Cardiac Corpuscles: A "New" Morphofunctional Entity? / Corpúsculos Cardíacos: ¿Una "Nueva" Entidad Morfofuncional?

SUMMARY: The existence of "transitional muscular structures" between subendocardial branches (Purkinje fibers) and ventricular working muscle fibers (WF) was first described by the German anatomist, Kurt Goerttler, in 1964. He designated them as "subendocardial nucleus organs." He supposed such fibers functioned as mechanoreceptors, controlling of the intensity of contraction of the ventricular musculature. Brazilian anatomist Ferraz de Carvalho described similar structures in 1993. A thorough literature search failed to identify any other research articles confirming or denying their existence. The objective of this work was to find such structures in subendocardial ventricular walls in human hearts. We collected fifteen formalin-preserved hearts from the Anatomy Department of São Paulo University and sectioned the apical portions on the right and left ventricles according to method used by Goerttler. We utilized conventional histology (light microscopy- LM), scanning electron microscopy (SEM), and a new preservation method called micro- plastination (MP). At the anterior wall of the right ventricle in the subendocardial region between the interventricular septum and moderator band, we found several bundles of fusiform and helicoidal fibers of similar histology to the WF. The bundles measured between 400 and 1150 µm in length and were separated from adjacent muscular fibers by thin collagen fiber, thus acting as a "pseudo capsule." Some structures seemed to be linked to PF and were appeared to be lymphatic and blood vessels and nerves. We called those structures "cardiac corpuscles" (CC). The observation of the previously "unknown" CC in this initial study confirmed the previous descriptions and its discovery may contribute to new perspectives in the study of cardiac muscle structure and function.

La existencia de "estructuras musculares de transición" entre los ramos subendocárdicos (fibras de Purkinje) y las fibras musculares ventriculares activas(FMV) fue descrita por primera vez por el anatomista alemán Kurt Goerttler en 1964, quien las denominó "órganos del núcleo subendocárdico". Supuso que tales fibras funcionaban como mecanoreceptores, controlando la intensidad de la contracción de la musculatura ventricular. El anatomista brasileño Ferraz de Carvalho describió estructuras similares en 1993. Una búsqueda bibliográfica exhaustiva no logró identificar ningún otro artículo de investigación que confirmara o negara su existencia. El objetivo de este trabajo fue encontrar dichas estructuras en las paredes ventriculares subendocárdicas de corazones humanos. Recolectamos 15 corazones conservados en formalina del Departamento de Anatomía de la Universidad de São Paulo y seccionamos las porciones apicales de los ventrículos derecho e izquierdo según el método utilizado por Goerttler. Utilizamos histología convencional (microscopía de luz-LM), microscopía electrónica de barrido (SEM) y un nuevo método de conservación llamado microplastinación (MP). En la pared anterior del ventrículo derecho en la región subendocárdica entre el tabique interventricular y la banda moderadora, encontramos varios haces de fibras fusiformes y helicoidales de histología similar a la FMV. Los haces medían entre 400 y 1150 µm de longitud y estaban separados de las fibras musculares adyacentes por una fina fibra de colágeno, actuando así como una "pseudocápsula". Algunas estructuras parecían estar vinculadas a la fibras de purkinje y parecían ser vasos linfáticos, sanguíneos y nerviosos. Llamamos a esas estructuras "corpúsculos cardíacos" (CC). La observación del CC previamente "desconocido" en este estudio inicial confirmó las descripciones anteriores y su descubrimiento puede contribuir a nuevas perspectivas en el estudio de la estructura y función del músculo cardíaco.

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.

Association Between Stress Testing-Induced Myocardial Ischemia and Clinical Events in Patients With Multivessel Coronary Artery Disease.

