binds HNF3ß more strongly than +1164G and that Hap-I-containing reporter gene constructs have increased basal and HNF3- and glucocorticoid-induced promoter activity in transiently transfected liver and kidney cells. Using a knock-in approach at the hypoxanthine-guanine phosphoribosyltransferase locus, we generated a transgenic mouse model containing the human renin (hREN) gene and either Hap-I or Hap-II. We show that transgenic animals containing Hap-I have increased blood pressure compared with those containing Hap-II. Moreover, the transcription factors glucocorticoid receptor, CCAAT enhancer-binding protein ß, and HNF3ß bound more strongly to chromatin obtained from the liver of transgenic animals containing Hap-I than to liver chromatin from Hap-II-containing animals. These findings suggest that, unlike Hap-II variants, Hap-I variants of the hAGT gene have increased transcription rates, resulting in elevated blood pressure.

A community-wide acute diarrheal disease outbreak associated with drinking contaminated water from shallow bore-wells in a tribal village, India, 2017.

BACKGROUND: In 2016, India reported 709 acute diarrheal disease (ADD) outbreaks (> 25% of all outbreaks). Tribal populations are at higher risk with 27% not having accessibility to safe drinking water and 75% households not having toilets. On June 26, 2017 Pedda-Gujjul-Thanda, a tribal village reported an acute diarrheal disease (ADD) outbreak. We investigated to describe the epidemiology, identify risk factors, and provide evidence-based recommendations. METHODS: We defined a case as ≥3 loose stools within 24 h in Pedda-Gujjul-Thanda residents from June 24-30, 2017. We identified cases by reviewing hospital records and house-to-house survey. We conducted a retrospective cohort study and collected stool samples for culture. We assessed drinking water supply and sanitation practices and tested water samples for faecal-contamination. RESULTS: We identified 191 cases (65% females) with median age 36 years (range 4-80 years) and no deaths. The attack-rate (AR) was 37% (191/512). Downhill colonies (located on slope of hilly terrains of the village) reported higher ARs (56%[136/243], p < 0.001) than others (20%[55/269]). Symptoms included diarrhea (100%), fever (17%), vomiting (16%) and abdominal pain (13%). Drinking water from five shallow bore-wells located in downhill colonies was significantly associated with illness (RR = 4.6, 95%CI = 3.4-6.1 and population attributable fraction 61%). In multi-variate analysis, drinking water from the shallow bore-wells located in downhill colonies (aOR = 7.9, [95% CI =4.7-13.2]), illiteracy (aOR =6, [95% CI = 3.6-10.1]), good hand-washing practice (aOR = 0.4, [95%CI = 0.2-0.7]) and household water treatment (aOR = 0.3, [95%CI = 0.2-0.5]) were significantly associated with illness. Two stool cultures were negative for Vibrio cholerae. Heavy rainfall was reported from June 22-24. Five of six water samples collected from shallow bore-wells located in downhill colonies were positive for faecal contamination. CONCLUSION: An ADD outbreak with high attack rate in a remote tribal village was associated with drinking water from shallow downhill bore-wells, likely contaminated via runoff from open defecation areas after heavy rains. Based on our recommendations, immediate public health actions including repair of leakages at contaminated water sources and alternative supply of purified canned drinking water to families, and as long-term public health measures construction of house-hold latrines and piped-water supply initiated.

Thermogravimetric studies on co-pyrolysis of raw/torrefied biomass and coal blends.

The pyrolysis and co-pyrolysis behaviours of cotton stalk (CS), torrefied cotton stalk (TCS) and mined coal, as single fuels, and their blends, have been examined through thermogravimetric analysis. Biomass has been torrefied at 250°C for 45 min to enhance physicochemical properties, and then mixed with mined coal for co-pyrolysis. Thermal degradation of CS and TCS is characterized by a reaction. However, this is not the case for mined coal, which shows a single-stage reaction. The thermal degradation of all blends was done in three stages: dehydration; biomass and small mined coal; and lignin or mined coal. A similar trend emerged for mass loss of individual fuels, which depended mainly on their ratios in the blend. The kinetics of pyrolysis and co-pyrolysis of all fuels were calculated at 20°Cmin-1 heating rate using the Coats-Redfern model-fitting method.

Impact of nonpharmacological interventions on COVID-19 transmission dynamics in India.

