Cardiovascular events in patients with coronary artery disease with and without myocardial ischemia: Long-term follow-up.

BACKGROUND: After the results of the ISCHEMIA Trial, the role of myocardial ischemia in the prognosis of coronary artery disease (CAD) was under debate. We sought to comparatively evaluate the long-term prognosis of patients with multivessel CAD with or without documented myocardial ischemia. METHODS: This is a single-center, retrospective, observational cohort study that included patients with CAD obtained from the research protocols database of "The Medicine, Angioplasty or Surgery Study," the MASS Study Group. Patients were stratified according to the presence or absence of myocardial ischemia. Cardiovascular events (overall mortality and myocardial infarction) were tracked from the registry entry up to a median follow-up of 8.7 years. Myocardial ischemia was assessed at baseline by a functional test with or without imaging. RESULTS: From 1995 to 2018, 2015 patients with multivessel CAD were included. Of these, 1001 presented with conclusive tests at registry entry, 790 (79%) presenting with ischemia and 211 (21%) without ischemia. The median follow-up was 8.7 years (IQR 4.04 to 10.07). The primary outcome occurred in 228 (28.9%) patients with ischemia and in 64 (30.3%) patients without ischemia (plog-rank=0.60). No significant interaction was observed with the presence of myocardial ischemia and treatment strategies in the occurrence of the combined primary outcome (pinteration=0.14). CONCLUSIONS: In this sample, myocardial ischemia was not associated with a worse prognosis compared with no ischemia in patients with multivessel CAD. These results refer to debates about the role of myocardial ischemia in the occurrence of cardiovascular events.

Long-term outcomes of patients with stable coronary disease and chronic kidney dysfunction: 10-year follow-up of the Medicine, Angioplasty, or Surgery Study II Trial.

BACKGROUND: Chronic kidney disease (CKD) is associated with a worse prognosis in patients with stable coronary artery disease (CAD); however, there is limited randomized data on long-term outcomes of CAD therapies in these patients. We evaluated long-term outcomes of CKD patients with CAD who underwent randomized therapy with medical treatment (MT) alone, percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG). METHODS: Baseline estimated glomerular filtration rate (eGFR) was obtained in 611 patients randomized to one of three therapeutic strategies in the Medicine, Angioplasty, or Surgery Study II trial. Patients were categorized in preserved renal function and mild or moderate CKD groups depending on their eGFR (≥90, 89-60 and 59-30 mL/min/1.73 m2, respectively). The primary clinical endpoint, a composite of overall death and myocardial infarction, and its individual components were analyzed using proportional hazards regression (Clinical Trial registration information: http://www.controlled-trials.com. Registration number: ISRCTN66068876). RESULTS: Of 611 patients, 112 (18%) had preserved eGFR, 349 (57%) mild dysfunction and 150 (25%) moderate dysfunction. The primary endpoint occurred in 29.5, 32.4 and 44.7% (P = 0.02) for preserved eGFR, mild CKD and moderate CKD, respectively. Overall mortality incidence was 18.7, 23.8 and 39.3% for preserved eGFR, mild CKD and moderate CKD, respectively (P = 0.001). For preserved eGFR, there was no significant difference in outcomes between therapies. For mild CKD, the primary event rate was 29.4% for PCI, 29.1% for CABG and 41.1% for MT (P = 0.006) [adjusted hazard ratio (HR) = 0.26, 95% confidence interval (CI) 0.07-0.88; P = 0.03 for PCI versus MT; and adjusted HR = 0.48; 95% CI 0.31-0.76; P = 0.002 for CABG versus MT]. We also observed higher mortality rates in the MT group (28.6%) compared with PCI (24.1%) and CABG (19.0%) groups (P = 0.015) among mild CKD subjects (adjusted HR = 0.44, 95% CI 0.25-0.76; P = 0.003 for CABG versus MT; adjusted HR = 0.56, 95% CI 0.07-4.28; P = 0.58 for PCI versus MT). Results were similar with moderate CKD group but did not achieve significance. CONCLUSIONS: Coronary interventional therapy, both PCI and CABG, is associated with lower rates of events compared with MT in mild CKD patients >10 years of follow-up. More study is needed to confirm these benefits in moderate CKD.

