A nitroalkene derivative of salicylate alleviates diet-induced obesity by activating creatine metabolism and non-shivering thermogenesis.

Obesity-related type II diabetes (diabesity) has increased global morbidity and mortality dramatically. Previously, the ancient drug salicylate demonstrated promise for the treatment of type II diabetes, but its clinical use was precluded due to high dose requirements. In this study, we present a nitroalkene derivative of salicylate, 5-(2-nitroethenyl)salicylic acid (SANA), a molecule with unprecedented beneficial effects in diet-induced obesity (DIO). SANA reduces DIO, liver steatosis and insulin resistance at doses up to 40 times lower than salicylate. Mechanistically, SANA stimulated mitochondrial respiration and increased creatine-dependent energy expenditure in adipose tissue. Indeed, depletion of creatine resulted in the loss of SANA action. Moreover, we found that SANA binds to creatine kinases CKMT1/2, and downregulation CKMT1 interferes with the effect of SANA in vivo. Together, these data demonstrate that SANA is a first-in-class activator of creatine-dependent energy expenditure and thermogenesis in adipose tissue and emerges as a candidate for the treatment of diabesity.

Benefits in cardiac function by CD38 suppression: Improvement in NAD+ levels, exercise capacity, heart rate variability and protection against catecholamine-induced ventricular arrhythmias.

CD38 enzymatic activity regulates NAD+ and cADPR levels in mammalian tissues, and therefore has a prominent role in cellular metabolism and calcium homeostasis. Consequently, it is reasonable to hypothesize about its involvement in cardiovascular physiology as well as in heart related pathological conditions. AIM: To investigate the role of CD38 in cardiovascular performance, and its involvement in cardiac electrophysiology and calcium-handling. METHODS AND RESULTS: When submitted to a treadmill exhaustion test, a way of evaluating cardiovascular performance, adult male CD38KO mice showed better exercise capacity. This benefit was also obtained in genetically modified mice with catalytically inactive (CI) CD38 and in WT mice treated with antibody 68 (Ab68) which blocks CD38 activity. Hearts from these 3 groups (CD38KO, CD38CI and Ab68) showed increased NAD+ levels. When CD38KO mice were treated with FK866 which inhibits NAD+ biosynthesis, exercise capacity as well as NAD+ in heart tissue decreased to WT levels. Electrocardiograms of conscious unrestrained CD38KO and CD38CI mice showed lower basal heart rates and higher heart rate variability than WT mice. Although inactivation of CD38 in mice resulted in increased SERCA2a expression in the heart, the frequency of spontaneous calcium release from the sarcoplasmic reticulum under stressful conditions (high extracellular calcium concentration) was lower in CD38KO ventricular myocytes. When mice were challenged with caffeine-epinephrine, CD38KO mice had a lower incidence of bidirectional ventricular tachycardia when compared to WT ones. CONCLUSION: CD38 inhibition improves exercise performance by regulating NAD+ homeostasis. CD38 is involved in cardiovascular function since its genetic ablation decreases basal heart rate, increases heart rate variability and alters calcium handling in a way that protects mice from developing catecholamine induced ventricular arrhythmias.

The additional prognostic value of myocardial perfusion SPECT in patients with known coronary artery disease with high exercise capacity.

BACKGROUND: The prognostic value of myocardial perfusion imaging (MPI) in patients with known coronary artery disease (CAD) and high exercise capacity is still unknown. We sought to determine the MPI additional prognostic value over electrocardiography (ECG) stress testing alone in patients with known CAD who achieved ≥ 10 metabolic equivalents (METs). METHODS AND RESULTS: We evaluated 926 patients with known CAD referred for MPI with exercise stress. Patients were followed for a mean of 32.4 ± 9.7 months for the occurrence of all-cause death or nonfatal myocardial infarction (MI). Those achieving ≥ 10 METs were younger, predominantly male, and had lower prevalence of cardiovascular risk factors. Patients reaching ≥ 10 METs had a lower annualized rate of hard events compared to their counterparts achieving < 10 METs (1.13%/year vs 3.95%/year, P < .001). Patients who achieved ≥ 10 METs with abnormal scans had a higher rate of hard events compared to those with normal scans (3.37%/year vs 0.57%/year, P = .023). Cardiac workload < 10 METs and an abnormal MPI scan were independent predictors of hard events. CONCLUSIONS: MPI is able to stratify patients with known CAD achieving ≥ 10 METs for the occurrence of all-cause death and nonfatal MI, with incremental prognostic value over ECG stress test alone.

The Prognostic Value and Clinical Use of Myocardial Perfusion Scintigraphy in Asymptomatic Patients after Percutaneous Coronary Intervention.