BACKGROUND: As of May 4, 2020, India has reported 42,836 confirmed cases and 1,389 deaths from COVID-19. India's multipronged response included nonpharmacological interventions (NPIs) like intensive case-based surveillance, expanding testing capacity, social distancing, health promotion, and progressive travel restrictions leading to a complete halt of international and domestic movements (lockdown). OBJECTIVES: We studied the impact of NPI on transmission dynamics of COVID-19 epidemic in India and estimated the minimum level of herd immunity required to halt it. METHODS: We plotted time distribution, estimated basic (R0) and time-dependent effective (Rt) reproduction numbers using software R, and calculated doubling time, the growth rate for confirmed cases from January 30 to May 4, 2020. Herd immunity was estimated using the latest Rtvalue. RESULTS: Time distribution showed a propagated epidemic with subexponential growth. Average growth rate, 21% in the beginning, reduced to 6% after an extended lockdown (May 3). Based on early transmission dynamics, R0was 2.38 (95% confidence interval [CI] =1.79-3.07). Early, unmitigated Rt= 2.51 (95% CI = 2.05-3.14) (March 15) reduced to 1.28 (95% CI = 1.22-1.32) and was 1.83 (95% CI = 1.71-1.93) at the end of lockdown Phase 1 (April 14) and 2 (May 3), respectively. Similarly, average early doubling time (4.3 days) (standard deviation [SD] = 1.86) increased to 5.4 days (SD = 1.03) and 10.9 days (SD = 2.19). Estimated minimum 621 million recoveries are required to halt COVID-19 spread if Rtremains below 2. CONCLUSION: India's early response, especially stringent lockdown, has slowed COVID-19 epidemic. Increased testing, intensive case-based surveillance and containment efforts, modulated movement restrictions while protecting the vulnerable population, and continuous monitoring of transmission dynamics should be a way forward in the absence of effective treatment, vaccine, and undetermined postinfection immunity.

Prevalence and risk factors of soil-transmitted helminth infections in school age children (6-14 years) - A cross-sectional study in an urban resettlement colony of Delhi.

BACKGROUND: Soil-transmitted helminth (STH) infections have adverse physical and mental effect, especially in preschool (3-6 years) and school-age children (6-14 years). They are associated with socio-behavioral factors of poverty and poor personal and community hygiene. OBJECTIVES: To determine the prevalence, intensity, and the type of helminths infection harbored by the school age children (6-14 years) and to examine the relationship between STH infection and their potential risk factors and associated variables. METHODS: This cross-sectional study was conducted from January to December 2016 among 250 school age children residing in an urban resettlement colony of East Delhi. Data were collected using a semistructured interview schedule. Stool sample was tested using the Kato Katz technique. Data were analyzed in SPSS software version 16, and multivariable regression analysis was done to calculate the odds of various risk factors. RESULTS: The prevalence of STH was found to be 54.8%, and majority (85.3%) of Ascaris and all Trichuris infections were of light intensity. Multivariable logistic regression analysis confirmed that children having poor handwashing behavior in school, irregular handwashing before eating, having pica, and lack of de-worming had higher odds of having STH infection. CONCLUSION: The prevalence of STH in the study area is substantially high, and the findings suggest that besides mass de-worming strategy, behavior change, and improvement in hygiene are required to control STH.

Middle lobe syndrome: An exceptional presentation of concomitant lepidic adenocarcinoma and bronchial anthracofibrosis.

Lepidic adenocarcinoma previously known as bronchioloalveolar carcinoma (BAC) is a non-small cell lung cancer with an indolent presentation. Bronchial anthracofibrosis (BAF) is caused by long-standing exposure to biomass fuel smoke often in poorly ventilated kitchen. Middle lobe syndrome (MLS) due to BAF is not uncommon however, lepidic adenocarcinoma then known as BAC, presenting as MLS has been documented only once before in the Polish literature. A 68-year-old never-smoker female with biomass fuel smoke exposure presented with cough and breathlessness. Imaging revealed MLS. Fiberoptic bronchoscopy visualised bluish-black hyperpigmentation with narrowing and distortion of right middle lobe bronchus suggestive of BAF. Transbronchial biopsy confirmed presence of lepidic adenocarcinoma. To our knowledge, this is the first detailed description of lepidic adenocarcinoma and BAF presenting as MLS.

Dexamethasone promotes hypertension by allele-specific regulation of the human angiotensinogen gene.