Abnormal release of cardiac biomarkers in the presence of myocardial oedema evaluated by cardiac magnetic resonance after uncomplicated revascularization procedures.

AIMS: To analyse the association of myocardial oedema (ME), observed as high T2 signal intensity (HT2) in cardiac magnetic resonance imaging, with the release of cardiac biomarkers, ventricular ejection, and clinical outcomes after revascularization. METHODS AND RESULTS: Patients with stable coronary artery disease with the indication for revascularization were included. Biomarker levels [troponin I (cTnI) and creatine kinase MB (CK-MB)] and T2-weighted and late gadolinium enhancement (LGE) images were obtained before and after the percutaneous or surgical revascularization procedures. The association of HT2 with the levels of biomarkers, with and without LGE, evolution of left ventricular ejection fraction (LVEF), and 5-year clinical outcomes were assessed. A total of 196 patients were divided into 2 groups: Group 1 (HT2, 40) and Group 2 (no HT2, 156). Both peak cTnI (8.9 and 1.6 ng/mL) and peak CK-MB values (44.7 and 12.1 ng/mL) were significantly higher in Group 1. Based on the presence of new LGE, patients were stratified into Groups A (no HT2/LGE, 149), B (HT2, 9), C (LGE, 7), and D (both HT2/LGE, 31). The peak cTnI and CK-MB values were 1.5 and 12.0, 5.4 and 44.7, 5.0 and 18.3, and 9.8 and 42.8 ng/mL in Groups A, B, C, and D, respectively, and were significantly different. The average LVEF decreased by 4.4% in Group 1 and increased by 2.2% in Group 2 (P = 0.057). CONCLUSION: ME after revascularization procedures was associated with increased release of cardiac necrosis biomarkers, and a trend towards a difference in LVEF, indicating a role of ME in cardiac injury after interventions.

Surgical and percutaneous revascularization outcomes based on SYNTAX I, II, and residual scores: a long-term follow-up study.

BACKGROUND: The objective of this study was to evaluate the association of SYNTAX scores I, II, and residual with cardiovascular outcomes of patients undergoing coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) and compare both procedures in a long-term follow-up. METHODS: This is a retrospective single-center study from the MASS registry at the Heart Institute of the University of São Paulo, Brazil in which 969 patients with stable coronary artery disease undergoing CABG (559) or PCI (410) were included. We assessed the SYNTAX scores I, II and residual in both interventions. Clinical endpoints were the first occurrence of a composite of overall death, myocardial infarction, stroke, or repeat revascularization (MACCE) and the total occurrence of each component of MACCE. RESULTS: In the CABG sample, SSI had a median of 23 (IQR 17-29.5), median SSII of 25.4 (IQR 19.2-32.8), and median rSS of 2 (IQR 0-6.5); in PCI SSI had a median of 14 (IQR 10-19.1), median SSII of 28.7 (IQR 23-34.2), and median rSS of 4.7 (IQR 0-9). Total of 174 events were documented and CABG patients had a lower rate of MACCE (15.6% vs. 21.2%; adjusted HR 1.98; 95% CI 1.13-3.47; P = 0.016) and repeat revascularization (3.8% vs. 11.5%; adjusted HR 4.35; CI 95% 1.74-10.85; P = 0.002) compared with PCI. No SYNTAX score tertile found a difference in death rate between procedures. In a multivariate analysis, the rSS was an independent predictor for MACCE (HR 1.04; 95% CI 1.01-1.06; P = 0.001). Regarding death, the only independent predictors were ejection fraction and renal function. CONCLUSION: Surgical revascularization resulted in a more complete revascularization and lower rates of major cardiac or cerebrovascular events in a long-term follow-up. Also, grading the incompleteness of revascularization through the residual SYNTAX score identified a higher event rate, suggesting that complete revascularization is associated with a better prognosis.

Effect of diabetic kidney disease on therapeutic strategies for coronary artery disease: ten year follow-up.

