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.

Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure.

BACKGROUND: SGLT2 inhibitors reduce the risk of heart failure (HF) mortality and morbidity, regardless of the presence or absence of diabetes, but the mechanisms underlying this benefit remain unclear. Experiments with nondiabetic HF rats tested the hypothesis that the SGLT2 inhibitor empagliflozin (EMPA) inhibits proximal tubule (PT) NHE3 activity and improves renal salt and water handling. METHODS: Male Wistar rats were subjected to myocardial infarction or sham operation. After 4 weeks, rats that developed HF and sham rats were treated with EMPA or untreated for an additional 4 weeks. Immunoblotting and quantitative RT-PCR evaluated SGLT2 and NHE3 expression. Stationary in vivo microperfusion measured PT NHE3 activity. RESULTS: EMPA-treated HF rats displayed lower serum B-type natriuretic peptide levels and lower right ventricle and lung weight to tibia length than untreated HF rats. Upon saline challenge, the diuretic and natriuretic responses of EMPA-treated HF rats were similar to those of sham rats and were higher than those of untreated HF rats. Additionally, EMPA treatment prevented GFR decline and renal atrophy in HF rats. PT NHE3 activity was higher in HF rats than in sham rats, whereas treatment with EMPA markedly reduced NHE3 activity. Unexpectedly, SGLT2 protein and mRNA abundance were upregulated in the PT of HF rats. CONCLUSIONS: Prevention of HF progression by EMPA is associated with reduced PT NHE3 activity, restoration of euvolemia, and preservation of renal mass. Moreover, dysregulation of PT SGLT2 may be involved in the pathophysiology of nondiabetic HF.

Postprandial increase in glucagon-like peptide-1 is blunted in severe heart failure.

The relationship between disturbances in glucose homeostasis and heart failure (HF) progression is bidirectional. However, the mechanisms by which HF intrinsically impairs glucose homeostasis remain unknown. The present study tested the hypothesis that the bioavailability of intact glucagon-like peptide-1 (GLP-1) is affected in HF, possibly contributing to disturbed glucose homeostasis. Serum concentrations of total and intact GLP-1 and insulin were measured after an overnight fast and 15 min after the ingestion of a mixed breakfast meal in 49 non-diabetic patients with severe HF and 40 healthy control subjects. Similarly, fasting and postprandial serum concentrations of these hormones were determined in sham-operated rats, and rats with HF treated with an inhibitor of the GLP-1-degrading enzyme dipeptidyl peptidase-4 (DPP4), vildagliptin, or vehicle for 4 weeks. We found that HF patients displayed a much lower increase in postprandial intact and total GLP-1 levels than controls. The increase in postprandial intact GLP-1 in HF patients correlated negatively with serum brain natriuretic peptide levels and DPP4 activity and positively with the glomerular filtration rate. Likewise, the postprandial increases in both intact and total GLP-1 were blunted in HF rats and were restored by DPP4 inhibition. Additionally, vehicle-treated HF rats displayed glucose intolerance and hyperinsulinemia, whereas normal glucose homeostasis was observed in vildagliptin-treated HF rats. We conclude that the postprandial increase in GLP-1 is blunted in non-diabetic HF. Impaired GLP-1 bioavailability after meal intake correlates with poor prognostic factors and may contribute to the establishment of a vicious cycle between glucose disturbance and HF development and progression.

Increased NHE3 abundance and transport activity in renal proximal tubule of rats with heart failure.

