Oscar Andrés Pinilla

Endurance Training in the Spontaneously Hypertensive Rat: Conversion of Pathological into Physiological Cardiac Hypertrophy

The effect of endurance training (swimming 90 min/d for 5 days a week for 60 days) on cardiac hypertrophy was investigated in the spontaneously hypertensive rat (SHR). Sedentary SHRs (SHR-Cs) and normotensive Wistar rats were used as controls. Exercise training enhanced myocardial hypertrophy assessed by left ventricular weight/tibial length (228±7 versus 251±5 mg/cm in SHR-Cs and exercised SHRs [SHR-Es], respectively). Myocyte cross-sectional area increased ≈40%, collagen volume fraction decreased ≈50%, and capillary density increased ≈45% in SHR-Es compared with SHR-Cs. The mRNA abundance of atrial natriuretic factor and myosin light chain 2 was decreased by the swimming routine (100±19% versus 41±10% and 100±8% versus 61±9% for atrial natriuretic factor and myosin light chain 2 in SHR-Cs and SHR-Es, respectively). The expression of sarcoplasmic reticulum Ca2+ pump was significantly augmented, whereas that of Na+/Ca2+ exchanger was unchanged (93±7% versus 167±8% and 158±13% versus 157±7%, sarcoplasmic reticulum Ca2+ pump and Na+/Ca2+ exchanger in SHR-Cs and SHR-Es, respectively; P<0.05). Endurance training inhibited apoptosis, as reflected by a decrease in caspase 3 activation and poly(ADP-ribose) polymerase-1 cleavage, and normalized calcineurin activity without inducing significant changes in the phosphatidylinositol 3-kinase/Akt pathway. The swimming routine improved midventricular shortening determined by echocardiography (32.4±0.9% versus 36.9±1.1% in SHR-Cs and SHR-Es, respectively; P<0.05) and decreased the left ventricular free wall thickness/left ventricular cavity radius toward an eccentric model of cardiac hypertrophy (0.59±0.02 versus 0.53±0.01 in SHR-Cs and SHR-Es, respectively; P<0.05). In conclusion, we present data demonstrating the effectiveness of endurance training to convert pathological into physiological hypertrophy improving cardiac performance. The reduction of myocardial fibrosis and calcineurin activity plus the increase in capillary density represent factors to be considered in determining this beneficial effect.

Sex-Related Difference in Left Ventricular Mass in Nonhypertensive Young Adults: Role of Arterial Pressure

BACKGROUND Blood pressure (BP) is higher in men than in women at similar ages through adult life. Interestingly, a similar pattern is detected in left ventricular mass (LVM), classically attributed to differences in body size. However, the existing difference in BP between sexes might be relevant in determining LVM and it has been not fully investigated. Therefore, we set out to determine the impact of nonhypertensive levels of BP on the sex-associated LVM difference. METHODS We conducted population-based study including 283 young students (52% male; age 20.62 ± 1.31 years). BP was determined twice using standard mercury sphygmomanometers in 2 occasions. LVM was determined with M-mode echocardiography. To dissect the relative contribution of BP, volume load, and body size to the sex-related difference in LVM, an analysis of covariance was performed. RESULTS Mean systolic and diastolic BP were 10.00 ± 0.96 and 4.59 ± 0.78 mm Hg higher and LVM was 34.87 ± 3.12 g larger in men than in women, respectively (P < 0.01, t test). When LVM was adjusted to mean BP, the sex difference was reduced by 16%. When LVM was adjusted to body size and hemodynamic load, this difference was reduced by 68.5%. CONCLUSIONS We report in a sample of young nonhypertensive students a difference in LVM between women and men that is partially explained (16%) by sex differences in BP, supporting an early effect of BP on cardiac mass even in the absence of hypertension. A more relevant effect could be expected as the population ages.

Carbonic anhydrase inhibitors reduce cardiac dysfunction after sustained coronary artery ligation in rats

BACKGROUND Two potent carbonic anhydrase (CA) inhibitors with widely differing membrane permeability, poorly diffusible benzolamide (BZ), and highly diffusible ethoxzolamide (ETZ) were assessed to determine whether they can reduce cardiac dysfunction in rats subjected to coronary artery ligation (CAL)-induced myocardial infarction. METHODS AND RESULTS Rats with evidence of heart failure (HF) at 32 weeks following a permanent left anterior coronary artery occlusion were treated with placebo, BZ, or ETZ (4 mg kgday-1) for 4 weeks at which time left ventricular function and structure were evaluated. Lung weight/body weight (LW/BW) ratio increased in CAL rats by 17±1% vs. control, suggesting pulmonary edema. There was a trend for BZ and ETZ to ameliorate the increase in LW/BW by almost 50% (9±5% and 9±8%, respectively, versus CAL) (P=.16, NS). Echocardiographic assessment showed decreased left ventricular midwall shortening in HF rats, 21±1% vs. control 32±1%, which was improved by BZ to 29±1% and ETZ to 27±1%, and reduced endocardial shortening in HF rats 38±3% vs. control 62±1%, partially restored by BZ and ETZ to ~50%. Expression of the hypoxia-inducible membrane-associated CAIX isoform increased by ~60% in HF rat hearts, and this effect was blocked by ETZ. CONCLUSIONS We conclude that CAL-induced myocardial interstitial fibrosis and associated decline in left ventricular function were diminished with BZ or ETZ treatment. The reductions in cardiac remodeling in HF with both ETZ and BZ CA inhibitors suggest that inhibition of a membrane-bound CA appears to be the critical site for this protection.

CARBONIC ANHYDRASE INHIBITORS ALLEVIATE CARDIAC DYSFUNCTION AFTER SUSTAINED CORONARY ARTERY LIGATION IN RATS

BACKGROUND: Heart failure often results from maladaptive remodeling of the myocardium after pathological hypertrophy of the heart. While carbonic anhydrase (CA) genes are overexpressed in the hypertrophic and failing human myocardium, carbonic anhydrase inhibition prevents and reduces cardiomyocyte hypertrophy in culture models of cardiomyocytes subjected to pro-hypertrophic stimuli. METHOD AND RESULTS: We aimed to test the role of the poorly membrane-permeable potent CA inhibitor, benzolamide (BZ), and the potent freely diffusible CA inhibitor ethoxzolamide (ETZ), in rats subjected to coronary artery ligation (CAL). Wistar rats with established signs of heart failure (HF) induced by sustained (eight month) left coronary artery ligation were treated with BZ or ETZ (4 mg.kg.day) by a month, and had the left ventricular function and structure evaluated. Lung weight/body weight ratio increased significantly in CAL rats, 17 1% increase compared to control, suggestive of pulmonary edema and a transition to the HF state; and this condition was ameliorated by BZ and ETZ, 9 5% and 9 8% increase respectively, compared to control. Functional echocardiographic recordings showed decreased left ventricular midwall shortening in HF rats, 21 1% vs. control 32 1%; which was improved by BZ 29 1%, and ETZ 27 1%, treatments. In addition, the left ventricular endocardial shortening was considerably reduced in HF rats 38 3% compared to control 62 1%, and it was partially restored by BZ 48 2%, and ETZ 46 1%. Finally, CAL induced an increased in interstitial fibrosis which was reversed by BZ and ETZ therapy. CONCLUSION: We conclude that CA inhibitors with different cell permeability contribute to improve the functional remodeling of the failing heart, and this condition is accompanied by the reduction of fibrotic tissue deposition in infarcted rat hearts. PIP 0664 -S V SECyT