BACKGROUND: The best treatment for coronary artery disease (CAD) in patients with type 2 diabetes (DM2) and chronic kidney disease is unknown. METHODS: This retrospective study included MASS registry patients with DM2 and multivessel CAD, stratified by kidney function. Primary endpoint was combined of mortality, myocardial infarction, or additional revascularization. RESULTS: Median follow-up was 9.5 years. Primary endpoint occurrences among strata 1 and 2 were 53.4% and 40.7%, respectively (P=.020). Mortality rates were 37.4% and 24.6% in strata 1 and 2, respectively (P<.001). We observed a lower rate of major adverse cardiovascular events (MACE) (P=.027 for stratum 1 and P<.001 for stratum 2) and additional revascularization (P=.001 for stratum 1 and P<.001 for stratum 2) for those in the surgical group. In a multivariate analysis, eGFR was an independent predictor of MACE (P=.034) and mortality (P=.020). CONCLUSIONS: Among subjects with DM2 and CAD the presence of lower eGFR rate was associated with higher rates of MACE and mortality, irrespective of treatment choice. CABG was associated with lower rates of MACE in both renal function strata. eGFR was an independent predictor of MACE and mortality in a 10-year follow-up.

Significant association of SYNTAX score on release of cardiac biomarkers in uncomplicated post-revascularization procedures among patients with stable multivessel disease: MASS-V Study group.

This study investigated the relationship between angiographic complexities of coronary artery disease (CAD) assessed by SYNTAX Score synergy between percutaneous coronary intervention with taxus and cardiac surgery score (SYNTAX Score) and cardiac biomarker elevation after revascularization procedures.This is a post-hoc analysis of the medicine, angioplasty or surgery study V study of patients with stable CAD. High-sensitivity troponin 1 (hs-TnI) and creatinine kinase-muscle/brain (CK-MB) were assessed before and after cardiovascular procedures. Baselines SYNTAX Scores (SXScores) were calculated by blinded investigators to patient characteristics.Of the 202 patients studied, the mean SXScore was 21.25 ±â€Š9.24; 40.10 ±â€Š7.09 in the high SXScore group and 19.06 ±â€Š6.61 in low/mid SXscore group (P < .0001). Positive correlations existed between SXScore and median peaks after procedural hs-TnI (r = 0.18, P = .009) and CK-MB (r = 0.24, P = .001) levels. In patients with high SXScores (≥33), the median peaks of post-procedural hs-TnI (P = .034)and CK-MB (P = .004) levels were higher than in low/mid SXScore group (<33).The release of hs-TnI at 6 (P = .002), 12 (P = .008), and 24 hours (P = .039) was higher in high SXScore group than in low/mid SXscore group (<33) as was the release of CK-MB at 6 (P < .0001), 12 (P < .0001), 24 (P = .001), 36 (P = .007), 48 (P = .008), and 72 hours (P = .023). After multivariable analysis, high SXScore was a significant independent predictor of release of CK-MB and hs-TnI peaks higher than the median.The increase in release of cardiac biomarkers was significantly associated with the extent of atherosclerosis identified by the SYNTAX Score.

BlsA Is a Low to Moderate Temperature Blue Light Photoreceptor in the Human Pathogen Acinetobacter baumannii.

Light is an environmental signal that produces extensive effects on the physiology of the human pathogen Acinetobacter baumannii. Many of the bacterial responses to light depend on BlsA, a bluelight using FAD (BLUF)-type photoreceptor, which also integrates temperature signals. In this work, we disclose novel mechanistic aspects of the function of BlsA. First, we show that light modulation of motility occurs only at temperatures lower than 24°C, a phenotype depending on BlsA. Second, blsA transcript levels were significantly reduced at temperatures higher than 25°C, in agreement with BlsA protein levels in the cell which were undetectable at 26°C and higher temperatures. Also, quantum yield of photo-activation of BlsA (lBlsA) between 14 and 37°C, showed that BlsA photoactivity is greatly compromised at 25°C and absent above 28°C. Fluorescence emission and anisotropy of the cofactor together with the intrinsic protein fluorescence studies suggest that the FAD binding site is more susceptible to structural changes caused by increments in temperature than other regions of the protein. Moreover, BlsA itself gains structural instability and strongly aggregates at temperatures above 30°C. Overall, BlsA is a low to moderate temperature photoreceptor, whose functioning is highly regulated in the cell, with control points at expression of the cognate gene as well as photoactivity.

