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PubMed2002

Peroxisome proliferators compete and ameliorate Hcy-mediated endocardial endothelial cell activation.

To determine whether homocysteine (Hcy)-mediated activation of endocardial endothelial (EE) cells is ameliorated by peroxisome proliferator-activated receptor (PPAR), we isolated EE cells from mouse endocardium. Matrix metalloproteinase (MMP) activity and intercellular adhesion molecule (ICAM)-1 in EE cells were measured in the presence and absence of Hcy, and ciprofibrate (CF; PPAR-alpha agonist) or 15-deoxy-Delta(12,14)-prostaglandin J(2) (PGJ(2); PPAR-gamma agonist) by zymography and Western blot analyses, respectively. Results suggest that Hcy-mediated MMP activation and ICAM-1 expression are ameliorated by CF and PGJ(2). To test the hypothesis that Hcy competes with other ligands for binding to PPARalpha and -gamma, we prepared cardiac nuclear extracts. Extracts were loaded onto an Hcy-cellulose affinity column. Bound proteins were eluted with CF and PGJ(2). To determine conformational changes in PPAR upon binding to Hcy, we measured PPAR fluorescence at 334 nm. Dose-dependent increase in PPAR fluorescence demonstrated a primary binding affinity of 0.32 +/- 0.06 microM. There was dose-dependent quenching of PPAR fluorescence by fluorescamine-homocysteine (F-Hcy). PPAR-alpha fluorescence quenching was abrogated by the addition of CF but not by PGJ(2). PPAR-gamma fluorescence quenching was abrogated by the addition of PGJ(2) but not by CF. These results suggest that Hcy competes with CF and PGJ(2) for binding to PPAR-alpha and -gamma, respectively, indicating a role of PPAR in amelioration of Hcy-mediated EE dysfunction.

Animals↗
PubMed2002

Transmural action potential and ionic current remodeling in ventricles of failing canine hearts.

Heart failure (HF) produces important alterations in currents underlying cardiac repolarization, but the transmural distribution of such changes is unknown. We therefore recorded action potentials and ionic currents in cells isolated from the endocardium, midmyocardium, and epicardium of the left ventricle from dogs with and without tachypacing-induced HF. HF greatly increased action potential duration (APD) but attenuated APD heterogeneity in the three regions. Early afterdepolarizations (EADs) were observed in all cell types of failing hearts but not in controls. Inward rectifier K(+) current (I(K1)) was homogeneously reduced by approximately 41% (at -60 mV) in the three cell types. Transient outward K(+) current (I(to1)) was decreased by 43-45% at +30 mV, and the slow component of the delayed rectifier K(+) current (I(Ks)) was significantly downregulated by 57%, 49%, and 58%, respectively, in epicardial, midmyocardial, and endocardial cells, whereas the rapid component of the delayed rectifier K(+) current was not altered. The results indicate that HF remodels electrophysiology in all layers of the left ventricle, and the downregulation of I(K1), I(to1), and I(Ks) increases APD and favors occurrence of EADs.

Action Potentials↗
PubMed2006

A novel strategy for increasing wall thickness of coronary venules prior to retroperfusion.

The sudden exposure of veins to arterial pressures during coronary venous retroperfusion may cause rupture of small venules. Our rationale is to first occlude the coronary vein, which will cause an increase in pressure intermediate to arterial and venous values, and hence lead to remodeling and increased wall thickness of the veins prior to retroperfusion. To accomplish this objective, five pigs were subjected to left anterior descending (LAD) vein ligation while six pigs served as sham. Myocardial tissue samples were obtained from the area adjacent to the LAD vein at four transmural locations of the left ventricular free wall: epicardial surface, subepicardium, midmyocardium, and endocardium. Arterioles and venules from the experimental and sham control groups were photographed, and the following measurements were made: inner and outer circumferences, inner and outer areas, major and minor diameters, and intima-media thickness. Each vessel was categorized in four different orders according to lumen diameter. Our results show that intima-media thickness was larger in the experimental group in all four regions of the heart and in all four orders of the vessels, although venules from the epicardial region showed the largest increase in thickness. The intima-media thickness-to-radius ratio was also larger in the experimental group and decreased from epicardial to endocardial region of the heart and from order 1 to order 4 of the vessels. The present study provides a rationale for the development of coronary retroperfusion strategy that avoids vessel rupture and hemorrhage in the postcapillary venules.

