Photobiomodulation therapy's effects on cardiac fibrosis activation after experimental myocardial infarction.

INTRODUCTION: Ischemic heart disease is the leading cause of death worldwide, and interventions to reduce myocardial infarction (MI) complications are widely researched. Photobiomodulation therapy (PBMT) has altered multiple biological processes in tissues and organs, including the heart. OBJECTIVES: This study aimed to assess the temporal effects of PBMT on cardiac fibrosis activation after MI in rats. In this proof-of-concept study, we monitored the change in expression patterns over time of genes and microRNAs (miRNAs) involved in the formation of cardiac fibrosis post-MI submitted to PBMT. MATERIALS AND METHODS: Experimental MI was induced, and PBMT was applied shortly after coronary artery ligation (laser light of wavelength 660 nm, 15 mW of power, energy density 22.5 J/cm2 , 60 seconds of application, irradiated area 0.785 cm2 , fluence 1.1 J/cm2 ). Ventricular septal samples were collected at 30 minutes, 3, 6, 24 hours, and 3 days post-MI to determine temporal PBMT's effects on messenger RNA (mRNA) expression associated with cardiac fibrosis activation and miRNAs expression. RESULTS: PBMT, when applied after ischemia, reversed the changes in mRNA expression of myocardial extracellular matrix genes induced by MI. Surprisingly, PBMT modified cardiac miRNAs expression related to fibrosis replacement in the myocardium. Expression correlations between myocardial mRNAs were assessed. The correlation coefficient between miRNAs and target mRNAs was also determined. A positive correlation was detected among miR-21 and transforming growth factor beta-1 mRNA. The miR-29a expression negatively correlated to Col1a1, Col3a1, and MMP-2 mRNA expressions. In addition, we observed that miR-133 and Col1a1 mRNA were negatively correlated. CONCLUSION: The results suggest that PBMT, through the modulation of gene transcription and miRNA expressions, can interfere in cardiac fibrosis activation after MI, mainly reversing the signaling pathway of profibrotic genes.

Cardiovascular and Quality of Life Outcomes of a 3-Month Physical Exercise Program in Two Brazilian Communities.

Background: A reduction in physical activity levels in older people is associated with declining quality of life and lower cardiorespiratory fitness levels associated with cardiovascular disease outcomes and mortality from all causes. Evidence supports the positive effect of community-based exercise (CEXE) programs on cardiovascular health and quality of life. This research aimed to examine the effects of a 3-month CEXE on health-related quality of life and cardiovascular risk factors in two Brazilian populations. Methods: Adults with an average age of 70.2 ± 5.4 years were recruited to engage in an individually designed group based CEXE program two to three times/week (aerobic exercise, circuit resistance training, and stretching exercises for 1 h each time). Once a week, competitions were held to improve socialization and collaboration capacity among group members. The CEXE group was compared with a sedentary group. Cardiovascular outcomes were blood pressure, triglycerides, body mass index, waist circumference, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, total cholesterol, and glycemia. Health-related quality of life was evaluated using the Short Form-36. Results: Of the cardiovascular outcomes studied, the CEXE program significantly reduced systolic blood pressure [5.7 (95% CI 0.2 to 11.3), p < 0.05] and the triglyceride-HDL-C ratio [0.8 (95% CI 0.05 to 1.5), p < 0.05], whereas HDL-C was significantly increased [4.4 (95% CI 0.02 to 8.8), p < 0.05]. A significant improvement in the Short Form-36 subscales occurred in CEXE but not in the control group: physical functioning score [increase of 24.2 (95% CI 11.8 to 36.5) vs. -9.2 (95% CI -21.5 to 3.2), p < 0.001], physical role functioning score [increase of 35.4 (95% CI 12.8 to 58.0) vs. 16.7 (95% CI -6.0 to 39.3), p < 0.01], and general health score [increase of 23.7 (95% CI: 36.9. to 10.4) vs. 2.4 (95% CI -10.9 to 15.7), p < 0.001]. Conclusion: This study shows that in older adults, a 12-week physical activity program can significantly decrease cardiovascular risk and improve health-related quality of life measures. An important transferable sociocultural strategy of our exercise program was to establish social interactions during and outside the CEXE program.