Dual platelet antiaggregation therapy after myocardial revascularization surgery.

Coronary artery bypass graft (CABG) is a consolidated treatment in patients with coronary artery disease (CAD) for both symptom control and improvement of prognosis. The patency of venous grafts is still the most vulnerable point of the surgical treatment since it presents a high prevalence of occlusion both in the immediate postoperative period and in the long-term follow-up. Aspirin plays a well-established role in this setting, and for a long time, clopidogrel use has been restricted to patients allergic to aspirin. Recently, subgroup analyses of studies with different anti-platelet therapies have shown reduced mortality and cardiovascular events in patients on dual anti-platelet antiplatelet therapy (DAPT) undergoing CABG, although such studies have not been designed to evaluate this patient profile. However, there is still an insufficient number of randomized studies using DAPT in this context, resulting in a disagreement between the European and American cardiology societies guidelines regarding their indication and generating doubts in clinical practice.

Critical analysis of the classic indications for myocardial revascularization.

Treatment of stable coronary artery disease (CAD) relies on improved prognosis and relief of symptoms. National and international guidelines on CAD support the indication of revascularization in patients with limiting symptoms and refractory to optimal medical treatment, as well as in clinical situations where there is a prognostic benefit of interventional treatment. Most of the studies that support the guidelines for indication of revascularization date back to the 1980s and1990s of the last century. Recent studies have revisited the theme and brought a new breath. The present review provides a critical analysis of classic indications for revascularization, reviewing evidence from the studies of the 1970s to the recent controversial ORBITA study.

CULPRIT-SHOCK study.

The treatment of patients with ST-segment elevation myocardial infarction concomitant with the presence of multivessel disease has been studied in several recent studies with the purpose of defining the need, as well as the best moment to approach residual lesions. However, such studies included only stable patients. The best therapeutic approach to cardiogenic shock secondary to acute coronary syndrome, however, remains controversial, but there are recommendations from specialists for revascularization that include non-event related injuries. Recently published, the CULPRIT-SHOCK study showed benefit of the initial approach only of the injury blamed for the acute event, in view of the multivessel percutaneous intervention, in the context of cardiogenic shock. In this perspective, the authors discuss the work in question, regarding methodological questions, limitations and clinical applicability.

Integration of Temperature and Blue-Light Sensing in Acinetobacter baumannii Through the BlsA Sensor.

BlsA is a BLUF photoreceptor present in Acinetobacter baumannii, responsible for modulation of motility, biofilm formation and virulence by light. In this work, we have combined physiological and biophysical evidences to begin to understand the basis of the differential photoregulation observed as a function of temperature. Indeed, we show that blsA expression is reduced at 37°C, which correlates with negligible photoreceptor levels in the cells, likely accounting for absence of photoregulation at this temperature. Another point of control occurs on the functionality of the BlsA photocycle itself at different temperatures, which occurs with an average quantum yield of photoactivation of the signaling state of 0.20 ± 0.03 at 15°C < T < 25°C, but is practically inoperative at T > 30°C, as a result of conformational changes produced in the nanocavity of FAD. This effect would be important when the photoreceptor is already present in the cell to avoid almost instantaneously further signaling process when it is no longer necessary, for example under circumstances of temperature changes possibly faced by the bacteria. This complex interplay between light and temperature would provide the bacteria clues of environmental location and dictate/modulate light photosensing in A. baumannii.

Ischemic left ventricle systolic dysfunction: An evidence-based approach in diagnostic tools and therapeutics.

Coronary artery disease (CAD) associated with left ventricular systolic dysfunction is a condition related to poor prognosis. There is a lack of robust evidence in many aspects related to this condition, from definition to treatment. Ischemic cardiomyopathy is a spectrum ranging from stunned myocardium associated with myocardial fibrosis to hibernating myocardium and repetitive episodes of ischemia. In clinical practice, relevance lies in identifying the myocardium that has the ability to recover its contractile reserve after revascularization. Methods to evaluate cellular integrity tend to have higher sensitivity, while the ones assessing contractile reserve have greater specificity, since a larger mass of viable myocytes is required in order to generate contractility change. Since there are many methods and different ways to detect viability, sensitivity and specificity vary widely. Dobutamine-cardiac magnetic resonance with late gadolinium enhancement has the best accuracy is this setting, giving important predictors of prognostic and revascularization benefit such as scar burden, contractile reserve and end-systolic volume index. The latter has shown differential benefit with revascularization in some recent trials. Finally, authors discuss interventional procedures in this population, focusing on coronary artery bypass grafting and evolution of evidence from CASS to post-STICH era.