The human angiotensinogen (hAGT) gene has polymorphisms in its 2.5-kb promoter that form two haplotype (Hap) blocks: -6A/G (-1670A/G, -1562C/T, and -1561T/C) and -217A/G (-532T/C, -793A/G, -1074T/C, and -1178G/A). Hap -6A/-217A is associated with human hypertension, whereas Hap -6G/-217G reduces cardiovascular risk. Hap -6A/-217A has increased promoter activity with enhanced transcription factor binding, including to the glucocorticoid receptor (GR). Glucocorticoid therapy frequently causes hypertension, the mechanisms for which are incompletely understood. We have engineered double transgenic (TG) mice containing the human renin gene with either Hap of the hAGT gene and examined the physiological significance of glucocorticoid-mediated allele-specific regulation of the hAGT gene. We have also studied the consequential effects on the renin angiotensin system and blood pressure. TG mice with Hap -6A and -6G were treated with and without a low dose of a GR agonist, dexamethasone (2.5 µg/ml), for 72 h. We found greater chromatin-GR binding with increased GR agonist-induced hAGT expression in liver and renal tissues of Hap -6A mice. Additionally, dexamethasone treatment increased circulating hAGT and angiotensin II levels in Hap -6A mice, as compared with -6G mice. Importantly, GR agonist significantly increased blood pressure and redox markers in TG mice with Hap-6A of the hAGT gene. Taken together, our results show, for the first time, that glucocorticoids affect hAGT expression in a haplotype-dependent fashion with SNPs in Hap -6A favoring agonist-induced GR binding. This leads to increased expression of the hAGT, up-regulation of the renin angiotensin system, and increased blood pressure and oxidative stress in Hap -6A mice.

Inhibition of infectious bursal disease virus by vector delivered SiRNA in cell culture.

Infectious Bursal Disease (IBD) is major threat to poultry industry. It causes severe immunosuppression and mortality in chicken generally at 3 to 6 weeks of age. RNA intereference (RNAi) emerges as a potent gene regulatory tool in last few years. The present study was conducted to evaluate the efficiency of RNAi to inhibit the IBD virus (IDBV) replication in-vitro. VP2 gene of virus encodes protein involved in capsid formation, cell entry and induction of protective immune responses against it. Thus, VP2 gene of IBDV is the candidate target for the molecular techniques applied for IBDV detection and inhibition assay. In this study, IBDV was isolated from field cases and confirmed by RT-PCR. The virus was then adapted on chicken embryo fibroblast cells (CEF) in which it showed severe cytopathic effects (CPE). The short hairpin RNA (shRNAs) constructs homologous to the VP2 gene were designed and one, having maximum score and fulfilling maximum Reynolds criteria, was selected for evaluation of effective inhibition. Selected shRNA construct (i.e., VP2-shRNA) was observed to be the most effective for inhibiting VP2 gene expression. Real time PCR analysis was performed to measure the relative expression of VP2 gene in different experimental groups. The VP2 gene was less expressed in virus infected cells co-transfected with VP2-shRNA as compared to mock transfected cells and IBDV+ cells (control) at dose 1.6 µ g. The result showed ∼95% efficient down regulation of VP2 gene mRNA in VP2-shRNA treated cells. These findings suggested that designed shRNA construct achieved high level of inhibition of VP2 gene expression in-vitro.

Phase space trajectories and Lyapunov exponents in the dynamics of an alpha-helical protein lattice with intra- and inter-spine interactions.

The nonlinear dynamics of intra- and inter-spine interaction models of alpha-helical proteins is investigated by proposing a Hamiltonian using the first quantized operators. Hamilton's equations of motion are derived, and the dynamics is studied by constructing the trajectories and phase space plots in both cases. The phase space plots display a chaotic behaviour in the dynamics, which opens questions about the relationship between the chaos and exciton-exciton and exciton-phonon interactions. This is verified by plotting the Lyapunov characteristic exponent curves.

Primary Malignant Melanoma of the Lung: Case Report and Literature Review.

Primary malignant melanoma of the lung (PMML) is an extremely rare tumour with only sporadic case reports. We report the occurrence of PMML in a 58-year-old female. Although extremely rare, it must be considered in the differential diagnosis of bronchogenic carcinoma and a detailed systemic examination must be done to rule out any primary skin or eye involvement.

A haplotype of angiotensin receptor type 1 associated with human hypertension increases blood pressure in transgenic mice.

