Role of Dapagliflozin in Ischemic Preconditioning in Patients with Symptomatic Coronary Artery Disease-DAPA-IP Study Protocol.

Background: Ischemic preconditioning (IP) is a powerful cellular protection mechanism. The cellular pathways underlying IP are extremely complex and involve the participation of cell triggers, intracellular signaling pathways, and end-effectors. Experimental studies have shown that sodium-glucose transport protein 2 (SGLT2) inhibitors promote activation of 5'-adenosine monophosphate (AMP)-activated protein kinase (AMPK), the main regulator of adenosine 5'-triphosphate homeostasis and energy metabolism in the body. Despite its cardioprotective profile demonstrated by numerous clinical trials, the results of studies on the action of SGLT2 inhibitors in IP are scarce. This study will investigate the effects of dapagliflozin on IP in patients with coronary artery disease (CAD). Methods: The study will include 50 patients with multivessel CAD, ischemia documented by stress testing, and preserved left ventricular ejection fraction (LVEF). Patients will undergo four exercise tests, the first two with a time interval of 30 min between them after washout of cardiovascular or hypoglycemic medications and the last two after 7 days of dapagliflozin 10 mg once a day, also with a time interval of 30 min between them. Discussion: The role of SGLT2 inhibitors on IP is not clearly established. Several clinical trials have shown that SGLT2 inhibitors reduce the occurrence cardiovascular events, notably heart failure. However, such studies have not shown beneficial metabolic effects of SGLT2 inhibitors, such as reducing myocardial infarction or stroke. On the other hand, experimental studies with animal models have shown the beneficial effects of SGLT2 inhibitors on IP, a mechanism that confers cardiac and vascular protection from subsequent ischemia-reperfusion (IR) injury. This is the first clinical study to evaluate the effects of SGLT2 inhibitors on IP, which could result in an important advance in the treatment of patients with stable CAD.

Exercise Testing, Family History, and Subclinical Atherosclerosis Markers for Cardiovascular Risk Reclassification in Middle-Aged Women

Abstract Background Cardiovascular diseases are the main cause of death in women and the accuracy of currently available risk scores is questionable. Objective To reclassify the risk estimated by the Framingham Risk Score (FRS) in asymptomatic middle-aged women by incorporating family history, exercise testing variables, and subclinical atherosclerosis markers. Methods This cross-sectional study included 509 women (age range, 46-65 years) without cardiovascular symptoms. Those at low or intermediate risk by the FRS were reclassified to a higher level considering premature family history of acute myocardial infarction and/or sudden death; four variables from exercise testing; and two variables related to subclinical atherosclerosis markers. The homogeneity of these variables according to the FRS was verified by Pearson chi-square test (p<0.05). Results According to the FRS, 80.2%, 6.2%, and 13.6% of the women were classified as low (<5%), intermediate (5-10%), and high (>10%) risks, respectively. The intermediate-risk stratum showed the highest increase (from 6.2% to 33.3%) with addition of family history; followed by addition of chronotropic index <80% (to 24.2%); functional capacity <85% (22.2%), coronary calcium score >0 (20.6%); decreased one-minute heart rate recovery ≤12 bpm (15.2%); carotid intima-media thickness >1 mm and/or carotid plaque (13.8%) and ST-segment depression (9.0%). The high-risk stratum increased to 14.4% with the addition of reduced heart rate recovery and to 17.1% with the coronary calcium score. Conclusion Incorporation of premature family history of cardiovascular events, exercise testing abnormal parameters, and subclinical atherosclerosis markers into the FRS led to risk reclassification in 3.0-29.7% of asymptomatic middle-aged women, mainly by an increase from low to intermediate risk.

Non Electrocardiographic alterations in exercise testing in asymptomatic women. Associations with cardiovascular risk factors.