Animals↗
PubMed2003

Endocardial versus epicardial electrical synchrony during LV free-wall pacing.

Cardiac resynchronization therapy has been most typically achieved by biventricular stimulation. However, left ventricular (LV) free-wall pacing appears equally effective in acute and chronic clinical studies. Recent data suggest electrical synchrony measured epicardially is not required to yield effective mechanical synchronization, whereas endocardial mapping data suggest synchrony (fusion with intrinsic conduction) is important. To better understand this disparity, we simultaneously mapped both endocardial and epicardial electrical activation during LV free-wall pacing at varying atrioventricular delays (AV delay 0-150 ms) in six normal dogs with the use of a 64-electrode LV endocardial basket and a 128-electrode epicardial sock. The transition from dyssynchronous LV-paced activation to synchronous RA-paced activation was studied by constructing activation time maps for both endo- and epicardial surfaces as a function of increasing AV delay. The AV delay at the transition from dyssynchronous to synchronous activation was defined as the transition delay (AVt). AVt was variable among experiments, in the range of 44-93 ms on the epicardium and 47-105 ms on the endocardium. Differences in endo- and epicardial AVt were smaller (-17 to +12 ms) and not significant on average (-5.0 +/- 5.2 ms). In no instance was the transition to synchrony complete on one surface without substantial concurrent transition on the other surface. We conclude that both epicardial and endocardial synchrony due to fusion of native with ventricular stimulation occur nearly concurrently. Assessment of electrical epicardial delay, as often used clinically during cardiac resynchronization therapy lead placement, should provide adequate assessment of stimulation delay for inner wall layers as well.

Animals↗
PubMed1978

Characteristics of coronary blood flow and transmural distribution in miniature pigs.

The relationship between phasic systolic and diastolic coronary blood flow and its transmural distribution has been studied in 29 Yucatan miniature pigs at rest and during heavy exercise, with and without adenosine infusion (1.5 mg . kg-1 . min-1) and with and without a subtotal coronary artery occlusion. Altered factors that affected coronary flow included vascular resistance, perfusion pressure, myocardial oxygen demand, and extra-vascular pressure. The data indicate that, at rest, endomural perfusion is significantly dependent on diastolic blood flow. However, the ability of the myocardial vessels to autoregulate during systole as well as during diastole was clearly shown with the use of adenosine infusion. This ability to regulate flow intrinsically appeared to transcend the endocardial dependency on diastolic perfusion under certain stressful conditions, e.g., during heavy exercise, when the diastolic duration was significantly reduced. Systolic transmural perfusion may then become a significant factor in meeting the blood flow demands of the myocardium. However, due to gradients in vascular resistance, perfusion pressure, and oxygen demand, the coronary reserve of the epicardium appears to be greater than that of the endocardium under any condition.

Adenosine↗
PubMed1981

Lysophosphoglycerides in ischemic myocardium effluents and potentiation of their arrhythmogenic effects.

Lysophosphoglycerides accumulate in ischemic myocardium. To determine whether lysophosphatidylcholine (LPC) concentrations increase in extracellular fluid and may be arrhythmogenic, the anterior descending coronary artery of the open-chest cat (n = 12) was perfused with a Krebs-albumin solution after 10 min of ischemia and the effluent assayed for LPC. A twofold increase in LPC (0.097 +/- 0.02 to 0.170 +/- 0.03 mM) was observed. Microelectrode intracellular recordings from from normal feline endocardium at pH 7.4 in vitro revealed little change in action potentials when superfused with feline plasma despite augmented LPC to twice normal levels (0.74 mM). However, at pH 6.7, marked changes were elicited by LPC-enriched plasma including diminished resting membrane potential (-96 +/- 1 to -35 +/- 7 mV), amplitude (102 +/- 3 to 36 +/- 8 mV), maximum rate of rise (Vmax) of phase 0 (178 +/- 24 to 26 +/- 11 V/s), and conduction velocity with fractionation of the action potential. Acidified control plasma decreased only Vmax (from 161 to 57 V/s). Thus LPC increases twofold in effluents from cat myocardium in vivo after 10 min of ischemia and, coupled with ischemia-induced acidosis, is sufficient to induce marked electrophysiological derangements in vitro.

Acidosis↗
PubMed1989

Monophasic action potential recordings in response to graded hyperkalemia in dogs.