BACKGROUND: The role of myocardial perfusion scintigraphy (MPS) in the follow-up of asymptomatic patients after percutaneous coronary intervention (PCI) is not established. OBJECTIVES: To evaluate the prognostic value and clinical use of MPS in asymptomatic patients after PCI. METHODS: Patients who underwent MPS consecutively between 2008 and 2012 after PCI were selected. The MPS were classified as normal and abnormal, the perfusion scores, summed stress score (SSS), and summed difference score (SDS) were calculated and converted into percentage of total perfusion defect and ischemic defect. The follow-up was undertaken through telephone interviews and consultation with the Mortality Information System. Primary endpoints were death, cardiovascular death, and nonfatal acute myocardial infarction (AMI), and secondary endpoint was revascularization. Logistic regression and COX method were used to identify the predictors of events, and the value of p < 0.05 was considered statistically significant. RESULTS: A total of 647 patients were followed for 5.2 ± 1.6 years. 47% of MPS were normal, 30% were abnormal with ischemia, and 23% were abnormal without ischemia. There were 61 deaths, 27 being cardiovascular, 19 non-fatal AMI, and 139 revascularizations. The annual death rate was higher in those with abnormal perfusion without ischemia compared to the groups with ischemia and normal perfusion (3.3% × 2% × 1.2%, p = 0.021). The annual revascularization rate was 10.3% in the ischemia group, 3.7% in those with normal MPS, and 3% in those with abnormal MPS without ischemia. The independent predictors of mortality and revascularization were, respectively, total perfusion defect greater than 6%, and ischemic defect greater than 3%. Forty-two percent of the patients underwent MPS less than 2 years after PCI, and no significant differences were observed in relation to those who underwent it after that period. CONCLUSION: Although this information is not contemplated in guidelines, in this study MPS was able to predict events in asymptomatic after PCI patients, regardless of when they were performed.

The Prognostic Value and Clinical Use of Myocardial Perfusion Scintigraphy in Asymptomatic Patients after Percutaneous Coronary Intervention / O Valor Prognóstico e o uso Clínico da Cintilografia de Perfusão Miocárdica em Pacientes Assintomáticos após Intervenção Coronariana Percutânea

Abstract Background: The role of myocardial perfusion scintigraphy (MPS) in the follow-up of asymptomatic patients after percutaneous coronary intervention (PCI) is not established. Objectives: To evaluate the prognostic value and clinical use of MPS in asymptomatic patients after PCI. Methods: Patients who underwent MPS consecutively between 2008 and 2012 after PCI were selected. The MPS were classified as normal and abnormal, the perfusion scores, summed stress score (SSS), and summed difference score (SDS) were calculated and converted into percentage of total perfusion defect and ischemic defect. The follow-up was undertaken through telephone interviews and consultation with the Mortality Information System. Primary endpoints were death, cardiovascular death, and nonfatal acute myocardial infarction (AMI), and secondary endpoint was revascularization. Logistic regression and COX method were used to identify the predictors of events, and the value of p < 0.05 was considered statistically significant. Results: A total of 647 patients were followed for 5.2 ± 1.6 years. 47% of MPS were normal, 30% were abnormal with ischemia, and 23% were abnormal without ischemia. There were 61 deaths, 27 being cardiovascular, 19 non-fatal AMI, and 139 revascularizations. The annual death rate was higher in those with abnormal perfusion without ischemia compared to the groups with ischemia and normal perfusion (3.3% × 2% × 1.2%, p = 0.021). The annual revascularization rate was 10.3% in the ischemia group, 3.7% in those with normal MPS, and 3% in those with abnormal MPS without ischemia. The independent predictors of mortality and revascularization were, respectively, total perfusion defect greater than 6%, and ischemic defect greater than 3%. Forty-two percent of the patients underwent MPS less than 2 years after PCI, and no significant differences were observed in relation to those who underwent it after that period. Conclusion: Although this information is not contemplated in guidelines, in this study MPS was able to predict events in asymptomatic after PCI patients, regardless of when they were performed.

