Imbalance of the autonomic nervous system at night in women with gestational diabetes.

AIMS: Autonomic nervous system dysfunction is observed in Type 2 diabetes. As gestational diabetes is a potent risk factor of later Type 2 diabetes, we set out to determine whether autonomic nervous system imbalance could already be observed in women with this condition. Because activity of the sympathetic nervous system tends to be relatively stable in the nocturnal hours, we performed the study at night. RESEARCH DESIGN AND METHODS: We studied 41 women with gestational diabetes, 22 healthy pregnant controls and 14 non-pregnant controls. We assayed plasma noradrenaline at 24.00, 04.00 and 07.00 h and performed an overnight Holter recording for heart rate variability analysis. In addition, we assayed plasma adrenomedullin, a cardiovascular protective hormone. RESULTS: Compared with non-pregnant controls, plasma noradrenaline levels were increased at 04.00 and 07.00 h in the gestational diabetic (P = 0.003) and pregnant control (P = 0.002) groups, with no difference between them. Heart rate variability, very-low-frequency and low-frequency power were lower in pregnant groups compared to the non-pregnant controls. Heart rate variability remained unchanged between specified sampling times in the gestational diabetic group, in contrast to fluctuation seen in the control groups. CONCLUSIONS: Gestational diabetes, compared with normal pregnancy, seems not to be a state of overall sympathetic nervous system activation. At the heart level, however, an inhibitory effect on autonomic nervous system modulation was seen. Plasma noradrenaline and heart rate variability correlated well, supporting the use of this function in future studies of overall sympathetic activity during pregnancy.

Common candidate gene variants are associated with QT interval duration in the general population.

OBJECTIVES: QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30-40% of the QT-interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population-based sample. METHODS: We genotyped 12 common LQTS and NOS1AP genetic variants in Health 2000, an epidemiological sample of 5043 Finnish individuals, using Sequenom MALDI-TOF mass spectrometry. ECG parameters were measured from digital 12-lead ECGs and QT intervals were adjusted for age, gender and heart rate with a nomogram (Nc) method derived from the present study population. RESULTS: The KCNE1 D85N minor allele (frequency 1.4%) was associated with a 10.5 ms (SE 1.6) or 0.57 SD prolongation of the adjusted QT(Nc) interval (P=3.6 x 10(-11)) in gender-pooled analysis. In agreement with previous studies, we replicated the association with QT(Nc) interval with minor alleles of KCNH2 intronic SNP rs3807375 [1.6 ms (SE 0.4) or 0.08 SD, P=4.7 x 10(-5)], KCNH2 K897T [-2.6 ms (SE 0.5) or -0.14 SD, P=2.1 x 10(-7)] and NOSA1P variants including rs2880058 [4.0 ms (SE 0.4) or 0.22 SD, P=3.2 x 10(-24)] under additive models. CONCLUSIONS: We demonstrate that each additional copy of the KCNE1 D85N minor allele is associated with a considerable 10.5 ms prolongation of the age-, gender- and heart rate-adjusted QT interval and could thus modulate repolarization-related arrhythmia susceptibility at the population level. In addition, we robustly confirm the previous findings that three independent KCNH2 and NOSA1P variants are associated with adjusted QT interval.

Prevalence and prognostic significance of short QT interval in a middle-aged Finnish population.

BACKGROUND: Short-QT syndrome is an inherited disorder characterized by a short QT interval and an increased risk of sudden cardiac death. The clinical significance of a short QT interval observed in a randomly recorded ECG is not known. Therefore, we assessed the prevalence and prognostic significance of a short QT interval in a general population. METHODS AND RESULTS: QT intervals were measured from the 12-lead ECGs of 10 822 randomly selected middle-aged subjects (5658 males, mean age 44+/-8.4 years) enrolled in a population study and followed up for 29+/-10 years. The end points were all-cause and cardiovascular mortality. In addition to Bazett's method (corrected QT interval, or QTc), the Fridericia (QTfc) and nomogram (QTnc) methods were used to correct the QT interval for heart rate. The cutoff values for short QT intervals were defined as 320 ms (very short) and 340 ms (short). The prevalence of QT interval <320 ms based on QTc, QTfc, and QTnc was 0.10%, 0.08%, and 0.06%, and the prevalence of QT interval <340 ms was 0.4%, 0.3%, and 0.3%, respectively. The majority of subjects with short QT intervals were males. All-cause or cardiovascular mortality did not differ between subjects with a very short or short QT interval and those with normal QT intervals (360 to 450 ms). There were no sudden cardiac deaths, aborted sudden cardiac deaths, or documented ventricular tachyarrhythmias among subjects with a QTfc <340 ms. CONCLUSIONS: A short QT interval does not appear to indicate an increased risk for all-cause or cardiovascular mortality in middle-aged nonreferral, community-based individuals.