OBJECTIVES: To estimate the prevalence of exercise testing alterations in middle-aged women without symptoms of heart disease and to verify the associations of functional capacity and heart rate behavior during and after exercise with cardiovascular risk factors. METHODS: A cross-sectional study was conducted with 509 asymptomatic women aged between 46 and 65 years who underwent clinical evaluations and exercise testing (Bruce protocol). The heart rate behavior was evaluated by the maximal predicted heart rate achieved, chronotropic index and recovery heart rate. RESULTS: The mean age was 56.4±4.8 years, and 13.4% of the patients had a Framingham risk score above 10%. In the exercise treadmill testing, 58.0% presented one or more of the following alterations (listed in order of ascending prevalence): symptoms (angina, dyspnea, and dizziness), ST-segment depression, arrhythmia, reduction in recovery heart rate of ≤12 bpm at 1 minute, altered maximal predicted heart rate achieved, abnormal blood pressure, functional capacity deficiency, and altered chronotropic index. In the multivariate analysis, the following associations (odds ratio) were observed for these alterations: chronotropic index was associated with obesity (2.08) and smoking (4.47); maximal predicted heart rate achieved was associated with smoking (6.45); reduction in the recovery heart rate at 1 minute was associated with age (1.09) and obesity (2.78); functional capacity was associated with age (0.92), an overweight status (2.29) and obesity (6.51). CONCLUSIONS: More than half of middle-aged women without cardiovascular symptoms present alterations in one or more exercise testing parameters. Alterations in the functional capacity or heart rate behavior, as verified by exercise testing, are associated with age, smoking, an overweight status and obesity.

Non Electrocardiographic alterations in exercise testing in asymptomatic women. Associations with cardiovascular risk factors

OBJECTIVES: To estimate the prevalence of exercise testing alterations in middle-aged women without symptoms of heart disease and to verify the associations of functional capacity and heart rate behavior during and after exercise with cardiovascular risk factors. METHODS: A cross-sectional study was conducted with 509 asymptomatic women aged between 46 and 65 years who underwent clinical evaluations and exercise testing (Bruce protocol). The heart rate behavior was evaluated by the maximal predicted heart rate achieved, chronotropic index and recovery heart rate. RESULTS: The mean age was 56.4±4.8 years, and 13.4% of the patients had a Framingham risk score above 10%. In the exercise treadmill testing, 58.0% presented one or more of the following alterations (listed in order of ascending prevalence): symptoms (angina, dyspnea, and dizziness), ST-segment depression, arrhythmia, reduction in recovery heart rate of ≤12 bpm at 1 minute, altered maximal predicted heart rate achieved, abnormal blood pressure, functional capacity deficiency, and altered chronotropic index. In the multivariate analysis, the following associations (odds ratio) were observed for these alterations: chronotropic index was associated with obesity (2.08) and smoking (4.47); maximal predicted heart rate achieved was associated with smoking (6.45); reduction in the recovery heart rate at 1 minute was associated with age (1.09) and obesity (2.78); functional capacity was associated with age (0.92), an overweight status (2.29) and obesity (6.51). CONCLUSIONS: More than half of middle-aged women without cardiovascular symptoms present alterations in one or more exercise testing parameters. Alterations in the functional capacity or heart rate behavior, as verified by exercise testing, are associated with age, smoking, an overweight status and obesity.

Avaliação prognóstica da doença coronária estável através de um novo escore / New prognostic score for stable coronary disease evaluation / Evaluación pronóstica de la enfermedad coronaria estable a través de un nuevo score