Inhibition of autophagy with chloroquine potentiates carfilzomib-induced apoptosis in myeloma cells in vitro and in vivo.

The proteasome inhibitor bortezomib is now the cornerstone of combination therapy of multiple myeloma (MM). Carfilzomib, a second-generation inhibitor, has shown a substantial benefit vs bortezomib in combination regimes. Here we have analyzed in detail the mechanism of cell death induced by carfilzomib and its crosstalk with autophagy and applied the results to the in vivo treatment of MM in a mouse model. Carfilzomib induced apoptosis essentially by the intrinsic pathway, through the up-regulation of Puma and Noxa proteins followed by the interaction of Puma, Noxa and Bim with Bax and of Noxa with Bak. Carfilzomib also produces an increase in the formation of autophagosomes but, as apoptosis progresses, autophagy is disrupted, probably owing to Beclin 1 and p62 inactivation. Cotreatment with chloroquine, which blocks autophagy, strongly potentiated apoptosis in vitro and in vivo. Accordingly, combination therapy with carfilzomib plus chloroquine was highly effective in the treatment of MM in a mouse xenograft model. Chloroquine also enhanced carfilzomib-induced calreticulin exposure in MM cells undergoing apoptosis, increasing the immunogenic ability of carfilzomib. These results support design of trials combining carfilzomib with chloroquine to improve MM therapy.

MHC-I modulation due to changes in tumor cell metabolism regulates tumor sensitivity to CTL and NK cells.

Tumor cells have a tendency to use glucose fermentation to obtain energy instead of mitochondrial oxidative phosphorylation (OXPHOS). We demonstrated that this phenotype correlated with loss of ERK5 expression and with reduced MHC class I expression. Consequently, tumor cells could evade cytotoxic T lymphocyte (CTL)-mediated immune surveillance, but also increase their sensitivity to natural killer (NK) cells. These outcomes were evaluated using two cellular models: leukemic EL4 cells and L929 transformed fibroblasts and their derived ρ° cell lines, which lack mitochondrial DNA. We have also used a L929 cell sub-line that spontaneously lost matrix attachment (L929dt), reminiscent of metastasis generation, that also downregulated MHC-I and ERK5 expression. MHC-I expression is lower in ρ° cells than in the parental cell lines, but they were equally sensitive to CTL. On the contrary, ρ° cells were more sensitive to activated NK cells than parental cells. On the other hand, L929dt cells were resistant to CTL and NK cells, showed reduced viability when forced to perform OXPHOS, and surviving cells increased MHC-I expression and became sensitive to CTL. The present results suggest that when the reduction in MHC-I levels in tumor cells due to glycolytic metabolism is partial, the increase in sensitivity to NK cells seems to predominate. However, when tumor cells completely lose MHC-I expression, the combination of treatments that increase OXPHOS with CTL-mediated immunotherapy could be a promising therapeutic approach.

Critical analysis of the classic indications for myocardial revascularization

SUMMARY Treatment of stable coronary artery disease (CAD) relies on improved prognosis and relief of symptoms. National and international guidelines on CAD support the indication of revascularization in patients with limiting symptoms and refractory to optimal medical treatment, as well as in clinical situations where there is a prognostic benefit of interventional treatment. Most of the studies that support the guidelines for indication of revascularization date back to the 1980s and1990s of the last century. Recent studies have revisited the theme and brought a new breath. The present review provides a critical analysis of classic indications for revascularization, reviewing evidence from the studies of the 1970s to the recent controversial ORBITA study.