Electrocardiographic assessment of left ventricular hypertrophy with time-voltage QRS and QRST-wave areas.

The sum of time-voltage QRS areas in the 12-lead electrocardiogram (ECG) has outperformed other 12-lead ECG indices for detection of left ventricular hypertrophy (LVH). We assessed indices of time-voltage QRS and T-wave (QRST) areas from body surface potential mapping (BSPM) for detection of and quantitation of the degree of LVH. We studied 42 patients with echocardiographic LVH (LVH group) and 11 healthy controls (controls). QRST area sums were calculated from 123-lead BSPM and from the 12-lead ECG for comparison. Leadwise discriminant indices and correlation coefficients were used to identify optimal recording locations for QRST area-based LVH assessment. BSPM QRS area sum was greater in the LVH group than in controls (3752 +/- 1259 vs 2278 +/- 627 microV s, respectively; P<0.001) and at 91% specificity showed 74% sensitivity for LVH detection. The 12-lead QRS area sum performed similarly. Taking T-wave areas into account did not improve the results. QRS area sum from two most informative leads (located in the upper and lower right precordium) also separated the LVH group from controls (61.1 +/- 23.5 vs 27.8 +/- 6.5 microV s, respectively; P<0.00001). This 2-lead QRS area sum showed 90% sensitivity with 100% specificity for LVH detection and maintained high correlation to indexed left ventricular mass (r=0.732; P<0.001). In conclusion, the BSPM QRS area sum compared to 12-lead QRS area sum does not substantially improve LVH assessment. The 2-lead QRS area sum may improve ECG QRS area-based LVH assessment.

Anabolic androgenic steroids produce dose-dependant increase in left ventricular mass in power atheletes, and this effect is potentiated by concomitant use of growth hormone.

Power athletes abuse anabolic androgenic steroids (AASs) and growth hormone (GH) to gain their muscular mass and strength. We wanted to determine how massive, self-administered doses of AASs with or without GH affect the left ventricular (LV) dimensions in power athletes. These substances are assumed to increase LVmass mainly by thickening the ventricular walls. Anecdotal evidence suggests a higher risk of cardiovascular events in AAS abusers. We were interested to see if LV dimensions and function in AAS abusers would indicate this increased risk. Twenty healthy male power athletes using massive doses of AAS without (n = 16) or with (n = 4) GH volunteered for the study. The controls were 15 sedentary male non-users of hormones. LV mass, geometry and filling were studied using standard echocardiographic methods. We found a significant association between LV mass and AAS dose (r = 0.54, p < 0.015). In contrast to the controls, LV mass (274 g in the athletes, 167 g in the controls) among the AAS abusers did not correlate with body weight or height. Concomitant use of AAS and GH further increased LV mass and associated with concentric remodelling of LV. Multiple regression analysis indicated that the mean AAS dose accounted for 29 %, age for 14 % and systolic blood pressure for 17 % of the variance in LV mass. We concluded that AAS abuse associates dose-dependently with myocardial hypertrophy and that concomitant use of GH associates with concentric remodelling of the LV. Our findings suggest that AASs and GH have a direct effect on the myocardium.

Postmyocardial infarction patients susceptible to ventricular tachycardia show increased T wave dispersion independent of delayed ventricular conduction.