FUNDAMENTO: A necessidade de melhorar a acurácia do teste de esforço, determinou o desenvolvimento de escores, cuja aplicabilidade já foi amplamente reconhecida. OBJETIVO: Avaliação prognóstica do coronariopata estável através de um novo escore simplificado. MÉTODOS: Um novo escore foi aplicado em 372 coronariopatas multiarteriais e função ventricular preservada, 71,8 por cento homens, idade média 59,5 (± 9,07) anos, randomizados para angioplastia, revascularização cirúrgica e tratamento clínico, acompanhados por 5 anos. Óbito cardiovascular foi o desfecho primário. Infarto do miocárdio não-fatal, óbito e re-intervenção formaram o desfecho combinado secundário. O escore baseou-se numa equação previamente validada resultante da soma de 1 ponto para: sexo masculino, história de infarto, angina, diabete, uso de insulina e ainda 1 ponto para cada década de vida a partir dos 40 anos. Teste positivo adicionou 1 ponto. RESULTADOS: Ocorreram 36 óbitos (10 no grupo angioplastia, 15 no grupo revascularização e 11 no grupo clínico), p = 0,61. Observou-se 93 eventos combinados: 37 no grupo angioplastia, 23 no grupo revascularização e 33 no grupo clínico (p = 0,058). 247 pacientes apresentaram escore clínico > 5 pontos e 216 > 6 pontos. O valor de corte > 5 ou > 6 pontos identificou maior risco, com p = 0,015 e p = 0,012, respectivamente. A curva de sobrevida mostrou uma incidência de óbito após a randomização diferente naqueles com escore > 6 pontos (p = 0,07), e uma incidência de eventos combinados diferente entre pacientes com escore < 6 e > 6 pontos (p = 0,02). CONCLUSÃO: O novo escore demonstrou consistência na avaliação prognóstica do coronariopata estável multiarterial.

BACKGROUND: The need to improve the exercise testing accuracy, pushed the development of scores, whose applicability was already broadly recognized. OBJECTIVE: Prognostic evaluation of stable coronary disease through a new simplified score. METHODS: A new score was applied in 372 multivessel coronary patients with preserved ventricular function, 71.8 percent male, age: 59.5 (± 9.07) years old, randomized to medical treatment, surgery (CABG) or angioplasty (PTCA), with 5 years of follow-up. Cardiovascular death was considered the primary endpoint. Non-fatal myocardial infarction, death and re-intervention were considered for a combined secondary endpoint. The score was based on an equation previously validated, resulting from a sum of one point for: male gender, infarction history, angina, diabetes, insulin use and one point for each decade of life after 40 years old. Positive exercise testing summed one additional point. RESULTS: Thirty six deaths was observed (10 in group PTCA, 15 in CABG and 11 in the clinical group), p = 0.61. We observed 93 combined events: 37 in PTCA group, 23 in CABG and 33 in the clinical group (p = 0.058). 247 patients presented clinical score > 5 points and 216 > 6 points. The cutoff point > 5 or > 6 points identified higher risk, p = 0.015 and p = 0.012, respectively. The survival curve showed a different death incidence after the randomization when score reached 06 points or more (p = 0.07), and a distinct incidence of combined events between the patients with score < 6 and > 6 points (p = 0.02). CONCLUSION: The new score was consistent for multiarterial stable coronary disease risk stratification.

FUNDAMENTO: La necesidad de mejorar la exactitud de las pruebas de estrés, determinó el desarrollo de los puntajes, cuya aplicación fue ampliamente reconocida. OBJETIVO: La evaluación pronóstica del coronariópata estable a través de un nuevo score simplificado. MÉTODOS: Un nuevo score se aplicó en 372 coronariópatas multiarteriales y función ventricular preservada, el 71,8 por ciento varones, edad media de 59,5 (± 9,07) años, randomizados para angioplastia, revascularización quirúrgica y tratamiento clínico, seguidos de cinco años. Muerte cardiovascular fue el resultado primario. El infarto de miocardio no fatal, la muerte y la re-intervención formaron el desenlace combinado secundario. El score se basó en una ecuación previamente validada resultante de la suma de 1 punto a: sexo masculino, antecedentes de infarto, angina, diabetes, uso de insulina y todavía un punto por cada década de vida después de 40 años. Prueba positiva añadida 1 punto. RESULTADOS: Hubo 36 muertes (10 en el grupo de angioplastia, 15 en el grupo de revascularización y 11 en el grupo clínico), p = 0,61. Se observó 93 eventos combinados: 37 en el grupo angioplastia, 23 en el grupo revascularización y 33 en el grupo clínico (p = 0,058). Presentaron score clínico > 5 puntos y 216 > 6 puntos 247 pacientes. El valor de corte > 5 o > 6 puntos identificó un mayor riesgo, con p = 0,015 y p = 0,012, respectivamente. La curva de sobrevida mostró una incidencia de muerte después de la aleatorización que aquellos con score > 6 puntos (p = 0,07), y una incidencia de eventos combinados diferentes entre los pacientes con score < 6 y > 6 puntos (p = 0,02). CONCLUSIÓN: El nuevo score demostró consistencia en la evaluación pronóstica del coronariópata estable multiarterial. (Arq Bras Cardiol 2011;96(5):411-419).

