Developmental changes in modulation of cardiac repolarization by sympathetic stimulation: the role of beta- and alpha-adrenergic receptors.

INTRODUCTION: Our goals were to study the role of development in determining the cardiac effects of sympathetic neural activation, and to identify the roles of alpha- and beta-adrenergic receptor-mediated pathways in modulating the effects of sympathetic stimulation. METHODS AND RESULTS: We compared responses of young and adult canine hearts in situ to right, left, and bilateral stellate ganglion stimulation. We focused on changes in heart rate, rhythm, QT interval, rate-corrected QT interval (QTc), and T wave amplitude. Right stellate stimulation (RSS) induced more pronounced sinus tachycardia in adult than young animals. Left stellate stimulation (LSS) induced junctional tachycardia in adult more than young animals. In adults, LSS and RSS prolonged QTc (LSS > RSS), whereas 1-week-olds manifested QTc shortening with RSS. LSS also increased T wave amplitude, most markedly in adults. In all studies, bilateral stellate stimulation induced responses intermediate between those seen with RSS and LSS. beta-Adrenergic blockade (propranolol) abolished all responses to LSS in adult hearts, but alpha-blockade (prazosin) attenuated only the LSS-induced prolongation in QTc. CONCLUSION: In the postnatal modulation of cardiac rhythm, rate, and repolarization by the sympathetic nervous system, beta-adrenergic receptors play a major role at all ages, whereas alpha-adrenergic receptors play a lesser role, which is manifested only in adults. Moreover, expression of junctional tachycardias, which are beta-adrenergically modulated, is seen only in the adults.

Sickle cell anemia causes a distinct pattern of glomerular dysfunction.

We characterized glomerular function in adults with sickle cell anemia (SSA): 12 with normal renal function (SSA-controls), and 15 with renal insufficiency (SSA-CRF). GFR was similar in SSA-controls and healthy-controls, however, renal plasma flow was increased in SSA-controls. In SSA-CRF, the albumin and IgG excretion rates were enhanced. The fractional clearances of all dextran sizes (26 to 64 A) were significantly increased in both SSA-controls and SSA-CRF versus healthy-controls. In SSA-CRF, the fractional clearance of dextrans > 58 A was enhanced. Analysis with an "isoporous+shunt" model revealed an increase in the mean restrictive pore radius (ro) by 5 A in SSA-controls and SSA-CRF, versus healthy-controls. In SSA-CRF, the total number of membrane pores was reduced > 70%, and the shunt parameter increased twofold. We conclude that SSA patients have a distinct pattern of glomerular dysfunction with generalized increased permeability to dextrans, resulting from an increase in pore radius. When CRF develops, the total number of membrane pores is reduced, and a size-selectivity defect occurs. The changes in dextran permeability cannot be attributed to purely hemodynamic changes (increased RPF or low filtration fraction), or to known modulators of membrane porosity. These findings suggest that unique mechanism(s) are implicated in the pathogenesis of sickle glomerulopathy.

Ultrarapid train stimulation versus conventional programmed electrical stimulation for induction of ventricular arrhythmias in patients with coronary artery disease.

Conventional programmed electrical stimulation (PES) of the ventricle is useful for establishing inducibility or noninducibility of clinical ventricular arrhythmias (VA) but is complex and time consuming. The present study was designed to compare a standard PES protocol with an alternative method using ultrarapid train stimulation in patients with VA and coronary artery disease (CAD). A prospective, randomized, crossover design was used. During each session in the electrophysiology laboratory, patients were studied using both the trains and PES protocols in randomized order. In 82 matched pairs of comparisons in 50 patients, results were concordant in 85% (p < 0.0001). There were no differences related to type of clinical arrhythmia or to the presence of antiarrhythmic drugs. There were no significant differences in the induction of nonclinical arrhythmias with the two methods (p < 0.0001 for concordance). There were no significant differences related to the cycle length of the trains (10, 20, or 30 ms, equivalent to 100, 50, or 33 Hz). The number of drive-extrastimuli sequences and the time required to complete the trains protocol was significantly shorter (p < 0.0001) using trains versus PES. Ultrarapid train stimulation provides results in CAD patients that are comparable with those of conventional PES protocols. There is a significant savings in time, adding practical value to intrinsic electrophysiologic interest. Trains may be useful when multiple inductions are desirable, for example, in the setting of antitachycardia pacing parameters in an implantable defibrillator (ICD), during ICD implantation, or in other circumstances where the main question is inducibility of ventricular arrhythmias.