INTRODUCTION: Experimentally, both delayed ventricular conduction and nonhomogeneous ventricular repolarization contribute to reentrant arrhythmias. We tested the hypothesis that increased T wave dispersion is independent of delayed ventricular conduction associated with arrhythmia vulnerability in postmyocardial infarction (post-MI) patients. METHODS AND RESULTS: We studied 32 post-MI patients with clinical or inducible monomorphic ventricular tachycardia (VT group), 28 post-MI patients without arrhythmias (MI group), and 13 healthy controls, using magnetocardiographic (MCG) mapping with signal averaging. Twelve-lead ECG was the reference. Filtered QRS duration (fQRS) and T wave peak to T wave end interval (TPE) were used as measures of ventricular conduction and nonhomogeneity in ventricular repolarization, respectively. In MCG, the VT group showed the longest fQRS (135+/-34 msec vs 114+/-22 msec in the MI group; P = 0.012). Mean TPE and maximum TPE in VT versus MI groups were 78+/-9 msec versus 70+/-6 msec (P < 0.001) and 117+/-23 msec versus 104+/-19 msec (P = 0.020), respectively. Maximum TPE did not correlate with fQRS in the VT group (r = 0.063; P = NS) but did correlate in the MI group (r = 0.396; P = 0.037). For identification of post-MI patients prone to VT, selection of cutoff values for fQRS >140 msec and mean TPE >81 msec gave sensitivity and specificity of 41% and 89%, and 31% and 96%, respectively. Their combination increased sensitivity to 63% while maintaining 89% specificity. CONCLUSION: Post-MI patients susceptible to VT show increased T wave dispersion independent of delayed ventricular conduction.

Relation of QT interval and QT dispersion to echocardiographic left ventricular hypertrophy and geometric pattern in hypertensive patients. The LIFE study. The Losartan Intervention For Endpoint Reduction.

OBJECTIVE: In hypertensive patients, left ventricular hypertrophy (LVH) predicts increased mortality, in part due to an increased incidence of sudden death. Repolarization-related arrhythmogenesis may be an important mechanism of sudden death in hypertensive patients with LVH. Increased QT interval and QT dispersion are electrocardiographic (ECG) measures of ventricular repolarization, and also risk markers for ventricular tachyarrhythmias. We assessed the relation of QT intervals and QT dispersion to echocardiographically determined left ventricular (LV) mass and geometry in a large population of hypertensive patients with ECG evidence of LVH. METHODS: QT intervals and QT dispersion were determined from baseline 12-lead ECGs in 577 (57% male; mean age 65 +/- 7 years) participants in the LIFE study. LV mass index (LVMI) and geometric pattern were determined by echocardiography and QT interval duration and QT dispersion were assessed in relation to gender-specific LVMI quartiles. RESULTS: In both genders, increasing LVMI was associated with longer rate-adjusted QT intervals. QT dispersion measures showed a weaker association with LVMI quartiles. Both concentric and eccentric LVH were associated with increased QT interval duration and QT dispersion. These relations remained significant after controlling for relevant clinical variables. CONCLUSIONS: In hypertensive patients with ECG evidence of LVH, increased LVMI and LVH are associated with a prolonged QT interval and increased QT dispersion. These findings suggest that an increased vulnerability to repolarization-related ventricular arrhythmias might in part explain the increased risk of sudden death in hypertensive patients with increased LV mass.

Relationship of the electrocardiographic strain pattern to left ventricular structure and function in hypertensive patients: the LIFE study. Losartan Intervention For End point.