New prognostic score for stable coronary disease evaluation.

BACKGROUND: The need to improve the exercise testing accuracy, pushed the development of scores, whose applicability was already broadly recognized. OBJECTIVE: Prognostic evaluation of stable coronary disease through a new simplified score. METHODS: A new score was applied in 372 multivessel coronary patients with preserved ventricular function, 71.8% male, age: 59.5 (± 9.07) years old, randomized to medical treatment, surgery (CABG) or angioplasty (PTCA), with 5 years of follow-up. Cardiovascular death was considered the primary endpoint. Non-fatal myocardial infarction, death and re-intervention were considered for a combined secondary endpoint. The score was based on an equation previously validated, resulting from a sum of one point for: male gender, infarction history, angina, diabetes, insulin use and one point for each decade of life after 40 years old. Positive exercise testing summed one additional point. RESULTS: Thirty six deaths was observed (10 in group PTCA, 15 in CABG and 11 in the clinical group), p = 0.61. We observed 93 combined events: 37 in PTCA group, 23 in CABG and 33 in the clinical group (p = 0.058). 247 patients presented clinical score ≥ 5 points and 216 ≥ 6 points. The cutoff point ≥ 5 or ≥ 6 points identified higher risk, p = 0.015 and p = 0.012, respectively. The survival curve showed a different death incidence after the randomization when score reached 06 points or more (p = 0.07), and a distinct incidence of combined events between the patients with score < 6 and ≥ 6 points (p = 0.02). CONCLUSION: The new score was consistent for multiarterial stable coronary disease risk stratification.

Noninvasive assessment of patients undergoing percutaneous intervention in myocardial infarction.

BACKGROUND: Restenosis after primary percutaneous coronary intervention (PPCI) remains an important clinical problem, even with stent implantation. The ability of noninvasive testing to diagnose restenosis has had only inconsistent demonstration. OBJECTIVE: Our objective was to evaluate the ability of exercise treadmill testing (ETT) and myocardial perfusion imaging (MPI) to diagnose restenosis in patients treated by PPCI within 12 hours of ST-elevation myocardial infarction (STEMI). METHODS: From August 2003 to January 2006, 64 patients (mean age of 56.2±10.2 years, 53 males) were enrolled after PPCI. Only patients with left ventricular ejection fraction (LVEF) > 40%, as assessed by resting transthoracic echocardiography (TTE), were included. ETT with 12-lead ECG monitoring and right precordial leads, as also MPI were performed at 6 weeks, 6 months, and one year after intervention. Coronary angiography was performed at six months. RESULTS: Single-vessel disease was observed in 46.9% of the patients. The left anterior descending coronary artery was treated in 48.4% of the patients. Angiographic restenosis occurred in 28.8%. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of ETT in detecting restenosis were not significant. Right precordial leads did not add information. MPI sensitivity, specificity, PPV, NPV, and accuracy correlated with restenosis only in the 6-month follow-up, both when considering summed difference score >2 (p=0.006) and >4 (p=0.014). CONCLUSION: ETT did not discriminate restenosis in this population. MPI performed at 6 months correlated with restenosis and proved useful during follow-up.