Melatonin, mitochondria and hypertension.

Melatonin, due to its multiple means and mechanisms of action, plays a fundamental role in the regulation of the organismal physiology by fine tunning several functions. The cardiovascular system is an important site of action as melatonin regulates blood pressure both by central and peripheral interventions, in addition to its relation with the renin-angiotensin system. Besides, the systemic management of several processes, melatonin acts on mitochondria regulation to maintain a healthy cardiovascular system. Hypertension affects target organs in different ways and cellular energy metabolism is frequently involved due to mitochondrial alterations that include a rise in reactive oxygen species production and an ATP synthesis decrease. The discussion that follows shows the role played by melatonin in the regulation of mitochondrial physiology in several levels of the cardiovascular system, including brain, heart, kidney, blood vessels and, particularly, regulating the renin-angiotensin system. This discussion shows the putative importance of using melatonin as a therapeutic tool involving its antioxidant potential and its action on mitochondrial physiology in the cardiovascular system.

Association between Carotid Intima Media Thickness and Heart Rate Variability in Adults at Increased Cardiovascular Risk.

Background: Atherosclerotic carotid intima-media thickness (IMT) may be associated with alterations in the sensitivity of carotid baroreceptors. The aim of this study was to investigate the association between carotid IMT and the autonomic modulation of heart rate variability (HRV). Methods: A total of 101 subjects were enrolled in this prospective observational study. The carotid IMT was determined by duplex ultrasonography. The cardiac autonomic function was determined through HRV measures during the Deep Breathing Test. Linear regression models, adjusted for demographics, comorbidities, body mass index, waist-hip-ratio, and left ventricular ejection fraction were used to evaluate the association between HRV parameters and carotid IMT. Results: Participants had a mean age of 60.4 ± 13.4 years and an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk score (using the Pooled Cohort Equations) of 16.4 ± 17. The mean carotid media thickness was highest (0.90 ± 0.19 mm) in the first quartile of the standard deviation of all RR intervals (SDNN) (19.7 ± 5.1 ms) and progressively declined in each subsequent quartile to 0.82 ± 0.21 mm, 0.81 ± 0.16 mm, and 0.68 ± 0.19 in quartiles 2 (36.5 ± 5.9 ms), 3 (57.7 ± 6.2 ms) and 4 (100.9 ± 22.2 ms), respectively. In multivariable adjusted models, there was a statistical significant association between SDNN and carotid IMT (OR -0.002; 95%CI -0.003 to -0.001, p = 0.005). The same significant association was found between carotid IMT and other measures of HRV, including coefficient of variation of RR intervals (CV) and dispersion of points along the line of identity (SD2). Conclusions: In a cohort of individuals at increased cardiovascular risk, carotid IMT as a marker of subclinical atherosclerosis was associated with alterations of HRV indicating an impaired cardiac autonomic control, independently of other cardiovascular risk factors.

Quantifying Effects of Pharmacological Blockers of Cardiac Autonomous Control Using Variability Parameters.

Objective: The aim of this study was to identify the most sensitive heart rate and blood pressure variability (HRV and BPV) parameters from a given set of well-known methods for the quantification of cardiovascular autonomic function after several autonomic blockades. Methods: Cardiovascular sympathetic and parasympathetic functions were studied in freely moving rats following peripheral muscarinic (methylatropine), ß1-adrenergic (metoprolol), muscarinic + ß1-adrenergic, α1-adrenergic (prazosin), and ganglionic (hexamethonium) blockades. Time domain, frequency domain and symbolic dynamics measures for each of HRV and BPV were classified through paired Wilcoxon test for all autonomic drugs separately. In order to select those variables that have a high relevance to, and stable influence on our target measurements (HRV, BPV) we used Fisher's Method to combine the p-value of multiple tests. Results: This analysis led to the following best set of cardiovascular variability parameters: The mean normal beat-to-beat-interval/value (HRV/BPV: meanNN), the coefficient of variation (cvNN = standard deviation over meanNN) and the root mean square differences of successive (RMSSD) of the time domain analysis. In frequency domain analysis the very-low-frequency (VLF) component was selected. From symbolic dynamics Shannon entropy of the word distribution (FWSHANNON) as well as POLVAR3, the non-linear parameter to detect intermittently decreased variability, showed the best ability to discriminate between the different autonomic blockades. Conclusion: Throughout a complex comparative analysis of HRV and BPV measures altered by a set of autonomic drugs, we identified the most sensitive set of informative cardiovascular variability indexes able to pick up the modifications imposed by the autonomic challenges. These indexes may help to increase our understanding of cardiovascular sympathetic and parasympathetic functions in translational studies of experimental diseases.

