Development of a new method for assessing the cardiac baroreflex: response to downward tilting in patients with diabetes mellitus.

OBJECTIVE: To investigate the clinical value of a new non-invasive method for assessing baroreflex sensitivity using downward tilting. PATIENTS: 34 patients with diabetes mellitus, mean (SD) age, 53.6 (11.8) years. DESIGN: Arterial blood pressure and ECG were recorded simultaneously while the patients were on a tilt table. After 20 minutes at a 70 degrees upright tilt, the patients were returned to the supine position at a speed of 3.2 degrees /s (downward tilting baroreflex sensitivity test, DT-BRS). A beat to beat systolic blood pressure increase associated with a corresponding lengthening of the RR interval was noted during downward tilting. Baroreflex sensitivity was also assessed using the conventional method of an intravenous injection of phenylephrine (Phe-BRS). Heart rate variability was analysed during rest and tilting. RESULTS: The slope of the regression line for systolic blood pressure v RR interval during downward tilting was highly correlated with Phe-BRS (r = 0.83, p < 0.0001). Both DT-BRS and Phe-BRS were correlated with the high frequency (HF) component of resting heart rate variability (p < 0.005) and with the ratio of the low frequency to the high frequency component (LF/HF) during upright tilting (p < 0.005). DT-BRS and Phe-BRS were also correlated with the difference between rest and tilting values of HF and LF/HF (p < 0.005). CONCLUSIONS: DT-BRS provides a physiological, non-invasive method for determining baroreflex sensitivity and may be a useful index of reflex cardiac vagal and sympathetic function in patients with diabetes mellitus.

[Present and future of cardiac function tests: electrophysiologic tests].

Various electrocardiographic and physiologic tests have been developing for almost 100 years since Einthoven established the standard 12 lead electrocardiogram(ECG) system. Recently, interest has focused on the new developing parameters associated with cardiac ventricular repolarization, such as transmural dispersion of repolarization, T wave alternans and QT dispersion. QT dispersion, measured as interlead difference of QT interval, has been suggested to reflect regional variation of ventricular repolarization. However, still unsolved basic problems give difficulties for clinical acceptance of this parameter. On the other hand, it is generally accepted that heart rate variability obtained from Holter ECG is useful tool to assess the autonomic tone. Head-up tilt test is a valuable diagnostic tool to identify patients with neurally mediated syncope and also useful for assessment of reflex cardiac autonomic function, such as baroreflex sensitivity. The number of electrophysiologic study(EPS) dramatically increased together with increase of radiofrequency catheter ablation. A new three-dimensional nonfluoroscopic electroanatomical mapping system(CARTO) is an exciting development in catheter ablation treatment. Transtelephonic ECG and its computer-assisted answering system are also useful for diagnose and treatment in the patients of paroxysmal cardiac symptoms.

Malignant neurocardiogenic vasovagal syncope associated with chronic exaggerated vagal tone.

A head-up tilt test was performed in a 23-year-old woman with a history of two syncopal episodes. The patient developed abrupt syncope with 48 seconds of sinus arrest. Analysis of the high frequency (HF) power of heart rate variability over 24 hours before and after metoprolol therapy showed a significantly elevated HF power in this patient compared to age- and sex-matched healthy subjects. It is suggested that an exaggerated resting vagal tone might be associated with the pathogenesis of prolonged asystole in our patient.

Bepridil prolongs the action potential duration of guinea pig ventricular muscle only at rapid rates of stimulation.