Avaliação não invasiva de pacientes submetidos à intervenção percutânea no infarto do miocárdio / Noninvasive assessment of patients undergoing percutaneous intervention in myocardial infarction

FUNDAMENTO: A reestenose pós-intervenção coronariana percutânea primária permanece um problema de relevância clínica, mesmo com o implante de stents. A capacidade das provas não invasivas para detecção de reestenose não foi totalmente demonstrada. OBJETIVO: Avaliar a habilidade do teste ergométrico (TE) e da cintilografia de perfusão miocárdica (CPM) no diagnóstico de reestenose em pacientes com infarto agudo do miocárdio, e supradenivelamento do segmento ST, submetidos à angioplastia coronariana percutânea primária (ACPP), com implante de stent nas primeiras 12 horas de evolução. MÉTODOS: De Ago/2003-Jan/2006, foram selecionados 64 pacientes (ps) (56,2 ± 10,2 anos, 53 homens) submetidos à ACPP. Apenas ps com fração de ejeção do ventrículo esquerdo > 40,0 por cento, definida por ecocardiograma de repouso, foram incluídos. Teste ergométrico, com as 12 derivações do ECG associadas a precordiais direitas, e CPM foram realizados 6 semanas, 6 meses e um ano após o tratamento. Foi realizada cinecoronariografia no 6º mês. RESULTADOS: Doença uniarterial ocorreu em 46,9 por cento dos ps, sendo a artéria descendente anterior tratada em 48,4 por cento. Reestenose angiográfica ocorreu em 28,8 por cento. Sensibilidade, especificidade, valor preditivo positivo (VPP), valor preditivo negativo (VPN) e acurácia do TE para detecção de reestenose não foram significativos. A adição de derivações precordiais direitas não proporcionou informações adicionais. Sensibilidade, especificidade, VPP, VPN e acurácia da CPM apresentaram correlação com reestenose apenas no 6º mês, considerando-se summed difference score > 2 (p = 0,006) e > 4 (p = 0,014). CONCLUSÃO: O TE não discriminou reestenose. A CPM realizada no 6º mês foi relacionada à reestenose e mostrou-se útil durante a evolução.

BACKGROUND: Restenosis after primary percutaneous coronary intervention (PPCI) remains an important clinical problem, even with stent implantation. The ability of noninvasive testing to diagnose restenosis has had only inconsistent demonstration. OBJECTIVE: Our objective was to evaluate the ability of exercise treadmill testing (ETT) and myocardial perfusion imaging (MPI) to diagnose restenosis in patients treated by PPCI within 12 hours of ST-elevation myocardial infarction (STEMI). METHODS: From August 2003 to January 2006, 64 patients (mean age of 56.2±10.2 years, 53 males) were enrolled after PPCI. Only patients with left ventricular ejection fraction (LVEF) > 40 percent, as assessed by resting transthoracic echocardiography (TTE), were included. ETT with 12-lead ECG monitoring and right precordial leads, as also MPI were performed at 6 weeks, 6 months, and one year after intervention. Coronary angiography was performed at six months. RESULTS: Single-vessel disease was observed in 46.9 percent of the patients. The left anterior descending coronary artery was treated in 48.4 percent of the patients. Angiographic restenosis occurred in 28.8 percent. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy of ETT in detecting restenosis were not significant. Right precordial leads did not add information. MPI sensitivity, specificity, PPV, NPV, and accuracy correlated with restenosis only in the 6-month follow-up, both when considering summed difference score >2 (p=0.006) and >4 (p=0.014). CONCLUSION: ETT did not discriminate restenosis in this population. MPI performed at 6 months correlated with restenosis and proved useful during follow-up.