ICU Blood Pressure Variability May Predict Nadir of Respiratory Depression After Coronary Artery Bypass Surgery.

OBJECTIVES: Surgical stress induces alterations on sympathovagal balance that can be determined through assessment of blood pressure variability. Coronary artery bypass graft surgery (CABG) is associated with postoperative respiratory depression. In this study we aimed at investigating ICU blood pressure variability and other perioperative parameters that could predict the nadir of postoperative respiratory function impairment. METHODS: This prospective observational study evaluated 44 coronary artery disease patients subjected to coronary artery bypass surgery (CABG) with cardiopulmonary bypass (CPB). At the ICU, mean arterial pressure (MAP) was monitored every 30 min for 3 days. MAP variability was evaluated through: standard deviation (SD), coefficient of variation (CV), variation independent of mean (VIM), and average successive variability (ASV). Respiratory function was assessed through maximal inspiratory (MIP) and expiratory (MEP) pressures and peak expiratory flow (PEF) determined 1 day before surgery and on the postoperative days 3rd to 7th. Intraoperative parameters (volume of cardioplegia, CPB duration, aortic cross-clamp time, number of grafts) were also monitored. RESULTS: Since, we aimed at studying patients without confounding effects of postoperative complications on respiratory function, we had enrolled a cohort of low risk EuroSCORE (European System for Cardiac Operative Risk Evaluation) with < 2. Respiratory parameters MIP, MEP, and PEF were significantly depressed for 4-5 days postoperatively. Of all MAP variability parameters, the ASV had a significant good positive Spearman correlation (rho coefficients ranging from 0.45 to 0.65, p < 0.01) with the 3-day nadir of PEF after cardiac surgery. Also, CV and VIM of MAP were significantly associated with nadir days of MEP and PEF. None of the intraoperative parameters had any correlation with the postoperative respiratory depression. CONCLUSIONS: Variability parameters ASV, CV, and VIM of the MAP monitored at ICU may have predictive value for the depression of respiratory function after cardiac surgery as determined by peak expiratory flow and maximal expiratory pressure. ClinicalTrials.gov Identifier: NCT02074371.

The Angiotensin-melatonin axis.

Accumulating evidence indicates that various biological and neuroendocrine circadian rhythms may be disrupted in cardiovascular and metabolic disorders. These circadian alterations may contribute to the progression of disease. Our studies direct to an important role of angiotensin II and melatonin in the modulation of circadian rhythms. The brain renin-angiotensin system (RAS) may modulate melatonin synthesis, a hormone with well-established roles in regulating circadian rhythms. Angiotensin production in the central nervous system may not only influence hypertension but also appears to affect the circadian rhythm of blood pressure. Drugs acting on RAS have been proven effective in the treatment of cardiovascular and metabolic disorders including hypertension and diabetes mellitus (DM). On the other hand, since melatonin is capable of ameliorating metabolic abnormalities in DM and insulin resistance, the beneficial effects of RAS blockade could be improved through combined RAS blocker and melatonin therapy. Contemporary research is evidencing the existence of specific clock genes forming central and peripheral clocks governing circadian rhythms. Further research on the interaction between these two neurohormones and the clock genes governing circadian clocks may progress our understanding on the pathophysiology of disease with possible impact on chronotherapeutic strategies.