Recent interest in sudden cardiac death during exercise in normal healthy people has highlighted the possible role of swings of extracellular potassium in arrhythmogenesis in conditions other than ischemia. Regional differences in action potential duration and conduction may be important. We have recorded monophasic action potentials (MAPs) from the endocardium and epicardium in nine open-chest dogs during graded intravenous infusion of potassium up to a plasma level of 9 mM. The animals were anesthetized with alpha-chloralose and urethan. Continuous, online arterial potassium monitoring was employed. MAP duration showed a biphasic response with initial shortening up to 7 mM, which tended to be more obvious on the epicardium. Regional activation time was measured as the difference between the onset of depolarization of the endocardial and epicardial MAP. Regional activation time also showed a biphasic response with initial shortening and subsequent delay. The QRS width of the scalar lead II electrocardiogram also showed biphasic changes, and the T wave amplitude progressively decreased. Our results suggest that regional differences in repolarization time may develop in the nonischemic myocardium in response to increased extracellular potassium levels mainly as a result of local changes in regional activation time rather than as a result of a direct effect on action potential duration.

Action Potentials↗
PubMed1990

Transmural hematocrit gradient in left ventricular myocardia of rats.

The transmural distribution of tissue hematocrit was determined in rat left ventricular myocardium. Intramyocardial distribution volumes of 99Tc-labeled red blood cells and 131I-labeled albumin were measured in hearts arrested in a relaxed state by KCl or in a contracted state by BaCl2. Hearts were frozen in situ immediately after arrest by bathing in a mixture of liquid nitrogen and isopentane. After excision of the heart, a parallelepipedic portion was cut in a transverse section of the left ventricular free wall and subjected to en face serial sectioning through the thickness of the wall from the epicardium to the endocardium. 99Tc and 131I activity allowed determination of red blood cell and plasma volume and consequently of tissue hematocrit in each section. In both the relaxed and the contracted states of the hearts, a significant decreasing gradient of tissue hematocrit was found from the outer to the inner layers of myocardium. Tissue hematocrit in the subendocardial layers was approximately 70% of its value in the subepicardial layers.

Animals↗
PubMed1991

Regional epicardial and endocardial two-dimensional finite deformations in canine left ventricle.

We evaluated subepicardial and subendocardial two-dimensional finite deformations in the left ventricular (LV) anterior, lateral, and posterior regions in the closed-chest, conscious dog heart. Eight dogs underwent placement of 22 radiopaque markers in the LV myocardium. Sets of three markers were implanted in the anterior, lateral, and posterior subepicardium and subendocardium at the mid-ventricular level; reference markers were placed at apical and basal sites. Eight hours later, biplane videofluoroscopy was performed. Finite deformations for each subepicardial and subendocardial region were analyzed during three consecutive beats at end expiration. Circumferential shortening occurred in all layers and regions; similarly, longitudinal shortening occurred in all layers except that of the posterior endocardium. Values of principal strain were -0.19 +/- 0.08 (SD) and -0.10 +/- 0.03 for the anterior subendocardium and subepicardium, -0.20 +/- 0.07 and -0.10 +/- 0.02 for the lateral subendocardium and subepicardium, and -0.13 +/- 0.02 and -0.10 +/- 0.03 for the posterior subendocardium and subepicardium respectively (P less than 0.05 subendocardium vs. subepicardium). Second principal strain tended to be near zero or positive (from -0.01 +/- 0.05 to 0.04 +/- 0.05) in all regions. The end-systolic direction of principal strain was -29 +/- 32 degrees and -34 +/- 29 degrees in the anterior subepicardium and subendocardium, -47 +/- 10 degrees and -30 +/- 37 degrees in the lateral subepicardium and subendocardium, and -4 +/- 29 degrees and +7 +/- 23 degrees in the posterior subepicardium and subendocardium. Anterior and lateral directions of principal strain were similar in the subepicardial and subendocardial layers and oriented along the epicardial fiber axis, but the posterior direction tended to be circumferentially oriented.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

The endocardial endothelium.

The heart wall with its complex trabecular structures is covered with a very thin layer of endocardial endothelial (EE) cells. EE cells appear early during cardiac development; they are involved in myocardial trabeculation and the formation of primitive nutrient vessels. This process precedes the development of coronary vessels, Purkinje fibers, and nerve fibers. EE has a different cell shape and cytoskeletal organization than vascular endothelium. The differences in permeability between EE and the coronary vascular endothelium in the subendocardial myocardium might assign characteristic electrochemical properties to the endocardium. Modulation of EE function by substances in the blood constitutes an important intracavitary autoregulation of muscle-pump performance of the heart, i.e., by altering the duration of contraction without significantly altering early contraction dynamics. Such an autoregulation resets the timing of ventricular relaxation and rapid filling with little effect on early systolic contraction and ejection. Both the release by the EE of various substances with inotropic properties and a trans-EE physicochemical control are postulated as possible underlying mechanisms.