OBJECTIVES: This study was designed to assess the relation of electrocardiographic (ECG) strain to increased left ventricular (LV) mass, independent of its relation to coronary heart disease (CHD). BACKGROUND: The classic ECG strain pattern, ST depression and T-wave inversion, is a marker for left ventricular hypertrophy (LVH) and adverse prognosis. However, the independence of the relation of strain to increased LV mass from its relation to CHD has not been extensively examined. METHODS: Electrocardiograms and echocardiograms were examined at study baseline in 886 hypertensive patients with ECG LVH by Cornell voltage-duration product and/or Sokolow-Lyon voltage enrolled in the Losartan Intervention For End point (LIFE) echocardiographic substudy. Strain was defined as a downsloping convex ST segment with inverted asymmetrical T-wave opposite to the QRS axis in leads V5 and/or V6. RESULTS: Strain occurred in 15% of patients, more commonly in patients with than without evident CHD (29%, 51/175 vs. 11%, 81/711, p < 0.001). When differences in gender, race, diabetes, systolic pressure, serum creatinine and high density lipoprotein cholesterol were controlled, strain on baseline ECG was associated with greater indexed LV mass in patients with (152 +/- 33 vs. 131 +/- 32 g/m2, p < 0.001) or without CHD (131 +/- 24 vs. 119 +/- 22 g/m2, p < 0.001). In logistic regression analyses, strain was associated with an increased risk of anatomic LVH in patients with CHD (relative risk 5.14, 95% confidence interval [CI] 1.16 to 22.85, p = 0.0315), without evident CHD (relative risk 2.91, 95% CI 1.50 to 5.65, p = 0.0016), and in the overall population when CHD was taken into account (relative risk 2.98, 95% CI 1.65 to 5.38, p = 0.0003). CONCLUSIONS: When clinical evidence of CHD is accounted for, ECG strain is likely to indicate the presence of anatomic LVH. Greater LV mass and higher prevalence of LVH in patients with strain offer insights into the known association of the strain pattern with adverse outcomes.

Effect of light on the feeding rates of pelagic and littoral mysid shrimps: a trade-off between feeding success and predation avoidance.

It has been shown that freshwater pelagic mysid shrimps capture zooplankton at a higher rate in light than in darkness. This has been suggested to be due to facilitation of visual predation on evasive zooplankton prey. To test this hypothesis with Baltic mysid shrimps, and to see whether pelagic (migrating) and littoral (non-migrating) mysids differ in this respect, we compared the feeding rates of Mysis mixta and Praunus flexuosus on the copepod Acartia spp. As light conditions change radically from the beginning of summer to late autumn at the Baltic latitudes, we conducted the experiments during three different times of the year to determine if there was a seasonal response to light in mysids. The feeding rates of pelagic mysids were significantly higher in total darkness than in light. In contrast, the feeding rates of littoral mysids did not differ in the dark and the light in the three different seasons. The decreased feeding of pelagic mysids under well-lit conditions may be an adaptation to avoid visual predation by pelagic fish. In contrast, littoral mysids, which live in the well-lit layer throughout the day, do not show a similar response. The fact that light did not increase feeding in either of the mysid species indicates that these mysid species do not use vision in capturing prey, but rely mainly on mechano-reception.

Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome.

OBJECTIVE: To study and compare the effects of mental and physical stress on long QT syndrome (LQTS) patients. DESIGN: Case-control study. MAIN OUTCOME MEASURES: QT intervals were measured from lead V3. Serum potassium and plasma catecholamine concentrations were also monitored. PATIENTS: 16 patients with type 1 LQTS (LQT1), 14 with type 2 LQTS (LQT2), both groups asymptomatic, and 14 healthy control subjects. INTERVENTIONS: Three types of mental stress tests and a submaximal exercise stress test. RESULTS: Heart rate responses to mental stress and exercise were similar in all groups. During mental stress, the mean QT interval shortened to a similar extent in controls (-29 ms), LQT1 patients (-34 ms), and LQT2 patients (-30 ms). During exercise, the corresponding QT adaptation to exercise stress was more pronounced (p < 0.01) in healthy controls (-47 ms) than in LQT1 (-38 ms) or LQT2 patients (-38 ms). During exercise changes in serum potassium concentrations were correlated to changes in QT intervals in controls, but not in LQTS patients. LQT1 and LQT2 patients did not differ in serum potassium, catecholamine or heart rate responses to mental or physical stress. CONCLUSIONS: QT adaptation to mental and exercise stress in healthy people and in patients with LQTS is different. In healthy people QT adaptation is more sensitive to physical than to mental stress while no such diverging pattern was seen in asymptomatic LQTS patients.

Effects of toxic and non-toxic cyanobacteria on grazing, zooplanktivory and survival of the mysid shrimp Mysis mixta.

We measured the effect of toxic and non-toxic cyanobacteria strains on grazing, predation rates and survival of the mysid shrimp Mysis mixta by means of laboratory experiments. Juvenile and adult M. mixta fed most actively on the non-toxic strains Aphanizomenon flos-aquae and Nodularia sphaerocarpa as on high quality food, the green flagellate Brachiomonas submarina, whereas grazing on the toxic N. spumigena was significantly lower than on the other strains. The mysids showed normal functional responses; decreasing clearance rates at increasing concentrations of cyanobacteria. In a separate predation experiment, the feeding rates on copepods declined in the presence of aggregated non-toxic cyanobacteria. However, we could not demonstrate increased mortality in a 7-week experiment where mysids were exposed to high concentrations of toxic N. spumigena

Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia.