1. We examined the electromechanical effects of the calcium antagonist, bepridil (1-20 microM), on isolated guinea pig ventricular muscles, driven at various stimulus frequencies (0.1, 0.5, 1, 2 and 5 Hz) in Tyrode's solution containing various K+ concentrations (1.4-43.2 mM). 2. Conventional microelectrode and tension-recording techniques were used. 3. We found that bepridil decreased the maximum upstroke velocity (Vmax) of the action potential with no change in the resting membrane potential (RMP). 4. The former effect depended on both stimulus frequency and the drug concentration used. 5. Bepridil lengthened the duration of the action potential at the level of 25% repolarization (APD25) at the highest frequency (5 Hz), but shortened it at lower frequencies (< or = 2 Hz). 6. The drug also lengthened the APD90 at the highest frequency (5 Hz) but without significant effect at lower frequencies (< or = 2 Hz). 7. Bepridil depolarized the RMP at relatively low extracellular K+ concentrations (< or = 2.7 mM), accompanied by a prolongation of APD90. 8. There were no such effects at much higher K+ concentrations (> or = 5.4 mM), and the drug markedly depressed the Vmax and the action potential amplitude. 9. The drug eliminated the positive staircase phenomenon of twitch contraction, in a concentration-dependent manner. 10. All these findings taken together suggest that bepridil prolongs the action potential duration by inhibiting outward potassium currents (IK and IK1), at rapid rates of stimulation (approximately 300/min), which is comparable to the physiological heart rate of a guinea pig. 11. The prolongation of APD seemed to be secondary to the bepridil-induced reduction of intracellular Ca2+ concentration, [Ca2+]i.

Increased susceptibility to hypoxia of prolonged action potential duration in ventricular papillary muscles from diabetic rats.

The action potential duration (APD) of ventricular muscles obtained from diabetic animals is reported to be prolonged. We studied the effect of varied periods of diabetes on APD prolongation using isolated ventricular papillary muscles from streptozocin-injected rats. We found that a diabetic period greater than 30 wk was necessary for the evolution of significant prolongation of APD. We then studied the effect of repeated hypoxia (PO2 40 mmHg) and normoxia (PO2 300 mmHg) on prolonged APD of diabetic muscles and compared the findings with those from control rats. Transmembrane potentials were recorded with conventional glass microelectrodes. Under normoxic conditions, the APDs of diabetic muscles were significantly prolonged, the maximum upstroke velocity of action potentials tended to be decreased, and the resting membrane potential was not changed significantly compared with controls. The first hypoxia (20 min) shortened the APD in both diabetic and control rats but more so in diabetic rats, thereby making the APD of diabetic rats virtually identical to the control rat APD during the hypoxia. On subsequent reoxygenation (30 min), these hypoxia-induced changes were almost recovered. The second hypoxia (20 min) produced more severe shortening of the APD in both muscle types, and the effect was again far greater in diabetic rats than controls, ending with a reversed sequence of APDs and the APD of diabetic muscles much shorter than the controls. Excessive shortening of APD in diabetic muscles during hypoxic conditions was speculated to be due to greater increases in the outward K+ current through ATP-regulated K+ channels that may be secondary to the more severe reduction of intracellular ATP concentrations in diabetic versus control hearts.

Chronic diabetes mellitus prolongs action potential duration of rat ventricular muscles: circumstantial evidence for impaired Ca2+ channel.

STUDY OBJECTIVE: The aim of the study was to investigate the effects of chronic diabetes mellitus on electromechanical properties of ventricular papillary muscles. DESIGN: Conventional glass microelectrodes and tension recording techniques were used in isolated hearts of rats made diabetic for 30-40 weeks by single intravenous injections of streptozotocin. SUBJECTS: Experimental animals were male Wistar rats of 200-250 g. Diabetic rats (n = 14) were given streptozotocin 65 mg.kg-1; controls (n = 15) were given vehicle only. MEASUREMENTS AND MAIN RESULTS: (1) The maximum upstroke velocity of the action potential duration of diabetic muscles was decreased compared to control, with no difference in the resting potential. (2) At all stimulation frequencies (0.2, 1 and 5 Hz), and particularly the lower ones, the action potential duration of diabetic muscles was longer than control. (3) In diabetic muscles, frequency dependent shortening of the late phase of action potential duration (APD75, APD90) was more pronounced, and frequency dependent lengthening of the early phase (APD25, APD50) was less pronounced. (4) A blocker of transient outward current, 4-aminopyridine, lengthened the early phase of action potential durations by the same amount in diabetic and control muscles. (5) A Ca2+ channel blocker, CoCl2, dramatically shortened all levels of action potential duration, with much greater effect on diabetic muscles. (6) Ryanodine lengthened the early phase of action potential duration and shortened the late phase in both diabetic and control muscles. It enhanced the difference between the groups in the early phase. (7) Developed tension in the presence of ryanodine (ryanodine resistant tension component) was greater in diabetic muscles than in control. CONCLUSIONS: The findings suggest that altered Ca2+ current, but not altered Na(+)-Ca2+ exchange current or altered transient outward current, significantly prolongs action potential duration in diabetic rat ventricular muscles.

