Cardiac-specific overexpression of mouse cardiac calsequestrin is associated with depressed cardiovascular function and hypertrophy in transgenic mice.

Calsequestrin is a high capacity Ca2+-binding protein in the sarcoplasmic reticulum (SR) lumen. To elucidate the functional role of calsequestrin in vivo, transgenic mice were generated that overexpressed mouse cardiac calsequestrin in the heart. Overexpression (20-fold) of calsequestrin was associated with cardiac hypertrophy and induction of a fetal gene expression program. Isolated transgenic cardiomyocytes exhibited diminished shortening fraction (46%), shortening rate (60%), and relengthening rate (60%). The Ca2+ transient amplitude was also depressed (45%), although the SR Ca2+ storage capacity was augmented, as suggested by caffeine application studies. These alterations were associated with a decrease in L-type Ca2+ current density and prolongation of this channel's inactivation kinetics without changes in Na+-Ca2+ exchanger current density. Furthermore, there were increases in protein levels of SR Ca2+-ATPase, phospholamban, and calreticulin and decreases in FKBP12, without alterations in ryanodine receptor, junctin, and triadin levels in transgenic hearts. Left ventricular function analysis in Langendorff perfused hearts and closed-chest anesthetized mice also indicated depressed rates of contraction and relaxation of transgenic hearts. These findings suggest that calsequestrin overexpression is associated with increases in SR Ca2+ capacity, but decreases in Ca2+-induced SR Ca2+ release, leading to depressed contractility in the mammalian heart.

The accuracy of self-report of smoking status in pregnant women.

Little is known about the accuracy of usual-care providers' detection of pregnant smokers. This study explored the proportion of pregnant women misclassified as nonsmokers by midwives in a public antenatal clinic. A sample of 204 women whom midwives classified as nonsmokers were asked to complete a self-administered questionnaire and to provide a urine specimen for cotinine analysis. Results indicate that midwives failed to detect a significant proportion of smokers. The conservative estimate of the proportion of midwife-identified nonsmokers who could be reclassified as smokers on the basis of the questionnaire and urinalysis procedures was 7.4% (95% CI 3.8-10.9%), the medium estimate was 8.8% (95% CI 4.9-12.7%) and the worst-case estimate was 15.2% (95% CI 10.3-20.1%). To increase the coverage achieved by smoking-cessation programs, antenatal clinics should consider incorporating biochemical measurements into routine screening procedures. Future studies examining smoking status in pregnancy should detail the methods used to classify subjects and document response rates in relation to each self-report and biochemical measurement.

Selenium as a protector of diastolic function during oxidant stress.

Interventional studies yielded conflicting results on reperfusion injury. They are unable to discriminate between lesions due to ischemia or to additional damage during reoxygenation. Since reactive oxygen metabolites have been implicated as a major cause of reperfusion injury, 375 nmol/min of hydrogen peroxide was infused in a Langendorff rat heart preparation as a model of oxidant stress without previous ischemic contractile dysfunction. Impaired endogenous defense was remodeled, using selenium-deficient hearts with reduced glutathione peroxidase activity. Measurements of hemodynamic parameters demonstrate increased myocardial susceptibility to oxidant stress in hearts with decreased antioxidant defense. Defined concentrations of hydrogen peroxide produce isolated impairment of active and passive diastolic properties of the ventricle in this model.

Simultaneous cardiac mechanics and phosphorus-31 NMR spectroscopy during global myocardial ischemia and reperfusion in the intact dog.

To investigate the high-energy phosphate metabolic correlates of left ventricular (LV) dysfunction during the onset and recovery from severe, global myocardial ischemia in vivo, seven preinstrumented closed-chest dogs had ECG-gated phosphorus-31 (31P) NMR-spectroscopy (NMR-S) studies performed and LV micromanometer and sonomicrometer data measured before, during, and every 5 min following severe occlusive global myocardial ischemia. Ischemic LV + dP/dtmax fell from 2396 +/- 576 mm Hg/s at baseline to 2185 +/- 478 mm Hg/s (p less than 0.05) and did not normalize until after 30 min of reperfusion. LV ejection fraction (EF) decreased significantly (0.32 +/- 0.07 EF units to 0.12 +/- 0.13 EF units; p less than 0.05) and did not recover by 30 min of reperfusion (0.27 +/- 0.09 units; P less than 0.05 vs baseline). Simultaneous 31P NMR-S studies demonstrated excellent beta-ATP signal-to-noise (10 +/- 4:1). Myocardial acidosis occurred during global ischemia (delta pH = -0.22 +/- 0.23 units; p less than 0.05), with recovery at 30 min of reperfusion. Inorganic phosphate/phosphocreatine ratio (Pi/PCr) increased significantly during ischemia (0.46 +/- 0.07 to 0.61 +/- 0.07; P less than 0.05), with delayed normalization of this ratio at 30 min of reperfusion. beta-ATP peak area did not change during ischemia. Pi/PCr and LV contractility (+dP/dtmax) were significantly correlated at baseline (r = -0.70) and during global ischemia (r = -0.78; p less than 0.01), but not during recovery (r = 0.006; p = NS). Therefore, the simultaneous evaluation of high-fidelity hemodynamic data and topical 31P NMR-S can be performed in the intact state.