IMPORTANCE: The long-term prognostic implications of myocardial ischemia documented during stress testing in patients with multivessel coronary artery disease (CAD) are unclear. OBJECTIVE: To assess whether documented stress testing-induced myocardial ischemia is associated with major adverse cardiovascular events or ventricular function changes in patients with stable multivessel CAD. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted using data from a single-center randomized clinical trial (Medicine, Angioplasty, or Surgery Study [MASS] II) to examine the association of myocardial ischemia documented during stress testing at baseline with cardiovascular events and ventricular function changes during follow-up. Participants were previously randomized (May 1, 1995, to May 31, 2000) to medical therapy, percutaneous coronary intervention with bare metal stents, or coronary artery bypass grafting. Event-free survival was estimated by the Kaplan-Meier method, and multivariable Cox regression models were calculated to assess the association between ischemia and the primary composite end point. The vital status was determined on February 28, 2011. Data were analyzed from February 1, 2016, to April 1, 2017. MAIN OUTCOMES AND MEASURES: Cardiovascular events (overall mortality, myocardial infarction, and revascularization for refractory angina) were tracked from the time of randomization to the end of the 10-year follow-up (mean [SD] duration, 11.4 [4.3] years). Myocardial ischemia was assessed at baseline and at 1-year intervals by exercise stress testing, and ventricular function (left ventricular ejection fraction) was assessed by echocardiography at baseline and after 10 years. Patients with documented ischemia were compared with those without ischemia regarding the outcomes and changes in ventricular function. RESULTS: Of 611 participants, 535 underwent exercise stress testing at baseline: 270 with documented ischemia and 265 without. Of these 535 patients, 373 (69.7%) were men, and the mean (SD) age for the entire cohort was 59.7 (9.2) years. No association was found between the presence of ischemia at baseline and survival free of combined cardiovascular events (hazard ratio, 1.00; 95% CI, 0.80-1.27; P = .95) after multivariable adjustment that included CAD initial randomized treatments. In addition, among 320 patients who underwent echocardiographic evaluation, the slight decline in left ventricular ejection fraction after 10 years was similar in both groups (median [SD] difference, -4.9% [18.7%] vs -6.6% [20.0%], respectively, for groups with and without ischemia; P = .97). CONCLUSIONS AND RELEVANCE: In this study, regardless of the therapeutic strategy applied, the presence of documented myocardial ischemia did not appear to be associated with an increased occurrence of major adverse cardiovascular events or changes in ventricular function in patients with multivessel CAD during a long-term follow-up.

Biomarker release after percutaneous coronary intervention in patients without established myocardial infarction as assessed by cardiac magnetic resonance with late gadolinium enhancement.

OBJECTIVES: This study aimed to evaluate the amount and pattern of cardiac biomarker release after elective percutaneous coronary intervention (PCI) in patients without evidence of a new myocardial infarction (MI) after the procedure as assessed by cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE). BACKGROUND: The release of myocardial necrosis biomarkers after PCI frequently occurs. However, the correlation between biomarker release and the diagnosis of procedure-related MI type 4a has been controversial. METHODS: Patients with normal baseline cardiac biomarkers who were referred for elective PCI were prospectively included. CMR with LGE was performed in all of the patients before and after the intervention. Measurements of troponin I (TnI) and creatine kinase MB fraction (CK-MB) were systematically performed before and after the procedure. Patients with a new LGE on the post-procedure CMR were excluded. RESULTS: Of the 56 patients with no evidence of a procedure-related MI as assessed by CMR after the PCI, 48 (85.1%) exhibited an elevation of TnI above the 99th percentile. In 32 patients (57.1%), the peak was greater than five times this limit. Additionally, 17 patients (30.4%) had a CK-MB peak above the 99th percentile limit, but this peak was greater than five times the 99th percentile in only two patients (3.6%). The median peak release of TnI was 0.290 (0.061-1.09) ng/mL, which was 7.25-fold higher than the 99th percentile. CONCLUSIONS: In contrast to CK-MB, an abnormal release of TnI often occurs after an elective PCI procedure, despite the absence of a new LGE on CMR.

Accuracy of Myocardial Biomarkers in the Diagnosis of Myocardial Infarction After Revascularization as Assessed by Cardiac Resonance: The Medicine, Angioplasty, Surgery Study V (MASS-V) Trial.