Animals↗
PubMed1993

Effect of residual stress on transmural sarcomere length distributions in rat left ventricle.

It has been previously shown that the myocardium in the walls of the unloaded passive left ventricle (LV) is not stress free. To assess the functional significance of residual stress in the ventricular wall, we compared the transmural distributions of sarcomere length (SL) in specimens of rat LV myocardium fixed in the unloaded (residually stressed) and stress-free states. When a cross-sectional ring cut from the equatorial region of the freshly arrested rat hearts was cut radially to relieve residual stress, it sprang open into an arc with a mean opening angle of 45 +/- 15 degrees (SD) (n = 8). During immersion fixation in glutaraldehyde, the opening angle increased 9.3 +/- 7.1 degrees (SD) overall. SLs were measured at 16 equally spaced transmural locations from the free wall in the stress-free tissue sections and were compared with control measurements from adjacent cross-sectional rings in which residual stress had not been relieved. Average SL for the stress-free tissue (n = 11) was 1.84 +/- 0.05 (SD) microns and for the unloaded tissue was 1.83 +/- 0.06 (SD) microns. However, analysis of covariance on the pooled data showed that the transmural distributions were significantly different (P < 0.0001). Whereas SL was uniform across the wall in the stress-free state with a mean gradient of -0.014 +/- 0.044 (SD) microns/total wall thickness, there was a significant decrease (P = 0.001) in SL from epicardium to endocardium in the intact unloaded tissue [slope = -0.114 +/- 0.054 (SD) microns/total wall thickness].(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗
PubMed1997

Contributions of the specialized conduction system to the activation sequence in the canine pulmonary conus.

This study was designed to characterize the relative contributions of the specialized conduction system and the myocardial architecture to the ventricular activation sequence. In animal experiments, the activation sequence within a 14 x 14-mm region on each surface of the pulmonary conus from isolated canine hearts was determined from electrograms recorded during ventricular drives applied at the periphery of the measurement region. Recordings were obtained simultaneously from electrode arrays mounted on the endocardium and epicardium. Activation sequences were determined before and after the right ventricular cavity was bathed with a dilute Lugol-normal Tyrode (LNT) solution that selectively inhibited excitation of Purkinje cells. Simulations of action potential propagation in three-dimensional models (14.4 mm long x 7.2 mm wide x 3.6 mm thick) that included the major features of the midwall architecture were performed to aid in the interpretation of the experimental findings. During endocardial pacing (7 animals, 43 total drives), LNT application markedly prolonged the endocardial (13.7 +/- 1.3 ms) and epicardial (5.7 +/- 1.0 ms) activation sequences. However, epicardial isochrone maps constructed with electrograms recorded before LNT application showed no signs of multiple breakthrough sites and, with the exception of overall timing, closely resembled isochrone maps constructed with electrograms recorded after LNT application. During epicardial pacing (9 animals, 55 total drives), LNT application prolonged the endocardial (3.7 +/- 0.6 ms) and epicardial (1.9 +/- 0.6 ms) activation sequences much less dramatically than during endocardial pacing, suggesting a primary contribution of myocardial architecture. However, in those instances where nonuniform anisotropy slowed epicardial expansion of the depolarization wavefront, the specialized conduction system contributed to the activation sequence to a greater extent.

Action Potentials↗
PubMed2001

Purkinje and ventricular contributions to endocardial activation sequence in perfused rabbit right ventricle.