Heart failure (HF) is associated with a reduced effective circulating volume that drives sodium and water retention and extracellular volume expansion. We therefore hypothesized that Na(+)/H(+) exchanger isoform 3 (NHE3), the major apical transcellular pathway for sodium reabsorption in the proximal tubule, is upregulated in an experimental model of HF. HF was induced in male rats by left ventricle radiofrequency ablation. Sham-operated rats (sham) were used as controls. At 6 wk after surgery, HF rats exhibited cardiac dysfunction with a dramatic increase in left ventricular end-diastolic pressure. By means of stationary in vivo microperfusion and pH-dependent sodium uptake, we demonstrated that NHE3 transport activity was significantly higher in the proximal tubule of HF compared with sham rats. Increased NHE3 activity was paralleled by increased renal cortical NHE3 expression at both protein and mRNA levels. In addition, the baseline PKA-dependent NHE3 phosphorylation at serine 552 was reduced in renal cortical membranes of rats with HF. Collectively, these results suggest that NHE3 is upregulated in the proximal tubule of HF rats by transcriptional, translational, and posttranslational mechanisms. Enhanced NHE3-mediated sodium reabsorption in the proximal tubule may contribute to extracellular volume expansion and edema, the hallmark feature of HF. Moreover, our study emphasizes the importance of undertaking a cardiorenal approach to contain progression of cardiac disease.

Unraveling the interplay between dipeptidyl peptidase 4 and the renin-angiotensin system in heart failure.

AIMS: Emerging evidence suggests the existence of a crosstalk between dipeptidyl peptidase 4 (DPP4) and the renin-angiotensin system (RAS). Therefore, combined inhibition of DPP4 and RAS may produce similar pharmacological effects rather than being additive. This study tested the hypothesis that combining an inhibitor of DPP4 with an angiotensin II (Ang II) receptor blocker does not provide additional cardioprotection compared to monotherapy in heart failure (HF) rats. MAIN METHODS: Male Wistar rats were subjected to left ventricle (LV) radiofrequency ablation or sham operation. Six weeks after surgery, radiofrequency-ablated rats who developed HF were assigned into four groups and received vehicle (water), vildagliptin, valsartan, or both drugs, for four weeks by oral gavage. KEY FINDINGS: Vildagliptin and valsartan in monotherapy reduced LV hypertrophy, alleviated cardiac interstitial fibrosis, and improved systolic and diastolic function in HF rats, with no additional effect of combination treatment. HF rats displayed higher cardiac and serum DPP4 activity and abundance than sham. Surprisingly, not only vildagliptin but also valsartan in monotherapy downregulated the catalytic function and expression levels of systemic and cardiac DPP4. Moreover, vildagliptin and valsartan alone or in combination comparably upregulate the components of the cardiac ACE2/Ang-(1-7)/MasR while downregulating the ACE/Ang II/AT1R axis. SIGNIFICANCE: Vildagliptin or valsartan alone is as effective as combined to treat cardiac dysfunction and remodeling in experimental HF. DPP4 inhibition downregulates classic RAS components, and pharmacological RAS blockade downregulates DPP4 in the heart and serum of HF rats. This interplay between DPP4 and RAS may affect HF progression and pharmacotherapy.

Exercise training inhibits inflammatory cytokines and more than prevents myocardial dysfunction in rats with sustained beta-adrenergic hyperactivity.

Myocardial hypertrophy and dysfunction occur in response to excessive catecholaminergic drive. Adverse cardiac remodelling is associated with activation of proinflammatory cytokines in the myocardium. To test the hypothesis that exercise training can prevent myocardial dysfunction and production of proinflammatory cytokines induced by beta-adrenergic hyperactivity, male Wistar rats were assigned to one of the following four groups: sedentary non-treated (Con); sedentary isoprenaline treated (Iso); exercised non-treated (Ex); and exercised plus isoprenaline (Iso+Ex). Echocardiography, haemodynamic measurements and isolated papillary muscle were used for functional evaluations. Real-time RT-PCR and Western blot were used to quantify tumour necrosis factor alpha, interleukin-6, interleukin-10 and transforming growth factor beta(1) (TGF-beta(1)) in the tissue. NF-B expression in the nucleus was evaluated by immunohistochemical staining. The Iso rats showed a concentric hypertrophy of the left ventricle (LV). These animals exhibited marked increases in LV end-diastolic pressure and impaired myocardial performance in vitro, with a reduction in the developed tension and maximal rate of tension increase and decrease, as well as worsened recruitment of the Frank-Starling mechanism. Both gene and protein levels of tumour necrosis factor alpha and interleukin-6, as well as TGF-beta(1) mRNA, were increased. In addition, the NF-B expression in the Iso group was significantly raised. In the Iso+Ex group, the exercise training had the following effects: (1) it prevented LV hypertrophy; (ii) it improved myocardial contractility; (3) it avoided the increase of proinflammatory cytokines and improved interleukin-10 levels; and (4) it attenuated the increase of TGF-beta(1) mRNA. Thus, exercise training in a model of beta-adrenergic hyperactivity can avoid the adverse remodelling of the LV and inhibit inflammatory cytokines. Moreover, the cardioprotection is related to beneficial effects on myocardial performance.