Resumo Fundamentos: O papel da cintilografia de perfusão miocárdica (CPM) no seguimento de pacientes assintomáticos após intervenção coronariana percutânea (ICP) não está estabelecido. Objetivos. Avaliar o valor prognóstico e o uso clínico da CPM em pacientes assintomáticos após ICP. Métodos: Foram selecionados pacientes que realizaram CPM consecutivamente entre 2008 e 2012 após ICP. As CPM foram classificadas em normais e anormais, os escores de perfusão, escore somado do estresse (SSS) e escore somado da diferença (SDS) foram calculados e convertidos em porcentagem de defeito perfusional total e de defeito isquêmico. O seguimento foi por meio de entrevistas telefônicas e consulta ao Sistema de Informação de Mortalidade. Desfechos primários foram morte, morte cardiovascular e infarto agudo do miocárdio (IAM) não fatal e desfecho secundário foi revascularização. Regressão logística e método de COX foram utilizados para identificar os preditores de eventos e o valor de p < 0,05 foi considerado estatisticamente significativo. Resultados: 647 pacientes foram acompanhados por 5,2 ± 1,6 anos. 47% das CPM foram normais, 30% anormais com isquemia e 23% anormais sem isquemia. Ocorreram 61 mortes, 27 cardiovasculares, 19 IAM não fatais e 139 revascularizações. A taxa anual de óbitos foi superior naqueles com perfusão anormal sem isquemia comparada aos grupos com isquemia e perfusão normal (3,3% × 2% × 1,2%, p = 0,021). A taxa anual de revascularização foi 10,3% no grupo com isquemia, 3,7% naqueles com CPM normal e 3% naqueles com CPM anormal sem isquemia. Foram preditores independentes de mortalidade e revascularização, respectivamente, defeito perfusional total maior que 6% e defeito isquêmico maior que 3%. Quarenta e dois por cento dos pacientes realizaram CPM menos de 2 anos após ICP e não foram observadas diferenças relevantes em relação aos que realizaram após esse período. Conclusão: Embora esta informação não esteja contemplada em diretrizes, neste estudo a CPM foi capaz de predizer eventos em pacientes assintomáticos após ICP, independente do momento de realização.

Prognostic value of a faster, low-radiation myocardial perfusion SPECT protocol in a CZT camera.

To determine the prognostic value of a new, ultrafast, low dose myocardial perfusion SPECT (MPS) protocol in a cadmium-zinc telluride (CZT) camera. CZT cameras have introduced significant progress in MPS imaging, offering high-quality images despite lower doses and scan time. Yet, it is unknown if, with such protocol changes, the prognostic value of MPS is preserved. Patients had a 1-day 99 m-Tc-sestamibi protocol, starting with the rest (185-222 MBq) followed by stress (666-740 MBq). Acquisition times were 6 and 3 min, respectively. MPS were classified as normal or abnormal perfusion scans and summed scores of stress, rest, and difference (SSS, SRS and SDS), calculated. Patients were followed with 6-month phone calls. Hard events were defined as death or nonfatal myocardial infarction. Late revascularization was that occurring after 60 days of MPS. 2930 patients (age 64.0 ± 12.1 years, 53.3% male) were followed for 30.7 ± 7.5 months. Mean dosimetry was 6 mSv and mean total study time, 48 ± 13 min. The annual hard event and late revascularization rate were higher in patients with greater extension of defect and ischemia. SSS was higher in patients with hard events compared to those without events (2.6 ± 4.9 vs. 5.0 ± 6.3, p < 0.001), as well as the SDS (0.7 ± 1.9 vs. 1.7 ± 3.4, p < 0.00). The same was true for patients with or without late revascularization (SSS: 2.5 ± 4.7 vs. 6.6 ± 7.1; SDS: 0.6 ± 1.7 vs. 2.9 ± 3.8, p < 0.01). A new, faster, low-radiation, MPS protocol in a CZT camera maintain the ability to stratify patients with increased risk of events, showing that, in the presence of greater extension of defect or ischemia, patients presented higher rates of hard events and late revascularization.

Prognostic performance of coronary computed tomography angiography in asymptomatic individuals as compared to symptomatic patients with an appropriate indication.

INTRODUCTION: Current Appropriatene Usa Criteria exclude coronary computed tomography angiography (CTA) in asymptomatic individuals. We compared the prognostic value of coronary CTA in asymptomatic individuals to symptomatic patients with "definitely appropriate" indications for coronary CTA. METHODS: Consecutive patients without previously known CAD referred for a CTA exam were divided into 2 groups. One group consisted ofasymptomatic individuals, the other of symptomatic patients with a "definitely appropriate" indication for coronary CT (unable to exercise and/or with an uninterpretable electrocardiogram and at an intermediate pre-test probability of obstructive coronary artery disease). Patients that did not fit into either groups were excluded. The segment stenosis score (SSS) was calculated based on coronary CTA and patients were followed for a composite endpoint of all-cause death, acute myocardial infarction and late revascularization. RESULTS: A total of 1080 patients (60 ± 12 years, 65% male) were included in the study (674 "asymptomatic" and 406 "appropriate"). SSS >4 was more frequent in "asymptomatic" than in "appropriate" CT data sets (27% vs 20%, p = 0.02). After a mean follow-up of 4.4 ± 1.8 yrs, 49 patients reached the composite endpoint. On multivariable analysis adjusting for CAD risk factors and symptoms, only a high-risk CTA study and past smoking were independently predictive of events. CONCLUSIONS: Although currently not regarded as "definitely appropriate", the use of coronary CTA in a selected asymptomatic population had higher yield for identifying high-risk individuals than appropriately indicated studies in symptomatic patients and provided thequal prognostic information.