BACKGROUND: The lack of a correlation between myocardial necrosis biomarkers and electrocardiographic abnormalities after revascularization procedures has resulted in a change in the myocardial infarction (MI) definition. METHODS: Patients with stable multivessel disease who underwent percutaneous or surgical revascularization were included. Electrocardiograms and concentrations of high-sensitive cardiac troponin I (cTnI) and creatine kinase (CK)-MB were assessed before and after procedures. Cardiac magnetic resonance and late gadolinium enhancement were performed before and after procedures. MI was defined as more than five times the 99th percentile upper reference limit for cTnI and 10 times for CK-MB in percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), respectively, and new late gadolinium enhancement for cardiac magnetic resonance. RESULTS: Of the 202 patients studied, 69 (34.1%) underwent on-pump CABG, 67 (33.2%) off-pump CABG, and 66 (32.7%) PCI. The receiver operating characteristic curve showed the accuracy of cTnI for on-pump CABG, off-pump CABG, and PCI patients was 21.7%, 28.3%, and 52.4% and for CK-MB was 72.5%, 81.2%, and 90.5%, respectively. The specificity of cTnI was 3.6%, 9.4%, and 42.1% and of CK-MB was 73.2%, 86.8%, and 96.4%, respectively. Sensitivity of cTnI was 100%, 100%, and 100% and of CK-MB was 69.2%, 64.3%, and 44.4%, respectively. The best cutoff of cTnI for on-pump CABG, off-pump CABG, and PCI was 6.5 ng/mL, 4.5 ng/mL, and 4.5 ng/mL (162.5, 112.5, and 112.5 times the 99th percentile upper reference limit) and of CK-MB was 37.5 ng/mL, 22.5 ng/mL, and 11.5 ng/mL (8.5, 5.1, and 2.6 times the 99th percentile upper reference limit), respectively. CONCLUSIONS: Compared with cardiac magnetic resonance, CK-MB was more accurate than cTnI for diagnosing MI. These data suggest a higher troponin cutoff for the diagnosis of procedure-related MI.

Impact of Chronic Kidney Disease on Long-Term Outcomes in Type 2 Diabetic Patients With Coronary Artery Disease on Surgical, Angioplasty, or Medical Treatment.

BACKGROUND: Coronary artery disease (CAD) among patients with diabetes and chronic kidney disease (CKD) is not well studied, and the best treatment for this condition is not established. Our aim was to compare three therapeutic strategies for CAD in diabetic patients stratified by renal function. METHODS: Patients with multivessel CAD that underwent coronary artery bypass graft (CABG), angioplasty (percutaneous coronary intervention [PCI]), or medical therapy alone (MT) were included. Data were analyzed according to glomerular filtration rate in three strata: normal (>90 mL/min), mild CKD (60 to 89 mL/min), and moderate CKD (30 to 59 mL/min). End points comprised overall rate of mortality, acute myocardial infarction, and need for additional revascularization. RESULTS: Among patients with normal renal function (n = 270), 122 underwent CABG, 72 PCI, and 76 MT; among patients with mild CKD (n = 367), 167 underwent CABG, 92 PCI, and 108 MT; and among patients with moderate CKD (n = 126), 46 underwent CABG, 40 PCI, and 40 MT. Event-free survival was 80.4%, 75.7%, 67.5% for strata 1, 2, and 3, respectively (p = 0.037). Survival rates among patients with no, mild, and moderate CKD are 91.1%, 89.6%, and 76.2%, respectively (p = 0.001) (hazard ratio 0.69; 95% confidence interval 0.51 to 0.95; p = 0.024 for stratum 1 versus 3). We found no differences for overall number of deaths or acute myocardial infarctions irrespective of strata. The need of new revascularization was different in all strata, favoring CABG (p < 0.001, p < 0.001, and p = 0.029 for no, mild, and moderate CKD, respectively). CONCLUSIONS: Mortality rates were higher in patients with mild and moderate CKD. Higher event-free survival was observed in the CABG group among patients with no and mild CKD. Besides, CABG was associated with less need for new revascularization compared with PCI and MT in all renal function strata. This trial was registered at http://www.controlled-trials.com as ISRCTN66068876.

The role of myocardial scintigraphy in the assessment of cardiovascular risk in patients with end-stage chronic kidney disease on the waiting list for renal transplantation.