Use of afterload hemodynamic stress as a practical method for assessing cardiac performance in rats with heart failure.

After myocardial infarction, the hemodynamics under basal conditions might appear to be unaltered, which makes it difficult to identify cardiac dysfunction by the usual approaches. Thus, we tested the response to sudden afterload stress in infarcted rats with apparently normal ejection function. Control (CT) and infarcted (MI) Wistar rats with various MI sizes were submitted to echocardiography 30 days after coronary occlusion, followed by assessment of hemodynamics under basal conditions and during a pharmacologically induced sudden pressure overload (phenylephrine 15-25 microg/kg, i.v.). Coronary occlusion resulted in cardiac remodeling proportional to MI size, although several functional parameters such as systolic pressure (SP), stroke volume (SV), and stroke work (SW) of all MI rats were similar to those of CT rats. However, the afterload stress that was produced led to a relative preservation of SV and an increase of SW in CT rats; MI rats exhibited a significant reduction in SV and SW generation, although global cardiac function was normal under basal conditions, as indicated by regular echocardiography and hemodynamics assessment. Thus, we propose the use of sudden pharmacologically induced afterload stress as a practical and efficient procedure for identifying impaired performance of the heart in anesthetized rats, providing an additional physiological variable to be evaluated in experimental therapeutic studies.

Hyperbaric oxygenation improves redox control and reduces mortality in the acute phase of myocardial infarction in a rat model.

Among the mechanisms of action of hyperbaric oxygenation (HBO), the chance of reducing injury by interfering with the mechanisms of redox homeostasis in the heart leads to the possibility of extending the period of viability of the myocardium at risk. This would benefit late interventions for reperfusion to the ischemic area. The objective of the present study was to investigate the changes in the redox system associated with HBO therapy maintained during the first hour after coronary occlusion in an acute myocardial infarction (MI) rat model. Surviving male rats (n=105) were randomly assigned to one of three groups: Sham (SH=26), myocardial infarction (MI=45) and infarction+hyperbaric therapy (HBO=34, 1 h at 2.5 atm). After 90 min of coronary occlusion, a sample of the heart was collected for western blot analysis of total protein levels of superoxide dismutase, catalase, peroxiredoxin and 3­nitrotyrosine. Glutathione was measured by enzyme­linked immunosorbent assay (ELISA). The detection of the superoxide radical anion was carried out by oxidation of dihydroethidium analyzed with confocal microscopy. The mortality rate of the MI group was significantly higher than that of the HBO group. No difference was noted in the myocardial infarction size. The oxidized/reduced glutathione ratio and peroxiredoxin were significantly higher in the SH and MI when compared to the HBO group. Superoxide dismutase enzymes and catalase were significantly higher in the HBO group compared to the MI and SH groups. 3­Nitrotyrosine and the superoxide radical were significantly lower in the HBO group compared to these in the MI and SH groups. These data demonstrated that hyperbaric oxygenation therapy decreased mortality by improving redox control in the hearts of rats in the acute phase of myocardial infarction.