Comparison of the prognostic value of myocardial perfusion imaging using a CZT-SPECT camera with a conventional anger camera.

BACKGROUND: Recent studies have shown that myocardial perfusion imaging (MPI) in cadmium-zinc-telluride (CZT) cameras allow faster exams with less radiation dose but there are little data comparing its prognosis information with that of dedicated cardiac Na-I SPECT cameras OBJECTIVE: The objective of this study is to compare the prognostic value of MPI using an ultrafast protocol with low radiation dose in a CZT-SPECT and a traditional one. METHODS: Group 1 was submitted to a two-day MIBI protocol in a conventional camera, and group 2 was submitted to a 1-day MIBI protocol in CZT camera. MPI were classified as normal or abnormal, and perfusion scores were calculated. Propensity score matching methods were performed RESULTS: 3554 patients were followed during 33±8 months. Groups 1 and 2 had similar distribution of age, gender, body mass index, risk factors, previous revascularization, and use of pharmacological stress. Group 1 had more abnormal scans, higher scores than group 2. Annualized hard events rate was higher in group 1 with normal scans but frequency of revascularization was similar to normal group 2. Patients with abnormal scans had similar event rates in both groups CONCLUSION: New protocol of MPI in CZT-SPECT showed similar prognostic results to those obtained in dedicated cardiac Na-I SPECT camera, with lower prevalence of hard events in patients with normal scan.

Prevalence and predictors of left intraventricular dyssynchrony determined by phase analysis in patients undergoing gatedSPECT myocardial perfusion imaging.

Left ventricular dyssynchrony (LVD) is an independent predictor of adverse cardiovascular events, death, and progression to heart failure. Myocardial perfusion imaging (MPI) with ECG-gated single-photon emission computed tomography (SPECT) can be used to diagnose LVD rapidly and automatically using phase analysis (PA). The objective of this study was to evaluate the prevalence and predictors of LVD in patients undergoing MPI. Clinical, electrocardiographic, and scintigraphic data from 1000 patients who underwent MPI with ECG-gated SPECT over a period of 1 year were analyzed retrospectively. TheEmoryCardiac Toolboxsoftware was used for PA, and LVD was diagnosed based on the following criteria: standard deviation of LV phase distribution ≥43° and/or phase histogram ≥140° in the resting and/or stress phase of the examination. Several variables were evaluated using univariate and multivariate analyses. The prevalence of LVD in the study population was 6.5 %, and the average age was 63.6 ± 12 years. The variables significantly associated with LVD were male gender, obesity, hypertension, diabetes, dyslipidemia, coronary artery disease (CAD), QRS interval ≥120 ms, LV dysfunction, and myocardial perfusion defects (especially fixed defects) on MPI. Although the PA parameters were greater at rest, both phases could be used for diagnosis. Multivariate analysis revealed that the variables significantly associated with LVD were male sex, obesity, history of CAD, and QRS interval ≥120 ms. The overall prevalence of LVD was 6.5 % in patients undergoing MPI in this study, and it reached 42 % in the presence of certain risk factors.

Dados Preliminares do Valor Prognóstico de um Novo Protocolo deCintilografia Miocárdica Ultrarrápido e com Menos Radiação emGamacâmara CZT / Preliminary Data on the Prognostic Value of a New Protocol of Ultra-fast Myocardial Scintigraphy with Less Radiation in CZT Gamma Camera