BACKGROUND: Familial polymorphic ventricular tachycardia is an autosomal-dominant, inherited disease with a relatively early onset and a mortality rate of approximately 30% by the age of 30 years. Phenotypically, it is characterized by salvoes of bidirectional and polymorphic ventricular tachycardias in response to vigorous exercise, with no structural evidence of myocardial disease. We previously mapped the causative gene to chromosome 1q42-q43. In the present study, we demonstrate that patients with familial polymorphic ventricular tachycardia have missense mutations in the cardiac sarcoplasmic reticulum calcium release channel (ryanodine receptor type 2 [RyR2]). METHODS AND RESULTS: In 3 large families studied, 3 different RyR2 mutations (P2328S, Q4201R, V4653F) were detected and shown to fully cosegregate with the characteristic arrhythmic phenotype. These mutations were absent in the nonaffected family members and in 100 healthy controls. In addition to identifying 3 causative mutations, we identified a number of single nucleotide polymorphisms that span the genomic structure of RyR2 and will be useful for candidate-based association studies for other arrhythmic disorders. CONCLUSIONS: Our data illustrate that mutations of the RyR2 gene cause at least one variety of inherited polymorphic tachycardia. These findings define a new entity of disorders of myocardial calcium signaling.

A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics.

OBJECTIVES: We took advantage of the genetic isolate of Finns to characterize a common long QT syndrome (LQTS) mutation, and to estimate the prevalence of LQTS. BACKGROUND: The LQTS is caused by mutations in different ion channel genes, which vary in their molecular nature from family to family. METHODS: The potassium channel gene KCNQ1 was sequenced in two unrelated Finnish patients with Jervell and Lange-Nielsen syndrome (JLNS), followed by genotyping of 114 LQTS probands and their available family members. The functional properties of the mutation were studied using a whole-cell patch-damp technique. RESULTS: We identified a novel missense mutation (G589D or KCNQ1-Fin) in the C-terminus of the KCNQ1 subunit. The voltage threshold of activation for the KCNQ1-Fin channel was markedly increased compared to the wild-type channel. This mutation was present in homozygous form in two siblings with JLNS, and in heterozygous form in 34 of 114 probands with Romano-Ward syndrome (RWS) and 282 family members. The mean (+/- SD) rate-corrected QT intervals of the heterozygous subjects (n = 316) and noncarriers (n = 423) were 460 +/- 40 ms and 410 +/- 20 ms (p < 0.001), respectively. CONCLUSIONS: A single missense mutation of the KCNQ1 gene accounts for 30% of Finnish cases with LQTS, and it may be associated with both the RWS and JLNS phenotypes of the syndrome. The relative enrichment of this mutation most likely represents a founder gene effect. These circumstances provide an excellent opportunity to examine how genetic and nongenetic factors modify the LQTS phenotype.

Magnetocardiographic QT dispersion during cardiovascular autonomic function tests.

QT dispersion is considered to reflect nonhomogeneity of ventricular repolarization. The autonomic nervous system modulates QT interval duration, but the effect may not be spatially homogenous. Magnetocardiography (MCG) registers the weak magnetic fields generated by myocardial electric currents with high localizing accuracy. We studied the effects of rapid cardiovascular autonomic nervous adjustment on QT dispersion in MCG. Ten healthy male volunteers were monitored during deep breathing, the Valsalva maneuver, sustained handgrip, hyperventilation, the cold pressor test and mental stress. 67 MCG channels and 12 ECG leads were recorded simultaneously. A computer algorithm was used for QT interval measurements. QT dispersion was defined as maximum - minimum or standard deviation of the QTpeak and QTend intervals. In MCG the QT(end) dispersion increased during deep inspiration compared with deep expiration (96+/-19 ms v. 73+/-27 ms, p = 0.05). Magnetic QT dispersion tended to increase during the bradycardia phase of the Valsalva maneuver, but the change was obvious only for QT(end) (55+/-26 ms v. 76+/-29 ms, p<0.05). Other tests had no significant effect on QT dispersion, not even the cold pressor test, although it causes strong sympathetic activation. Magnetic and electric QT(peak) and QT(end) intervals correlated closely (r = 0.93 and 0.91), whereas the QT dispersion measures showed no correlation. In conclusion, magnetic QT dispersion is not modified by rapid changes in autonomic tone, but maneuvers involving deep respiratory efforts and changes in ventricular loading affect QT dispersion measurements.