Linear periodization of strength training in blocks attenuates hypertension and diastolic dysfunction with normalization of myocardial collagen content in spontaneously hypertensive rats.

BACKGROUND AND METHOD: This study evaluated the effects of a linear block strength training programme on the parameters of cardiac remodelling in spontaneously hypertensive rats. Thirty-nine rats were equally distributed in four groups: normotensive sedentary, normotensive trained, hypertensive sedentary and hypertensive trained. The strength training protocol was organized in three mesocycles of 4 weeks, with an increase in the training load organized in a linear fashion for each block, considering the weight established in the maximum loaded load test. The following parameters were evaluated: ventricular function assessed by echocardiogram, caudal blood pressure, ventricular haemodynamics and cardiac masses. Two-way analysis of variance was used to determine the differences between the group and time. RESULTS: After 12 weeks of training, the hypertensive trained group presented the following results: increased muscle strength, reduced blood pressure, reduced heart rate, isovolumetric relaxation time and total collagen content, with increased cardiac function, without promoting changes in the mass and nuclear volume of cardiomyocytes. Also, blood pressure reduction seems to be associated with both muscle strength adjustments and total load progress. CONCLUSION: The findings of this study showed that the training programme carried out attenuated systemic arterial pressure and preserved the ventricular function of spontaneously hypertensive rats without cardiac mass change.

Digitoxin Attenuates Heart Failure, Reduces Myocardial Hypertrophy, and Preserves the Calcium-Binding Proteins in Infarcted Rats.

We previously showed that digitoxin prolongs the survival of rats with heart failure due to myocardial infarction (MI). In this study, we evaluated the effect of digitoxin on myocardial structure, ventricular function, and proteins involved in calcium kinetics. Seventy-two rats with MI >35% of the left ventricle were randomly assigned to 4 treatment groups: sham (n = 15), digitoxin (n = 11), infarction (n = 20), and infarction + digitoxin (n = 26). The rats were assessed 120 days after surgery by echocardiogram, hemodynamics, papillary muscle mechanics, collagen content, cardiomyocyte nuclear volume, and Western blot analysis of proteins involved in calcium kinetics. Digitoxin was administered via the rat chow. Two-way analysis of variance was used for comparisons. Myocardial infarction caused inotropic impairment, pulmonary congestion, increase of nuclear volume, myocardial collagen, and Na+/Ca2+ exchanger levels, and decreased SERCA2 and phosphorylated phospholamban levels. Treatment with digitoxin showed improvements in cardiac remodeling, inotropism, ventricular performance, pulmonary congestion, collagen accumulation, nuclear volume, and proteins involved in calcium kinetics. In rats with heart failure due to MI, long-term treatment with digitoxin attenuates congestive heart failure, mitigates myocardial remodeling and contractile impairment, and preserves myocardial levels of proteins involved in calcium kinetics.

Doppler echocardiographic predictors of mortality in female rats after myocardial infarction.

BACKGROUND: Doppler echocardiogram is useful for the evaluation of anatomical and functional changes in late myocardial infarction (MI) in rats. However, no studies have evaluated the prognostic value of echocardiographic parameters 1 week after MI. METHODS AND RESULTS: Doppler echocardiogram was performed in 84 female Wistar rats 1 week after MI to determine infarction size, left chambers dimensions, fractional area change (FAC) of the left ventricle (LV), mitral inflow and tissue Doppler, myocardial performance index (MPI), and signs of pulmonary hypertension. The 365-day follow-up showed 53.6% mortality rate. Nonsurvivors showed larger (P < .05) MI size and cavity dimensions, poorer diastolic and systolic function, and higher frequency of pulmonary hypertension. Parameters at early stage of MI associated with higher mortality risk by Cox multivariate regression model were FAC or=0.60 (RR 3.49, 95% CI, 1.80-6.76), LV systolic area >or=0.26 cm(2) (RR 4.38, 95% CI, 1.88-10.21), E/E' ratio >or=20.3 (RR 2.12, 95% CI, 1.15-4.34), and E/A ratio associated with FAC (RR 2.99, 95% CI, 1.44-6.18). CONCLUSION: Some diastolic and systolic Doppler echocardiographic parameters in rats may be able to predict late mortality risk after MI.