The renin-angiotensin system plays an important role in the regulation of blood pressure via angiotensin II and the angiotensin II receptor type 1 (AT1R). Human AT1R gene promoter has four SNPs: T/A at -777, T/G at -680, A/C at -214, and A/G at -119, that are in linkage disequilibrium. Variants -777T, -680T, -214A, and -119A almost always occur together (named haplotype I), and variants -777A, -680G, -214C, and -119G almost always occur together (named haplotype II) in Caucasian subjects. Genomic DNA analyses, from 388 normotensive and 374 hypertensive subjects, link haplotype I of the human AT1R (hAT1R) gene with hypertension in Caucasians (p = 0.004, χ(2) = 8.46). Our results show increased basal promoter activity of the hAT1R gene in cells (H295R and A7r5) transfected with reporter construct containing haplotype I. We also show increased binding of the transcription factor, USF2, to oligonucleotide containing nucleoside -214A as opposed to -214C. Recombineering of a 166-kb bacterial artificial chromosome containing 68 kb of the 5'-flanking region, 45 kb of the coding sequence, and 53 kb of the 3'-flanking region of the hAT1R gene was employed to generate transgenic mice with either haplotype. We show that (a) hAT1R mRNA level is increased in the kidney and heart of transgenic mice containing haplotype I as compared with haplotype II; (b) USF2 binds more strongly to the chromatin obtained from the kidney of transgenic mice containing haplotype I as compared with haplotype II; and (c) blood pressure and oxidative stress are increased in transgenic mice containing haplotype I as compared with haplotype II.

Amoebic colitis presenting as ileocaecal intussusception - a rare case.

Ileocaecal intussusception is a common cause of acute intestinal obstruction presenting as a surgical emergency. We report a case of amoebic colitis in a 62 years old man complaining of acute colicky pain in the right iliac fossa, associated with a three-day history of constipation but no other gastrointestinal tract symptoms. There was rebound tenderness on palpation of the right iliac fossa. Ultrasound scans revealed free fluid and a loop within a loop image in this area. At laparotomy, we discovered an Ileocaecal intussusception associated with a gangrenous caecum. A right hemicolectomy was performed with satisfactory outcome. The final diagnosis of amoebic colitis was obtained post-operatively using serology and pathology. This rare aetiology must be considered in patients with acute pain in the right iliac fossa in the tropical regions. Tropical surgeons must be aware of this scenario before they label a case of intussusception as idiopathic. The identification and treatment of invasive amoebic infection may reduce the recurrence of idiopathic intussusception.

PET/CT Assessment of Flow-Mediated Epicardial Vasodilation in Obesity and Severe Obesity.

Background: It is not known whether the transition from obesity and severe obesity, as 2 different metabolic disease entities, affect flow-mediated and, thus, endothelium-dependent epicardial vasodilation. Objectives: The purpose of this study was to investigate the effect of obesity and severe obesity on flow-mediated epicardial vasomotion with positron emission tomography/computed tomography-determined longitudinal decrease in myocardial blood flow (MBF) from the base-to-apex direction of the left ventricle or gradient. Methods: 13N-ammonia positron emission tomography/computed tomography evaluated global MBF during pharmacologically induced hyperemia and at rest for assessment of coronary microvascular function. In addition, the Δ longitudinal MBF gradient (hyperemia minus rest) was determined. Patients were then grouped according to the body mass index (BMI) into normal weight (NW) (BMI 20.0-24.9 kg/m2, n = 27), overweight (OW) (BMI 25.0-29.9 kg/m2, n = 29), obesity (OB) (BMI 30.0-39.9 kg/m2, n = 53), and severe obesity (morbid obesity: BMI ≥40 kg/m2, n = 43). Results: Compared to NW, left ventricular Δ longitudinal MBF gradient progressively declined in OW and OB (0.04 ± 0.09 mL/g/min vs -0.11 ± 0.14 mL/g/min and -0.15 ± 0.11 mL/g/min; P ≤ 0.001, respectively) but not significantly in SOB (-0.01 ± 0.11 mL/g/min, P = 0.066). Regadenoson-induced global hyperemic MBF was lower in OB than in NW (1.88 ± 0.40 mL/g/min vs 2.35 ± 0.32 mL/g/min; P ≤ 0.001), while comparable between NW and SOB (2.35 ± 0.32 mL/g/min vs 2.26 ± 0.40 mL/g/min; P = 0.302). The BMI of the study population was associated with the Δ longitudinal MBF gradient in a U-turn fashion (r = 0.362, standard error of the estimate = 0.124; P < 0.001). Conclusions: Increased body weight associates with abnormalities in coronary circulatory function that advances from an impairment flow-mediated, epicardial vasodilation in overweight and obesity to coronary microvascular dysfunction in obesity, not observed in severe obesity. The U-turn of flow-mediated epicardial vasomotion outlines obesity and severe obesity to affect epicardial endothelial function differently.