Interactions between peripheral conduction system and myocardial wave fronts control the ventricular endocardial activation sequence. To assess those interactions during sinus and paced ventricular beats, we recorded unipolar electrograms from 528 electrodes spaced 0.5 mm apart and placed over most of the perfused rabbit right ventricular free wall endocardium. Left ventricular contributions to electrograms were eliminated by cryoablating that tissue. Electrograms were systematically processed to identify fast (P) deflections separated by >2 ms from slow (V) deflections to measure P-V latencies. By using this criterion during sinus mapping (n = 5), we found P deflections in 22% of electrograms. They preceded V deflections at 91% of sites. Peripheral conduction system wave fronts preceded myocardial wave fronts by an overall P-V latency magnitude that measured 6.7 +/- 3.9 ms. During endocardial pacing (n = 8) at 500 ms cycle length, P deflections were identified on 15% of electrodes and preceded V deflections at only 38% of sites, and wave fronts were separated by a P-V latency magnitude of 5.6 +/- 2.3 ms. The findings were independent of apical, basal, or septal drive site. Modest changes in P-V latency accompanied cycle length accommodation to 125-ms pacing (6.8 +/- 2.6 ms), although more pronounced separation between wave fronts followed premature stimulation (11.7 +/- 10.4 ms). These results suggested peripheral conduction system and myocardial wave fronts became functionally more dissociated after premature stimulation. Furthermore, our analysis of the first ectopic beats that followed 12 of 24 premature stimuli revealed comparable separation between wave fronts (10.7 +/- 5.5 ms), suggesting the dissociation observed during the premature cycles persisted during the initiating cycles of the resulting arrhythmias.

Animals↗
PubMed1976

Technique for serial right and left ventricular endocardial biopsy in dogs.

A method is described for obtaining left and right ventricular endocardial biopsies repeatedly over a period of 3-6 mo in the dog. The left ventricular endocardial biopsy technique consists of the placement of a catheter via the venous route across the atrial septum and into the left ventricle. The biopsy catheter is in turn placed within this transseptal catheter. Tissues obtained by this method were satisfactory for both light and electron microscopic examination. At postmortem examination, only minimal and insignificant damage existed at the biopsy site. Consequently, we recommend this technique for the study of progressive pathologic changes in the endocardium that occur during the course of an experiment which can be identified and quantified in comparison to the control state.

Animals↗
PubMed2000

Light and electron microscopy of the bulbus arteriosus of the European eel (Anguilla anguilla).

The bulbus arteriosus of teleost fish acts as an elastic reservoir that dilates during ventricular systole to store a large part of the cardiac stroke volume. Despite its functional importance, the knowledge of the structure of the bulbus wall is still fragmentary. We have undertaken a series of studies in order to establish a general morphological plan of the teleost bulbus. The bulbus arteriosus of the European eel is studied here by means of conventional light, and transmission and scanning electron microscopy. The inner surface of the bulbus wall is irregular due to the presence of branching ridges that flatten and disappear toward the ventral aorta. The ridge surface is covered by flattened endocardial cells that show moderately dense bodies. In the ridge tissue, cells near the endocardium are mostly undifferentiated and appear isolated in a loose filamentous matrix. Ridge cells progressively cluster toward the middle layer, become surrounded by a dense matrix, and adopt characteristics typical of smooth muscle cells. This suggests the existence of a differentiation gradient. The middle layer is formed by typical smooth muscle cells embedded in a meshwork matrix that contains thin and thick filaments. Stretching of this meshwork suggests an active role of smooth muscle cells in bulbus wall dynamics. Furthermore, large areas of the extracellular space are occupied by elastin-like material. The amount of this material decreases toward the external layer. Collagen is demonstrated across the entire thickness of the bulbus wall, its amount and organization increasing from the inner toward the outer bulbus surface. The existence of matrix gradients should progressively increase wall strength, maintaining bulbus dilation within safe physiological parameters. The epicardium is formed by flattened cells that contain numerous pinocytotic vesicles, suggesting an active interchange of solutes with the pericardial cavity.

Anguilla↗
PubMed1984

Chronic Chagas' myocardiopathy. Demonstration of in vivo bound immunoglobulins in heart structures by the immunoperoxidase technique.