Cardiovascular responses evoked by activation or blockade of GABA(A) receptors in the hypothalamic PVN are attenuated in transgenic rats with low brain angiotensinogen.

Previous evidence indicates that a balance between inhibitory gabaergic and excitatory angiotensinergic factors in the PVN is important for cardiovascular control. We investigated the cardiovascular response evoked from activation or blockade of GABA(A) receptors in the paraventricular nucleus (PVN), in transgenic rats with low brain angiotensinogen [TGR(ASrAOGEN)]. Brain Ang II and Ang-(1-7) levels were also determined. In functional experiments, TGR(ASrAOGEN) and Sprague-Dawley rats (SD, control) were anesthetized with urethane and blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were recorded. Brain Ang II and Ang-(1-7) levels were largely reduced in TGR(ASrAOGEN) compared with SD rats. Inhibition of PVN neurons with the GABA(A) agonist, muscimol (1 nmol/100 nL), resulted in an attenuated fall in all cardiovascular variables in TGR(ASrAOGEN) compared with SD rats. This difference was particularly pronounced in HR (TGR Mus -23±6 bpm vs. -77±9 bpm SD Mus; P<0.05) and RSNA (TGR -3±10% vs.-29±8% SD; P<0.05). Furthermore, the sympathetic response evoked by blockade of GABA(A) receptors in the PVN of TGR(ASrAOGEN) was also largely suppressed. The present data indicate that the sympathetic outflow mediated by PVN neurons under basal conditions is suppressed in TGR(ASrAOGEN) rats corroborating the functional significance of brain angiotensin production in the central regulation of sympathetic output to the cardiovascular system.

Differential diagnosis between experimental endophthalmitis and uveitis in vitreous with Raman spectroscopy and principal components analysis.

Raman spectroscopy has been used for the diagnosis of various eye diseases. A diagnostic tool based on Raman spectroscopy has been developed to discriminate endophthalmitis from uveitis in vitreous tissues of rabbits' eyes in vitro. Twenty-two New Zealand rabbits suffering from endophthalmitis induced by Staphylococcus aureus (n=10), non-infectious uveitis induced by lipopolysaccharide from Escherichia coli (LPS) (n=10 animals) and control (n=2) were included in the study. After eye inoculation, vitreous tissues were dissected and a fragment was submitted to dispersive Raman spectroscopy using near-infrared laser excitation (830 nm, 100 mW) and spectrograph/CCD camera for detection of Raman signal with integration time of 50 s. A routine was developed to classify the spectra of endophthalmitis and uveitis using principal components analysis (PCA) and Mahalanobis distance. The mean Raman spectra of tissues with uveitis and endophthalmitis showed several bands in the region of 800-1800 cm(-1), which have been attributed to nucleic acids, amino acids and proteins from inflamed tissue and proliferating bacteria. The bands at 1004, 1258, 1339, 1451 and 1635 cm(-1) showed statistically significant differences between both diseases. It was observed that principal components PC1, PC3 and PC4 showed statistically significant differences for the two tissue types, indicating that these PCs can be used to discriminate between the two groups. The diagnostic model showed 94% sensitivity, 95% specificity and 95% accuracy using PC3×PC4. The Raman spectroscopy technique has been shown to be useful in differentiating uveitis and endophthalmitis in vitreous tissues in vitro, and these results may be clinically relevant for differentiating vitreous tissues to optimise the diagnosis of inflammatory and infectious vitreoretinal diseases.

Local renin-angiotensin system and the brain--a continuous quest for knowledge.

The ancient renin-angiotensin system (RAS) was discovered more than a hundred years ago by identifying the rate-limiting enzyme of the system and its relevance to blood pressure regulation. Forty years ago, Detlev Ganten et al. postulated the existence of a tissue RAS. In these forty years, he kept developing the knowledge of these systems either directly or by training or attracting the interest of many researchers. Through the present review, we try to highlight recent advancements that originated from the postulation of local brain RAS. Although a large amount of knowledge accumulated, this system continues to intrigue and stimulate the interest and imagination of many researchers.