The making of diabetic guinea pigs by streptozotocin and high incidence of triggered activity in the ventricular muscle.

Myoplasmic Ca2+ metabolism is reported to be impaired in diabetic rat heart. We studied the possibility that the ventricular muscles of diabetic guinea pig are prone to develop delayed afterdepolarizations (DADs) and triggered activity (TA), because DADs and TA are believed to be a possible index of increased level of intracellular Ca2+ concentration. To establish an experimental diabetic model from the guinea pig, male animals were divided into four groups: 1) control group: intracardiac injection of citrate buffer; 2) IP group: intraperitoneal injection of streptozotocin (STZ, 200 mg/kg); 3) IC group: intracardiac injection of STZ; and 4) Ins-IC group: intracardiac injection of STZ after pretreatment with insulin (20 IU/kg). We found that: 1) only in the Ins-IC group was the fasting plasma glucose concentration (determined 40 days after STZ injection) significantly higher than in the control group; 2) oral glucose tolerance test performed 40 days after treatment also showed glucose intolerance in the Ins-IC group. These findings evinced the successful making of diabetic guinea pigs by an intracardiac one-shot injection of STZ during development of insulin-induced hypoglycemia. In vitro electrophysiological experiments were performed on ventricular papillary muscle from diabetic animals (Ins-IC group) by conventional glass microelectrode techniques. Transmembrane action potentials were elicited by pulse trains with various rates (2-5 Hz) and durations (10-30 stimuli) in the presence of ouabain (1 microM) and various Ca2+ concentrations (1.8-7.2 mM). The incidence of TA in the muscles from diabetic animals was significantly higher (chi 2-test, p less than 0.05) than that from controls. The findings gave evidence that Ca2+ homeostasis in the myocardium of diabetic guinea pigs is impaired, and this may be a cause of arrhythmia.

Electrophysiologic effects of a short-chain acyl carnitine, L-propionylcarnitine, on isolated canine Purkinje fibers.

The effects of L-propionylcarnitine (PC), a derivative of L-carnitine, on action potentials of canine Purkinje fibers in vitro, were studied under acidic conditions (pH 6.9), using conventional microelectrode techniques. The concentrations of 10(-5) M to 3 X 10(-3) M had no significant effect on action potential amplitude, maximal upstroke velocity of phase 0, and resting potential. However, higher concentrations of PC (10(-2) M and 3 X 10(-2) M) decreased some of these action potential parameters and such high concentrations of PC consistently prolonged the action potential duration (APD), most of which was attributed to the lengthening of phase 3. Under hypoxic conditions (PO2 less than or equal to 40 mm Hg) the drug (10(-2) M) also lengthened the APD with eventual cancellation of the hypoxia-induced shortening in the APD. The drug also prolonged the APD of slow response with a slight decrease in Vmax. In addition, PC significantly (p less than 0.05) depolarized the maximal diastolic potential of the fibers only at low [K+]o (less than or equal to 2.7 mM) and not at high [K+]o (greater than or equal to 5.4 mM). These observations suggest that the PC-induced prolongation of APD is, at least in part, due to a decrease in membrane K+ conductance, an effect partly shared with other amphiphilic intermediates of lipid metabolism, such as palmitylcarnitine or lysophosphatidylcholine.