A cintilografia miocárdica de perfusão (CMP) é um dos métodos mais utilizados na avaliação de pacientes com suspeita de coronariopatia por seu valor diagnóstico e prognóstico. Duas de suas maiores limitações são o uso de radiação e a duração prolongada dosexames. Entretanto, novas Gamacâmaras de CZT (GC-CZT) têm permitido reduzir as doses dos radiotraçadores empregadas e o tempo de aquisição. O valor prognóstico desses novos protocolos não é conhecido.Objetivo: Determinar o valor prognóstico de um novo protocolo de CMP ultrarrápido e de baixa radiação numa GC-CZT. População: Pacientes com suspeita de coronariopatia consecutivamente submetidos a CMP numa GC-CZT no período de novembro de 2011 a junho de 2012.Metodologia: Foi utilizado protocolo de mesmo dia, iniciado pela fase de repouso com dose de 5 mCi e posterior estresse com dose de 15 mCi de Tc-99m sestamibi. Os tempos de aquisição foram de 6 e 3 minutos, respectivamente. Os exames foram classificados como normais ou anormais e escores de perfusão (SSS, SRS e SDS) foram calculados. Pacientes foram acompanhados mediante contato telefônico semestral. Os eventos avaliados foram morte, infarto não fatal e revascularização tardia (> 60 dias após CMP). Foi utilizado método de Coxpara identificar os preditores.Resultados: Setecentos e noventa e dois pacientes foram acompanhados por 21,3 ± 3,7 meses. A idade média foi de 65,2 ± 12,7 anos, sendo 50,3% do sexo masculino e o IMC médio de 26,9 ± 4,7. Hipertensão arterial foi o fator de risco mais frequente (59,5%), seguidode dislipidemia (51,9%) e diabetes (23,3%). Estresse físico foi empregado em 438 (55,3%) pacientes; 618 (78%) CMP foram normais. A dosimetria média dos exames foi 6 mSv e a duração média, de 48 ± 11 minutos. Durante o seguimentos ocorreram 12 óbitos, 4 infartos não fatais...

Myocardial perfusion scintigraphy (MPS) is one of the most used imaging methods for the evaluation of patients for coronary artery disease (CAD) due to its diagnostic and prognostic value. Two of its main limitations are radiation use and scan duration. However, CZT cameras (CZT-C) have allowed tracer dose and scan time reductions. However, the prognostic value of these new protocols is not known. Objective: To determine the prognostic value of a new, ultrafast, low dose protocol in a CZT-C. Population: Patients with suspect CAD undergoing MPS from 11/2011 to 6/2012 were studied. Methods: They had a 1-day Tc-99m sestamibi protocol starting with rest study (5 mCi dose) followed by stress (15 mCi). Acquisition times were 6 and 3 minutes respectively. MPS studied were classified as normal or abnormal and perfusion scores (SSS, SRS and SDS) were calculated. Patients were accompanied by 6-month phone calls. Events were defined as death, nonfatal myocardial infarction and late revascularization (> 60 days after MPS) and analyzed with the Cox method.Results: 792 patients were followed for 21.3 ± 3.7 months. Age was 65.2 ± 12.7 years, 50.3% were male and body mass index was 26.9 ± 4.7. Hypertension was the most frequent risk factor (59.5%), followed by hypercholesterolemia (51.9%) and diabetes (23.3%). Exercise was used in 438 (55.3%); 618 (78%) MPS studies were normal. Mean dosimetry was 6 mSv and mean scan time, 48 ± 11 minutes. During follow-up, there were 12 deaths...

Prognostic evaluation in obese patients using a dedicated multipinhole cadmium-zinc telluride SPECT camera.

The purpose of this study is to evaluate the prognostic value of myocardial perfusion SPECT obtained in CZT cameras (CZT-SPECT) with multipinhole collimation in obese patients. CZT-SPECT may be technically challenging in the obese, and its prognostic value remains largely unknown. Patients underwent single-day, rest/stress (supine and prone) imaging. Images were visually inspected and graded as poor, fair or good/excellent. Summed stress and difference scores (SSS and SDS, respectively) were converted into percentages of total perfusion defect and of ischemic defect by division by the maximum possible score. Obesity was defined as a body mass index (BMI) ≥ 30 kg/m(2) and classified as class I (BMI 30-34.9 kg/m(2)), II (BMI 35-39.9 kg/m(2)), or III (BMI ≥ 40 kg/m(2)). Patients were followed-up by telephone interview for the occurrence of all-cause death, myocardial infarction or revascularization. A Cox proportional hazards analysis was used to assess the independent predictors of death. Among 1396 patients, 365 (26.1 %) were obese (mean BMI 33.9 ± 3.6; 17.5 % class I, 3.4 % class II, and 3.4 % class III). Image quality was good/excellent in 94.5 % of the obese patients. The annualized mortality rates were not significantly different among obese and non-obese patients, being <1 % with normal CZT-SPECT, and increased with the degree of scan abnormality in both obese and non-obese patients. Age, the use of pharmacologic stress and an abnormal CZT-SPECT, but not obesity, were independent predictors of death. In obese patients, single-day rest/stress CZT-SPECT with a multipinhole camera provides prognostic discrimination with high image quality.