RESUMO O tratamento da doença arterial coronariana estável (DAC) se baseia na melhora do prognóstico e alívio de sintomas. Diretrizes nacionais e internacionais sobre a DAC respaldam a indicação de revascularização em pacientes com sintomas limitantes e refratários ao tratamento medicamentoso, bem como em situações clínicas nas quais há benefício prognóstico do tratamento intervencionista. Grande parte dos estudos que norteiam as diretrizes de indicação de revascularização data das décadas de 1980 e 1990. Estudos recentes têm revisitado o tema e trazido novo fôlego. A presente revisão faz uma análise crítica das indicações clássicas de revascularização, revisando a evidência desde os estudos da década de 1970 ao recente e polêmico estudo Orbita.

Dual platelet antiaggregation therapy after myocardial revascularization surgery

SUMMARY Coronary artery bypass graft (CABG) is a consolidated treatment in patients with coronary artery disease (CAD) for both symptom control and improvement of prognosis. The patency of venous grafts is still the most vulnerable point of the surgical treatment since it presents a high prevalence of occlusion both in the immediate postoperative period and in the long-term follow-up. Aspirin plays a well-established role in this setting, and for a long time, clopidogrel use has been restricted to patients allergic to aspirin. Recently, subgroup analyses of studies with different anti-platelet therapies have shown reduced mortality and cardiovascular events in patients on dual anti-platelet antiplatelet therapy (DAPT) undergoing CABG, although such studies have not been designed to evaluate this patient profile. However, there is still an insufficient number of randomized studies using DAPT in this context, resulting in a disagreement between the European and American cardiology societies guidelines regarding their indication and generating doubts in clinical practice.

RESUMO A cirurgia de revascularização miocárdica (CRM) é tratamento fundamental em pacientes com doença arterial coronariana (DAC) tanto para controle de sintomas quanto para melhora do prognóstico. A patência dos enxertos venosos ainda hoje é o ponto mais vulnerável do tratamento cirúrgico, por apresentar alta prevalência de oclusão tanto no pós-operatório imediato como no seguimento em longo prazo. A aspirina tem papel bem estabelecido neste cenário e, por muito tempo, o uso do clopidogrel ficou restrito a pacientes alérgicos a aspirina. Recentemente, análises de subgrupos de estudos com diferentes terapias antiplaquetárias demonstraram redução de mortalidade e eventos cardiovasculares em pacientes em uso de dupla antiagregação plaquetária (Dapt) submetidos à CRM, ainda que tais estudos não tenham sido desenhados para avaliar este perfil de pacientes. Contudo, há ainda uma quantidade insuficiente de estudos randomizados com uso de Dapt nesse contexto, resultando em uma discordância entre as diretrizes europeia e americana de cardiologia quanto à sua indicação e gerando dúvidas na prática clínica.

CULPRIT-SHOCK study

SUMMARY The treatment of patients with ST-segment elevation myocardial infarction concomitant with the presence of multivessel disease has been studied in several recent studies with the purpose of defining the need, as well as the best moment to approach residual lesions. However, such studies included only stable patients. The best therapeutic approach to cardiogenic shock secondary to acute coronary syndrome, however, remains controversial, but there are recommendations from specialists for revascularization that include non-event related injuries. Recently published, the CULPRIT-SHOCK study showed benefit of the initial approach only of the injury blamed for the acute event, in view of the multivessel percutaneous intervention, in the context of cardiogenic shock. In this perspective, the authors discuss the work in question, regarding methodological questions, limitations and clinical applicability.

RESUMO O tratamento de pacientes com infarto do miocárdio com elevação do segmento ST concomitante à presença de doença multiarterial tem sido estudado em vários estudos recentes com o objetivo de definir a necessidade, bem como o melhor momento, de abordagem das lesões residuais. No entanto, tais estudos incluíam apenas pacientes estáveis. A melhor abordagem terapêutica do choque cardiogênico secundário à síndrome coronariana aguda, no entanto, ainda permanece controversa, havendo porém recomendação de especialistas para uma revascularização que inclua as lesões não relacionadas ao evento. Publicado recentemente, o estudo CULPRIT-SHOCK mostrou benefício da abordagem inicial apenas da lesão culpada pelo evento agudo, perante a intervenção percutânea multiarterial, no contexto do choque cardiogênico. No presente ponto de vista, os autores discutem o trabalho em questão, no que concerne a questões metodológicas, limitações e aplicabilidade clínica.