Left ventricle radio-frequency ablation in the rat: a new model of heart failure due to myocardial infarction homogeneous in size and low in mortality.

BACKGROUND: The purpose of the current study was to create a model of myocardial infarction (MI) that is homogeneous in size with a low immediate (24 hours) mortality. METHODS AND RESULTS: Male and female rats (n = 256) underwent left ventricle (LV) ablation (Ab) by a radiofrequency current (1000 kHz; 12 watts for 12 seconds) to promote a MI. A transmural MI occurred in all rats. Post-Ab complex arrhythmias were frequent (atrioventricular block, ventricular tachycardia, and fibrillation), which rapidly and spontaneously reverted to sinus rhythm. Among 66 male rats, immediate mortality occurred in 7.5%. Small MI size dispersion was characterized by smaller variability following Ab (x +/- SD: 45 +/- 8%) when compared with coronary occlusion (Oc; 40 +/- 19%). The histopathologic evaluations identified lesions similar to those which occurred following Oc, with scarring complete at 4 weeks. The hemodynamic and Doppler echocardiograms showed comparable increases in LV dimension, end-diastolic pressure, and pulmonary water content 1 and 4 weeks post-MI. Papillary muscle mechanics 6 weeks post-MI had matched inotropic and lusitropic dysfunction. CONCLUSIONS: LV Ab gave rise to a MI within a narrow size limit and with a low immediate mortality. LV Ab resulted in histopathologic evolution, ventricular dilation, and dysfunction, impairment in myocardial mechanics, and congestive outcome that reproduced a MI from Oc.

Digitoxin prolongs survival of female rats with heart failure due to large myocardial infarction.

BACKGROUND: We analyzed whether digitoxin affects the survival of rats with congestive heart failure. METHODS AND RESULTS: The influence of digitoxin (0.1 mg.100 g.day, orally) on the survival of infarcted female rats (n=170) randomized as Control Infarcted (CI, n=85) or Digitoxin (D, n=85) was evaluated for 280 days. Mean survival was 235+/-7 days for CI and 255+/-5 days for D (log-rank test: P=.0602). Digitoxin did not affect survival in rats with congestive heart failure from myocardial infarction <40% of the left ventricle, but did prolong survival in rats with infarction >or=40%. The log-rank test defined higher mortality (P=.0161) in CI >40% (56%) than in D >40% (34%), with a hazard ratio of 2.03. Pulmonary water content and papillary muscle mechanics were analyzed in CI (n=7) and D (n=14) survivors. Significant differences were observed regarding pulmonary water content (CI: 82+/-0.3; D: 80+/-0.3%; P=.0014), developed tension (CI: 2.7+/-0.3; D: 3.8+/-0.3g/mm(2); P=.0286) and +dT/dt (CI: 24+/-3; D: 39+/-4 mg mm(2).s; P=.0109). CONCLUSION: In conclusion, long-term digitoxin administration reduced cardiac impairment after myocardium infarction, attenuated myocardial dysfunction, reduced pulmonary congestion, and provided the first evidence regarding the efficiency of digitoxin in prolonging survival in experimental cardiac failure.

Hyperbaric oxygenation applied immediately after coronary occlusion reduces myocardial necrosis and acute mortality in rats.