Diastolic dysfunction of perfused rat hearts induced by hydrogen peroxide. Protective effect of selenium.

Oxidant substances such as hydrogen peroxide are postulated to cause cardiac dysfunction and injury in a number of pathological conditions. Selenium is an essential nutrient which serves as an oxidant defense through the selenoenzyme glutathione peroxidase. This enzyme metabolizes hydrogen peroxide; its activity in rat heart is reduced to 5% of control by selenium deficiency. Left ventricular function of selenium-deficient and control rat hearts was studied in a Langendorff preparation under isovolumic conditions. A stabilization period of 20 min was followed by a 70 min infusion of hydrogen peroxide at 375 or 1500 nmol/min. When no hydrogen peroxide was infused, perfusion for 90 min had no effect on systolic or diastolic function and no effect of selenium deficiency was detected. Hydrogen peroxide infusion into selenium-deficient hearts at 375 nmol/min led to impaired isovolumic relaxation and a substantial increase in end-diastolic pressure after 45 min which worsened progressively until the experiment was terminated. By contrast no effect was observed on systolic contractile function as assessed by peak pressure or developed pressure. Infusion of this dose of hydrogen peroxide into control hearts had no significant effect on diastolic or systolic function. However, infusion of 1500 nmol hydrogen peroxide/min into control hearts caused diastolic dysfunction after 30 min without affecting systolic function. These results indicate that hydrogen peroxide injury to the perfused rat heart is manifested by diastolic dysfunction before systolic dysfunction occurs. Selenium deficiency lowers the dose of hydrogen peroxide needed to cause diastolic dysfunction. This suggests that the selenoenzyme glutathione peroxidase protects the heart against hydrogen peroxide injury.

Experience with calcium antagonist drugs in congestive heart failure.

Several clinical studies have demonstrated beneficial hemodynamic effects of calcium antagonist drugs when used as arterial vasodilators in the treatment of certain patients with moderate to severe congestive heart failure. These drugs usually decrease systemic vascular resistance and improve ejection phase indexes of left ventricular function in such patients. However, calcium antagonists have intrinsic negative inotropic effects and other vasodilators such as nitroprusside, hydralazine and captopril appear to be more beneficial when used in the treatment of severe congestive heart failure.

Differential effects of systemic and intracoronary calcium channel blocking agents on global and regional left ventricular function in conscious dogs.

We examined the differential effects of intravenous (IV) equimolar doses of diltiazem (D), verapamil (V), and nifedipine (N) upon left ventricular (LV) function in 12 healthy unsedated dogs. We also attempted to isolate direct myocardial effects of these agents from reflex and peripheral effects by using intracoronary (IC) equimolar drug administration in an additional six animals. Despite equivalent dose-related increases in heart rate and declines in arterial pressure intravenous V (0.04, 0.1, 0.17 mg/kg) and N (0.3 mg/kg) but not D (0.04, 0.1, 0.17 mg/kg) depressed LV function. Peak effects after high dose V included increased heart rate (HR) (68%) and reduced mean aortic pressure (MAP) (17%), dP/dt max (22%), and percent shortening of the LV minor diameter (% delta D) (33%) (all p less than or equal to 0.001). By contrast, equimolar D increased HR (68%) and decreased MAP (20%) but produced no change in dP/dt or % delta D while low dose N (0.03 mg/kg) depressed dP/dt and % delta D by 37% and 45%, respectively (both p less than or equal to 0.001) despite similar changes in HR and MAP. Pretreatment with propranolol (2 mg/kg) and matching HR and loading conditions to control failed to uncover myocardial depression after D. Equimolar IC D, V (4, 8, 16 micrograms/kg), or N (3 micrograms/kg) each produced dose-related reductions in percent regional shortening which were greatest with N (58% at 3 micrograms/kg) and least with D (9% at 16 micrograms/kg). These data suggest that calcium channel blockers vary in their propensity to reduce LV function and that the myocardial depressant effects of these agents are partially offset by reflex and peripheral vascular actions.