BACKGROUND: The usefulness of stress myocardial perfusion scintigraphy for cardiovascular (CV) risk stratification in chronic kidney disease remains controversial. We tested the hypothesis that different clinical risk profiles influence the test. METHODS: We assessed the prognostic value of myocardial scintigraphy in 892 consecutive renal transplant candidates classified into four risk groups: very high (aged≥50 years, diabetes and CV disease), high (two factors), intermediate (one factor) and low (no factor). RESULTS: The incidence of CV events and death was 20 and 18%, respectively (median follow-up=22 months). Altered stress testing was associated with an increased probability of cardiovascular events only in intermediate-risk (one risk factor) patients [30.3 versus 10%, hazard ratio (HR)=2.37, confidence interval (CI) 1.69-3.33, P<0.0001]. Low-risk patients did well regardless of scan results. In patients with two or three risk factors, an altered stress test did not add to the already increased CV risk. Myocardial scintigraphy was related to overall mortality only in intermediate-risk patients (HR=2.8, CI 1.5-5.1, P=0.007). CONCLUSIONS: CV risk stratification based on myocardial stress testing is useful only in patients with just one risk factor. Screening may avoid unnecessary testing in 60% of patients, help stratifying for risk of events and provide an explanation for the inconsistent performance of myocardial scintigraphy.

Validation of a strategy to diagnose coronary artery disease and predict cardiac events in high-risk renal transplant candidates.

BACKGROUND: We validated a strategy for diagnosis of coronary artery disease (CAD) and prediction of cardiac events in high-risk renal transplant candidates (at least one of the following: age > or =50 years, diabetes, cardiovascular disease). METHODS: A diagnosis and risk assessment strategy was used in 228 renal transplant candidates to validate an algorithm. Patients underwent dipyridamole myocardial stress testing and coronary angiography and were followed up until death, renal transplantation, or cardiac events. RESULTS: The prevalence of CAD was 47%. Stress testing did not detect significant CAD in 1/3 of patients. The sensitivity, specificity, and positive and negative predictive values of the stress test for detecting CAD were 70, 74, 69, and 71%, respectively. CAD, defined by angiography, was associated with increased probability of cardiac events [log-rank: 0.001; hazard ratio: 1.90, 95% confidence interval (CI): 1.29-2.92]. Diabetes (P=0.03; hazard ratio: 1.58, 95% CI: 1.06-2.45) and angiographically defined CAD (P=0.03; hazard ratio: 1.69, 95% CI: 1.08-2.78) were the independent predictors of events. CONCLUSION: The results validate our observations in a smaller number of high-risk transplant candidates and indicate that stress testing is not appropriate for the diagnosis of CAD or prediction of cardiac events in this group of patients. Coronary angiography was correlated with events but, because less than 50% of patients had significant disease, it seems premature to recommend the test to all high-risk renal transplant candidates. The results suggest that angiography is necessary in many high-risk renal transplant candidates and that better noninvasive methods are still lacking to identify with precision patients who will benefit from invasive procedures.

Detection of functional recovery using low-dose dobutamine and myocardial contrast echocardiography after acute myocardial infarction treated with successful thrombolytic therapy.

OBJECTIVE: We studied the value of low-dose dobutamine stress echocardiography (LDDE) and myocardial contrast echocardiography (MCE) in early prediction of left ventricular functional recovery (LVFR) after acute myocardial infarction (AMI) treated with successful thrombolysis. DESIGN: LDDE and MCE using second-harmonic intermittent imaging were performed in first week after AMI. LVFR was defined as an absolute > or =5% increase in ejection fraction, from early to 6 months of follow-up by Technetium-99m-Sestamibi single-photon emission computed tomography. PATIENTS: Out of 50 patients studied, 19 evolved with LVFR (group 1) and 31 without LVFR (group 2). Regional dysfunction was detected in 103 (37%) infarcted-related segments in group 1 and in 173 (63%) segments in group 2. RESULTS: Sensitivity, specificity, positive, and negative predictive values and accuracy for detecting LVFR by LDDE were 94.7% (18/19), 87.1% (27/31), 81.8% (18/22), 96.4% (27/28), and 90% (45/50), respectively, and by MCE were 94.7% (18/19), 51.6% (16/31), 54.5% (18/33), 94.1% (16/17), and 68% (34/50). In group 1, functional improvement was observed in 86.9% (53/61) of segments with contractile reserve by LDDE and in 65.8% (52/79) of segments with microvascular perfusion by MCE. In group 2, functional improvement was observed in 78.3% (18/23) of segments with contractile reserve by LDDE and in 25.5% (25/98) of segments with microvascular perfusion by MCE. All segments without perfusion by MCE evolved without functional recovery. CONCLUSION: LDDE was an accurate predictor of late left ventricular function recovery after AMI, while MCE was sensitive and has a high negative predictive value demonstrating that microvascular perfusion is essential for LVFR.