1. Because in ischaemia there is a critical lack of O2, it has been reasoned that increasing O2 delivery to the ischaemic myocardium could serve as adjunctive therapy for acute myocardial infarction (MI). Accordingly, in the present study, the effect of early hyperbaric oxygenation (HBO) on mortality and MI size after coronary occlusion was examined in rats. 2. After coronary occlusion, male Wistar rats were randomly assigned to receive either HBO for 1 h in a hyperbaric chamber (100% O(2) at 253 kPa; n = 106) or ambient O2 as the control (n = 111). The extent of myocardial necrosis was assessed (triphenyltetrazolium) immediately after treatment in the HBO (n = 50) and control (n = 47) groups. The remaining rats were evaluated 24 h after occlusion to enable calculation of MI size and mortality. 3. Immediately after therapy, the size of the MI was significantly greater in the control group compared with that in the HBO group (40 +/- 3 vs 27 +/- 2% of the left ventricle (LV), respectively; P < 0.001). The 24 h mortality of control rats was higher than that of HBO rats (34 vs 16%, respectively; P = 0.02). Control rats that survived 24 h had a larger MI than did HBO rats that survived 24 h (40 +/- 4 vs 29 +/- 3% of the LV, respectively; P = 0.005). Furthermore, large necrotic areas (> 40% of the LV) were more frequent in control than HBO rats (55 vs 27% of infarcted hearts, respectively; P = 0.01). There was less pulmonary congestion observed in HBO rats compared with control rats. 4. In conclusion, early therapy with HBO during the onset of an acute ischaemic event decreases the necrotic area and reduces acute mortality. These data support further investigation of HBO as an adjuvant therapy for acute MI.

Delayed Reperfusion-Coronary Artery Reperfusion Close to Complete Myocardial Necrosis Benefits Remote Myocardium and Is Enhanced by Exercise.

The present study aimed to analyze the effects of reperfusion of a distant coronary artery on cardiac function, the ultrastructure, and the molecular environment of the remote myocardium immediately after the completion of myocardial regional necrosis: delayed reperfusion (DR). Additionally, the effects of prior exercise on the outcomes of DR were investigated. Female rats with permanent occlusion or delayed reperfusion were randomly assigned to an exercise (swimming, 1 h/day, 5 days/week for 8 weeks) or sedentary protocol. Thus, the study included the following four groups: sedentary permanent occlusion, exercise permanent occlusion, sedentary delayed reperfusion, and exercise delayed reperfusion. The descending coronary artery was occluded for 1 h. Reperfusion was confirmed by contrast echocardiography, and the rats were observed for 4 weeks. Permanent occlusion and DR caused similar myocardial infarction sizes among the four groups. Interestingly, exercise significantly decreased the mortality rate. Delayed reperfusion resulted in significant benefits, including enhanced hemodynamics and papillary muscle contraction, as well as reduced apoptosis and collagen content. Protein calcium kinetics did not change. Meanwhile, developed tension and the Frank-Starling mechanism were enhanced, suggesting that calcium sensitivity was intensified in myofilaments. Remarkable remote myocardial benefits occurred after distant DR, and prior exercise intensified cardiac recovery. Our findings provide valuable information about DR. Our data might explain the better clinical outcomes in recent studies showing that late reperfusion could improve heart failure in patients with myocardial infarction. In conclusion, DR has remote myocardial benefits, including inotropism enhancement, pulmonary congestion reduction, and collagen and apoptosis attenuation, which are enhanced by prior exercise.

Exercise training prevents beta-adrenergic hyperactivity-induced myocardial hypertrophy and lesions.

BACKGROUND: Sustained beta-adrenoreceptor activation promotes cardiac hypertrophy and cellular injury. AIMS: To evaluate the cardioprotective effect of exercise on damage induced by beta-adrenergic hyperactivity. METHODS: Male Wistar rats were randomised into four groups (n=8 per group): sedentary non-treated control (C), sedentary treated with isoproterenol 0.3 mg/kg/day administered subcutaneously for 8 days (I), exercised non-treated (E) and exercised plus isoproterenol administered during the last eight days of exercise (IE). Exercised animals ran on a treadmill for 1 h daily 6 times a week for 13 weeks. RESULTS: Isoproterenol caused increases in left ventricle (LV) wet and dry weight/body weight ratio, LV water content and cardiomyocyte transverse diameter. Additionally, isoproterenol induced severe cellular lesions, necrosis, and apoptosis, increased collagen content and reduced capillary and fibre fractional areas. Notably, all of these abnormalities were completely prevented by exercise. CONCLUSION: Our data have demonstrated that complete cardioprotection is possible through exercise training; by preventing beta-adrenergic hyperactivity-induced cardiac hypertrophy and structural injury.