Chagas' disease (CHDis) has been described as the commonest form of chronic myocarditis. Although autoimmune phenomena involving the myocardium have been suggested in both human and experimental CHDis, no immunoperoxidase techniques have been used for the detection of immunological deposits in chronic Chagas' myocardiopathy (ChrCHM). The goal of this paper was to show that there is a coincidence between the immunoperoxidase and the immunofluorescence techniques in evidencing autologous deposits in ChrCHM. 4 patients suffering from ChrCHM were selected; their ages ranged from 39 to 52 years (means: 48.5 years). The Shültze and Caves endocavitary bioptome via the right internal jugular vein was used to obtain 3 to 4 right endomyocardial specimens measuring 1-2 mm each. Direct immunofluorescence examination, immunoperoxidase technique (PAP), and routine histological procedure were performed in all cases. Agreement between immunofluorescence and immunoperoxidase techniques was present in all chagasic specimens studied. Patients suffering from ChrCHM showed deposits of IgG, IgA, IgM, and C3 at the interstitial area, capillaries and endocardium and/or myocardial fiber surfaces when serum EVI antibody was positive. Serum EVI antibody was found to be positive in 3 out of 4 patients. The presence of the complement together with immunoglobulin may suggest an immune reaction (in vivo bound immunoglobulins in heart structures) and not just a passive deposition secondary to myocardial damage. As EVI antibody is present to a significant extent in CHDis, a reliable and simple technique like immunoperoxidase may be helpful to clarify the role of these antibodies in the pathogenesis of CHDis.

Adult↗
PubMed1992

Endomyocardial biopsies in chronic chagasic cardiomyopathy. Immunohistochemical and ultrastructural findings.

Mononuclear cellular infiltrates and extensive fibrosis, with or without apical ventricular aneurysms, are the usual morphological findings in chronic chagasic cardiomyopathy. These lesions are thought to be mediated by immune phenomena rather than by continuing parasitic invasion of the heart. In the present report, we correlated clinical, immunohistochemical and ultrastructural findings in 30 endomyocardial biopsies from patients with chronic chagasic cardiomyopathy. In 12 of these biopsies, immunocytochemical techniques were used to identify and count leukocytes (common leukocyte antigen, CLA), T lymphocytes (UCHL-1 antibody) and B lymphocytes (L-26 antibody). The biopsy specimens showed variable degrees of myocardial hypertrophy and mononuclear infiltrates. No tissue forms of trypanosomes were found. The endocardium averaged 24 +/- 12.6 microns (mean +/- SD) in thickness. The mean myocyte diameter was 20 +/- 7.33 microns. The hearts were severely fibrotic containing a mean of 24.1 +/- 12.8% of fibrous tissue (range 8.2-49%), mast cells were scarce. Mononuclear cell infiltrates were found in 25 of the 30 biopsies. In 12 biopsies, immunohistochemical studies showed that the majority of the lymphocytes were T lymphocytes and associated with necrotic or degenerating myocytes. 10 of the 12 biopsy samples showed 5 or more CLA-positive mononuclear cells/high power field. In these 10 patients, T and B lymphocytes represented 32 and 13% of the total mononuclear infiltrating cells, respectively. The remaining cells were monocytes and macrophages.

Adult↗
PubMed2002

Testosterone diminishes the proarrhythmic effects of dofetilide in normal female rabbits.

BACKGROUND: Recent clinical and experimental data suggest that testosterone may protect males against the deleterious effects of repolarization-prolonging drugs. This study tests the hypothesis that 5alpha-dihydrotestosterone (DHT) protects normal females against drug-induced excessive prolongation of repolarization. METHODS AND RESULTS: We used microelectrode techniques to study isolated preparations of rabbit ventricular endocardium from age-matched normal control female rabbits and female rabbits treated with DHT for 4 weeks. Serum 17beta-estradiol levels were identical in the control and DHT-treated animals, whereas DHT levels were high (equaling those in normal males) only in the DHT-treated animals. Basal action potential duration to 90% repolarization (APD90) was significantly shorter in DHT-treated (155+/-7.4 ms, n=32) than control females (178+/-6.7 ms, n=29; P<0.05) at cycle length=1000 ms. The increase in APD90 induced by 10(-8) mol/L dofetilide at cycle length=1000 ms was significantly less in DHT-treated females than normal females (DeltaAPD90=8+/-7 and 29+/-5 ms, respectively, P<0.05). At 10(-6) mol/L dofetilide, the incidence of early afterdepolarizations was 28% in DHT-treated and 55% in normal female rabbits (P<0.05). CONCLUSIONS: Elevating DHT levels diminishes the effects of dofetilide to increase APD and induce early afterdepolarizations in females. Moreover, treatment of females with DHT results in prolongation of APD and an incidence of early afterdepolarization equal to values previously reported by us for dofetilide-treated normal males. That serum levels of 17beta-estradiol were the same in DHT-treated and untreated females suggests that estradiol is not involved in the response to dofetilide. Thus, these data suggest that DHT and perhaps other androgenic hormones may protect normal females against the risk of dofetilide-induced arrhythmia.

Action Potentials↗