Effects of cardiovascular autonomic function tests on QT dispersion in the 12-lead electrocardiogram of healthy patients.

Changes in autonomic tone modulate QT interval duration. How cardiovascular autonomic reflexes affect QT dispersion, a suggested marker of arrhythmia risk, is not well established. We studied 10 healthy young adult volunteer men during quiet and deep breathing, the Valsalva maneuver, sustained handgrip, hyperventilation, the cold pressor test, and mental stress. An automated method was used for measurement of QT-peak and QT-end intervals, and QT dispersion was defined as maximum-minimum of the measured intervals. QT-peak dispersion was greater on deep expiration than deep inspiration (49 +/- 20 ms vs 37 +/- 14 ms, P < .05). QT-end dispersion decreased in the tachycardia phase of the Valsalva maneuver (45 +/- 23 ms vs 35 +/- 21 ms, P < .05), but QT dispersion did not change during the other interventions. Rapid cardiovascular autonomic reflex adjustment does not change QT dispersion in healthy young adult men. However, large intrathoracic volume and intrathoracic pressure changes during forced respiratory movements might confound QT dispersion measurements.

Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects.

Analysis of the entire coding region of the HERG gene of 39 Finnish LQTS patients revealed eight mutations, six of which are hitherto unreported. All these mutations are located in the evolutionarily conserved regions of HERG, including the transmembrane domains (P451L, Y569H, 1631delAG, G584S, G601S, T613M) and the cytoplasmic N-terminus (453delC, R176W) of the channel. Our present and earlier results suggest that the LQT2 subtype accounts for approximately 20-30% of LQTS cases in Finland. We also report the first common amino acid polymorphism (K897T) of the HERG channel, with allele frequencies of 0.84 and 0.16. Investigation of 170 genetically homogenous LQT1 patients suggests that this polymorphism may influence QT interval in female individuals.

Homozygosity for a HERG potassium channel mutation causes a severe form of long QT syndrome: identification of an apparent founder mutation in the Finns.

OBJECTIVES: We studied the clinical characteristics and molecular background underlying a severe phenotype of long QT syndrome (LQTS). BACKGROUND: Mutations of cardiac ion channel genes cause LQTS, manifesting as increased risk of ventricular tachycardia and sudden death. METHODS: We studied two siblings showing prolonged QT intervals corrected for heart rate (QTc), their asymptomatic parents with only marginally prolonged QTc intervals and their family members. The potassium channel gene HERG was screened for mutations by deoxyribonucleic acid sequencing, and the electrophysiologic consequences of the mutation were studied in vitro using the whole-cell patch-clamp technique. RESULTS: A novel missense mutation (L552S) in the HERG channel, present in the homozygous state in the affected siblings and in the heterozygous state in their parents, as well as in 38 additional subjects from six LQTS families, was identified. One of the homozygous siblings had 2:1 atrioventricular block immediately after birth, and died at the age of four years after experiencing unexplained hypoglycemia. The other sibling had an episode of torsade de pointes at the age of two years. The mean QTc interval differed significantly (p < 0.001) between heterozygous symptomatic mutation carriers (500 +/- 59 ms), asymptomatic mutation carriers (452 +/- 34 ms) and noncarriers (412 +/- 23 ms). When expressed in vitro, the HERG-L552S formed functional channels with increased activation and deactivation rates. CONCLUSIONS: Our data demonstrate that homozygosity for a HERG mutation can cause a severe cardiac repolarization disorder without other phenotypic abnormalities. Absence of functional HERG channels appears to be one cause for intrauterine and neonatal bradycardia and 2:1 atrioventricular block.