Atrial fibrillation promotion in a rat model of heart failure induced by left ventricle radiofrequency ablation.

BACKGROUND: Atrial fibrillation (AF) frequently coexists with congestive heart failure (CHF). The increased susceptibility to AF in CHF has been attributed to a variety of structural and electrophysiological changes in the atria, particularly dilation and interstitial fibrosis. We evaluated atrial remodeling and AF vulnerability in a rat model of CHF induced by left ventricle (LV) radiofrequency (RF) ablation. METHODS: Wistar rats were divided into 3 groups: RF-induced CHF (Ab, n = 36), CHF animals treated with spironolactone (AbSpi, n = 20) and sham controls (Sham, n = 29). After 12 weeks, animals underwent echocardiographic and electrophysiological evaluation and were sacrificed for histological (atrial fibrosis) and Western blotting (TGF-ß1, collagen I/III, connexin 43 and CaV1.2) analysis. RESULTS: Mild LV dysfunction and marked atrial enlargement were noted in both ablated groups. AF inducibility (episodes ≥2 s) increased in the Ab group compared to sham animals (31/36, 86%; vs. 15/29, 52%; p = 0.005), but did not differ from the AbSpi group (16/20, 80%; p = NS). Sustained AF (>30 s) was also more frequent in the Ab group compared to shams (56% vs. 28%; p = 0.04). Spironolactone reduced atrial fibrosis (p < 0.01) as well as TGF-ß1 (p < 0.01) and collagen I/III (p < 0.01) expression but did not affect connexin 43 and CaV1.2 expression. CONCLUSIONS: Rats with RF-induced CHF exhibit pronounced atrial structural remodeling and enhanced AF vulnerability. This model may be useful for studying AF substrate in CHF.

Low-Level Laser Application in the Early Myocardial Infarction Stage Has No Beneficial Role in Heart Failure.

Low-level laser therapy (LLLT) has been targeted as a promising approach that can mitigate post-infarction cardiac remodeling. There is some interesting evidence showing that the beneficial role of the LLLT could persist long-term even after the end of the application, but it remains to be systematically evaluated. Therefore, the present study aimed to test the hypothesis that LLLT beneficial effects in the early post-infarction cardiac remodeling could remain in overt heart failure even with the disruption of irradiations. Female Wistar rats were subjected to the coronary occlusion to induce myocardial infarction or Sham operation. A single LLLT application was carried out after 60 s and 3 days post-coronary occlusion, respectively. Echocardiography was performed 3 days and at the end of the experiment (5 weeks) to evaluate cardiac function. After the last echocardiographic examination, LV hemodynamic evaluation was performed at baseline and on sudden afterload increases. Compared with the Sham group, infarcted rats showed increased systolic and diastolic internal diameter as well as a depressed shortening fraction of LV. The only benefit of the LLLT was a higher shortening fraction after 3 days of infarction. However, treated-LLLT rats show a lower shortening fraction in the 5th week of study when compared with Sham and non-irradiated rats. A worsening of cardiac function was confirmed in the hemodynamic analysis as evidenced by the higher LV end-diastolic pressure and lower +dP/dt and -dP/dt with five weeks of study. Cardiac functional reserve was also impaired by infarction as evidenced by an attenuated response of stroke work index and cardiac output to a sudden afterload stress, without LLLT repercussions. No significant differences were found in the myocardial expression of Akt1/VEGF pathway. Collectively, these findings illustrate that LLLT improves LV systolic function in the early post-infarction cardiac remodeling. However, this beneficial effect may be dependent on the maintenance of phototherapy. Long-term studies with LLLT application are needed to establish whether these effects ultimately translate into improved cardiac remodeling.