Repercussions of raloxifen, tamoxifen and estrogen on aortic atherosclerotic lesions of female rabbits submitted to ovariectomy and hypercholesterol diet.

BACKGROUND: The role of hormone-replacement therapy in decreasing the risk of cardiovascular disease in women has not been firmly established. Recent studies have shown that the selective estrogen receptor modulators raloxifene, and tamoxifene, posses hypolipidemic and antiatherogenic properties. METHODS AND RESULTS: Forty-three adult female rabbits were submitted to ovariectomy (moment 1). Three weeks after surgical recovery, they were grouped in five groups as follows (moment 2): control group (9)--normal diet; cholesterol group (8)--0.5% cholesterol added to diet; raloxifen group (8); tamoxifen group (9); estrogen group (9)--diet added by 0.5% cholesterol and 60 mg raloxifen, 20 mg tamoxifen or 0.625 mg equine conjugated estrogen. The animals from all groups were sacrificed after 13 weeks (moment 3) and the thoracic and abdominal aortas were studied. We collected digital images of the observed atherosclerotic lesions in the vessel lumen by means of a computerized method. We analyzed serum levels of total cholesterol and fractions (HDL, VLDL, and LDL), as well as triglycerides. Among the animals that received hyper cholesterol diet and medication, we noticed a reduction of the total area of atherosclerotic plaques in the tamoxifen (P < 0.05) or estrogen group (P < 0.05) compared to the cholesterol group. Serum levels of total, LDL- and HDL-cholesterol were higher for the raloxifen, tamoxifen, estrogen, and cholesterol (P = 0.0001). CONCLUSION: Female rabbits treated with a high cholesterol diet associated to tamoxifen or estrogen had a statistically significant reduction in aortic atherosclerotic plaques. Even though there was a significant increase in cholesterol levels, we did not find any correlation between cholesterol levels and degree of aortic atherosclerotic lesion.

Stroke and ischemic heart disease mortality trends in Brazil from 1979 to 1996.

Stroke and ischemic heart disease (IHD) mortality rates were analyzed in Brazilian subjects older than 30 years of age from 1979 to 1996. Population estimates were based on census surveys. Mortality data were obtained from the Ministry of Health. For stroke, the age-adjusted death rate (ADR) dropped from 200 to 164 and from 168 to 130 deaths/100,000 population in men and women, respectively (p < 0.001), in the interval study. For IHD, the ADR dropped from 194 to 164 and from 119 to 105 deaths/100,000 population in men and women, respectively (p < 0.001), in the same time period. Mortality from stroke and IHD combined was greater in men for all age groups (p < 0.001). Stroke was the most frequent cause of death in both women and men except for men aged between 40 and 69 years, in whom IHD was more common. Stroke and IHD were the main causes of death in the Brazilian population.

Delisting of infants and children from the heart transplantation waiting list after carvedilol treatment.

OBJECTIVES: We performed a prospective, randomized, double-blind, placebo-controlled study of carvedilol effects in children with severe, chronic heart failure (HF), despite the use of conventional therapy. BACKGROUND: Little is known about the effects of carvedilol in youngsters with chronic HF and severe left ventricular (LV) dysfunction. METHODS: We conducted a double-blind, placebo-controlled study of 22 consecutive children with severe LV dysfunction. The children had chronic HF and left ventricular ejection fraction (LVEF) <30%. Patients were randomly assigned to receive either placebo (8 patients) or the beta-blocker carvedilol (14 patients) at 0.01 mg/kg/day titrated up to 0.2 mg/kg/day, followed-up for six months. RESULTS: During the follow-up and the up-titration period in the carvedilol group, four patients died and one underwent heart transplantation. In patients receiving carvedilol evaluated after six months, a significant increase occurred in LVEF, from 17.8% (95% confidence interval [CI], 14.1 to 21.4%) to 34.6% (95% CI, 25.2 to 44.0%); p = 0.001. Modified New York Heart Association (NYHA) functional class improved in nine patients taken off the transplant waiting list. All nine patients were alive at follow-up. In the placebo group, during the six-month follow-up, two patients died, and two underwent heart transplantation. Four patients persisted with HF symptoms (NYHA functional class IV). No significant change occurred in LVEF or fractional shortening. CONCLUSIONS: Carvedilol added to standard therapy may reduce HF progression and improve cardiac function, allowing some youngsters to be removed from the heart transplantation waiting list.