Early detection and the course of glomerular injury in patients with sickle cell anemia.

We performed a cross sectional analysis of glomerular function in 34 adult patients with sickle cell anemia (SSA). Patients were divided according to GFR and albumin excretion rate (AER): SSA controls (normal GFR and AER, N = 10), albuminuria (increased AER, but normal GFR, N = 7) and chronic renal failure (CRF, low GFR, N = 17). GFR did not correlate with age (that is, duration of disease), but was inversely related to AER and IgG excretion rates (r = -0.61 and -0.69, respectively, P < 0.001) and directly related to the hematocrit (r = 0.56, P < 0.001). Renal plasma flow was disproportionately higher than GFR, so that filtration fraction was low in all groups. Albuminuria was accompanied, even in patients with normal GFR, by a reduction in ultrafiltration coefficient (16 +/- 3 in albuminuria vs. 25 +/- 3 in controls, P < 0.05). A more severe loss of ultrafiltration coefficient and glomerular permselectivity occurred in CRF. We conclude that renal failure in SSA occurs because of glomerular injury with loss of ultrafiltration coefficient and glomerular permselectivity. The earliest clinically detectable abnormality is an increase in albumin and IgG excretion. When albuminuria is present, the ultrafiltration coefficient is already diminished even if GFR is preserved. Detection of albuminuria can identify established glomerular injury in SSA.

Chloroethylclonidine increases the incidence of lethal arrhythmias during coronary occlusion in anesthetized dogs.

We studied the role of alpha1-adrenoceptors in the modulation of ventricular tachycardia and fibrillation in chloralose-anesthetized dogs subjected to 30 min left anterior descending coronary artery occlusion. Study groups were control, and those treated with the alpha1-adrenoceptor-subtype blockers WB4101 (0.5 mg/kg i.v.) or chloroethylclonidine (1.9 mg/kg i.v.). For the first set of experiments all animals were in sinus rhythm and heart rate was slower in the chloroethylclonidine-pretreated animals than the WB4101-treated group (P < 0.05). During occlusion, ventricular tachycardia and ventricular fibrillation incidence did not differ among control, WB4101 or chloroethylclonidine (3 dogs with ventricular fibrillation in each group and 0, 2 and 3 dogs respectively with ventricular tachycardia), but ventricular premature depolarizations were significantly reduced by both interventions, and nonsustained ventricular tachycardia was suppressed by WB4101. In a second set of experiments, animals were atrially paced at a cycle length of 300 ms, and divided into control, WB4101-treated or chloroethylclonidine-treated, as above. Here, 9/10 chloroethylclonidine-treated animals developed ventricular tachycardia and fibrillation during occlusion, whereas only 4/10 controls and 4/10 WB4101-treated animals did so (P < 0.05). In conclusion, during sinus rhythm, both types of alpha1-adrenoceptor subtype blockade significantly suppressed ventricular premature depolarizations and neither affected ventricular tachycardia and fibrillation. In contrast, when heart rate was held constant, chloroethylclonidine clearly enhanced the occurrence of ventricular fibrillation during occlusion. These results suggest the alpha1-adrenoceptor subtype blocked by chloroethylclonidine, but not that blocked by WB4101, is capable of increasing the incidence of lethal arrhythmias that occur at rapid atrial rates during ischemia.

A comparison of ventricular arrhythmias induced with programmed stimulation versus alternating current.

In patients undergoing implantation and testing of the implantable cardioverter defibrillator (ICD), alternating current (AC) may be used to induce ventricular tachyarrhythmias in a prompt, safe, and efficient manner. These arrhythmias have been previously reported to be similar to those induced during programmed electrical stimulation (PES). We compared the ventricular tachyarrhythmias induced by both methods in 14 patients: 8 male, 6 female; mean age 61 years; coronary disease in 10, cardiomyopathy in 4; mean ejection fraction 31%. The presenting arrhythmia was nonsustained ventricular tachycardia (VT) in four, sustained monomorphic ventricular tachycardia (SMVT) in five, ventricular fibrillation (VF) in four, and unknown in one patient with syncope. PES (single, double, triple extrastimuli; burst pacing) and AC (1-2 sec application) stimulation via right ventricular endocardial electrode catheter was performed off antiarrhythmic drugs in the nonsedated state. PES induced SMVT in nine, polymorphic VT in two, and VF in three. AC induced VF in all patients. Although AC can reliably induce ventricular tachyarrhythmias during defibrillation threshold and ICD testing, there is poor correlation to PES induced tachyarrhythmias.