Immediate functional effects of left ventricular reduction: a Doppler echocardiographic study in the rat.

BACKGROUND: Immediate functional effects of left ventricle reduction (LVR) are not yet fully defined. Those effects have been studied in the experimental model of myocardial infarction scar plication (MISP) in the rat. METHODS AND RESULTS: A Doppler echocardiogram was performed immediately before and after MISP in 20 rats with infarction of the left ventricle (LV) larger than 40%. LV diastolic volume reduction (475 +/- 114 versus 185 +/- 65 muL) was accompanied by heart rate decrease (230 +/- 25 versus 166 +/- 27 beats/min) and increase of ejection fraction (37 +/- 7 versus 67 +/- 12%), fractional shortening (18 +/- 3 versus 46 +/- 8%) and posterior wall shortening velocity (1.50 +/- 0.62 versus 2.01 +/- 0.46 cm/s). LV diastolic volume/stroke volume slope was steeper after LVR, suggesting enhancement of the Frank-Starling mechanism. Restrictive pattern of left atrial emptying was alleviated after LVR (E wave: 101 +/- 15 versus 66 +/- 14 cm/s; E/A ratio: 6.8 +/- 2.9 versus 5.0 +/- 2.2; E wave deceleration time: 36 +/- 6 versus 51 +/- 10 msec) even though left atrial diameter (0.69 +/- 0.07 versus 0.66 +/- 0.06 cm) and A wave (18.0 +/- 9.4 versus 15.8 +/- 7.8 cm/s) did not vary. Additionally, a pulmonary flow profile suggesting pulmonary hypertension was observed in 12 of 17 animals before, and in only 3 after, LVR. CONCLUSION: LVR favors cardiac function not only by reducing afterload. The present data are in consonance with previous suggestions that the Frank-Starling mechanism is enhanced after MISP and, in addition to LV ejection function improvement, the unprecedented facilitation of left atrial emptying after LVR was particularly noteworthy. Even though LVR restricts ventricular distensibility, atrial emptying can be facilitated, probably on account of LV ejection improvement.

[Mechanical function is normal in remanent myocardium during the healing period of myocardial infarction--despite congestive heart failure]. / A função mecânica do miocárdio remanescente a um infarto do miocárdio é normal durante o período de cicatrização, embora exista insuficiência cardíaca.

OBJECTIVE: The temporal relation between ventricular dysfunction (VD) after myocardial infarction (MI) and remanent myocardium mechanics is not yet clear. The present work investigated--through Doppler echocardiography (ECHO)--ventricular function in rats with extensive MI, as well as the mechanical function of papillary muscles (PM) at the end of the healing period. METHODS: ECHO and PM of 9 Wistar rats (MI) were studied against 9 controls (C) three weeks after LV myocardial infarction. The following were determined: developed tension (DT) and its first negative and positive derivative, time-to-peak tension (TPT), resting tension (RT), and relaxation time at 50% of DT at 0.5, 1.0, 1.5, 2.0 and 2.5 calcium concentrations (mM). Tetanic contractions were carried out after ryanodine administration at 1.5, 2.5 and 5.0 calcium concentrations. RESULTS: VD was characterized by ECHO, with marked abnormality of diastolic volume and LV and ejection fraction in addition to clear restrictive pattern of blood flow through the mitral valve. No significant difference was found in myocardial mechanics data either for MI or for C rats. CONCLUSION: The heart failure (HF) reported by MI rats with > 40% MI at the end of the healing period is not myocardial function dependent. Chamber structural changes and lower population of myocites should base VD and HF.