Comparison of ECG variables of dispersion of ventricular repolarization with direct myocardial repolarization measurements in the human heart

INTRODUCTION: QT dispersion (QTD) from the 12-lead ECG has been widely adopted as a noninvasive index of dispersion of ventricular repolarization (DVR). QTD, however, has never been validated by direct comparison with myocardial DVR in the human heart. METHODS AND RESULTS: Monophasic action potential (MAP) recordings obtained in an earlier study were retrospectively matched with 12-lead ECGs available from within 24 hours of the invasive procedure. MAPs were available from an average of 8+/-3 left endocardial sites in 4 patients with left ventricular hypertrophy (LVH) and 7 patients with normal ECGs, and 6+/-2 epicardial sites in 3 patients of each group during normal ventricular activation. Local repolarization time (RT) was determined as MAP duration at 90% repolarization plus the local activation time. Dispersion of RT was calculated as the difference between the earliest and latest RT. ECGs were digitized and analyzed with recently described interactive QTD analysis software. In addition to standard QTD (defined as QTmax-QTmin), all currently proposed ECG dispersion variables were compared and correlated with the invasive measurements of DVR. QTD exhibited a reasonable correlation with dispersion of RT (R = 0.67; P < 0.01). Several other variables designed to measure DVR exhibited a similar, but not better, correlation. Among them, the QT peak/QT end ratio in V3 (R = -0.72; P < 0.01) and averaged over all analyzable leads (R = -0.59; P < 0.01) exhibited a good correlation with dispersion of RT, which was further improved when endocardial measurements were considered alone. T area measures did not correlate with dispersion of RT, but discriminated LVH. CONCLUSION: DVR can be assessed by means of a 12-lead surface ECG. Several of the variables under study exhibit a similar accuracy in determination of true myocardial dispersion of repolarization. Variables involving the terminal part of repolarization, such as the QT peak/QT ratio, even from a single lead, may add to the determination of DVR from the human heart.     

Amiodarone in congestive heart failure

Originally developed as an antianginal agent, amiodarone was soon found to have antiarrhythmic properties and to be a non-competitive inhibitor of alpha and beta-adrenergic receptors. Many trials studying the use of amiodarone in patients with heart failure have now been performed and are reviewed in this article. The trials appear to show that amiodarone possesses significant antiarrhythmic activity, even in heart failure patients. The drug appears to be well tolerated and proarrhythmia is uncommon. Based on the findings of a large Argentinian randomised trial (GESICA) and the Congestive Heart Failure Survival Trial of Antiarrhythmic Therapy (CHF STAT), it would appear there is a role for amiodarone in patients with non-ischaemic cardiomyopathy, but prospective studies are required to confirm this. The benefit of amiodarone in patients with non-ischaemic cardiomyopathy might be related to the beta-blocking effect that is seen with the use of conventional beta-blockers. Further studies, including the Sudden Cardiac Death Heart Trial (SCD HeFT), should help determine the role of amiodarone in heart failure patients.     

Modulation of atrial repolarization by site of pacing in the isolated rabbit heart

BACKGROUND: Single-site or multisite atrial pacing may reduce the incidence of atrial fibrillation in humans. The therapeutic mechanisms may include synchronization of atrial repolarization (repolarization "memory") and/or decreased dispersion of atrial repolarization. These responses have not been well documented in intact atria. METHODS AND RESULTS: Monophasic action potential recordings were made from six atrial epicardial sites in 39 isolated perfused rabbit heart preparations during 3 hours of continuous right atrial, left atrial, or biatrial pacing. Action potential recordings obtained at times 0, 45, 90, 135, and 180 minutes were computer analyzed for activation time (AT) and 90% action potential duration (APD) at each site. No consistent relationship could be demonstrated between APD and AT at any time during atrial pacing (all P > .05). On average, left atrial APDs were longer than right atrial APDs by up to 6.3 ms at all times, regardless of the site of pacing (P < or = .05). At all times, dispersion of atrial repolarization was minimized by left atrial pacing compared with right atrial pacing (21.6 +/- 9.1 versus 32.4 +/- 15.1 ms, respectively, at time 0; P < .05). Biatrial pacing provided no further reduction in dispersion of repolarization compared with left atrial pacing (all P > .05). CONCLUSIONS: No relationship can be demonstrated between atrial AT and APD in the isolated rabbit heart preparation. This differs from ventricular repolarization "memory," which is demonstrable under the same conditions. Left atrial APD is, on average, longer than right atrial APD, suggesting spatial heterogeneity in repolarization. Dispersion of atrial repolarization is minimized by left atrial pacing in this preparation with no further advantage to biatrial pacing.     

Autoradiographic assessment of blood flow heterogeneity in the hamster heart

OBJECTIVE: Provide regional flow measurement in the hearts of small mammals using a new, higher-resolution technique based on the deposition of a molecular marker. METHODS: We determined the instantaneous extraction and retention of the "molecular microsphere" radiolabeled desmethylimipramine in retrogradely perfused hamster hearts. In a separate series of experiments, autoradiography was used to measure regional myocardial deposition densities in hamster hearts of about 0.5 g with spatial area resolution of 16 x 16 microns. RESULTS: Radiolabeled desmethylimipramine is almost 100% extracted during a single transcapillary passage and is retained in the tissue for many minutes. Autoradiographic images demonstrated a spatial flow heterogeneity with standard deviations of 31 +/- 4% of the mean flow (N = 5) in 16 x 16 x 20-micronm3 voxels. This is equivalent to the projections made using fractal relationships from cruder observations obtained with microspheres in the hearts of baboons, sheep, and rabbits. CONCLUSIONS: Autoradiography using a molecular deposition marker provides quantitative information on myocardial flow heterogeneities with resolution at the size of cardiac myocytes. Because the regions resolved are smaller than the volume of regions supplied by single arterioles, the results must slightly exaggerate the true heterogeneity of regional flows.     

Amiodarone causes endothelium-dependent vasodilation in human hand veins in vivo

OBJECTIVE: Amiodarone, a class III antiarrhythmic agent, is a potent coronary vasodilator. However, direct evidence for its vasodilatory effects in human vasculature in vivo is not available. The aim of the study was to investigate the short-term effects of amiodarone in preconstricted human hand veins and to explore the underlying mechanisms. METHODS: Thirty-one healthy male volunteers were studied with the use of the dorsal hand vein compliance technique. The hand veins of the subjects were preconstricted with the alpha 1-adrenergic receptor agonist phenylephrine, and amiodarone, inhibitors of nitric oxide formation (NG-monomethyl-L-arginine, L-NMMA), and adenosine triphosphate-dependent potassium channels (glyburide [INN, glibenclamide]) were infused in the presence or absence of a cyclooxygenase inhibitor (acetylsalicylic acid), and the venodilator effect was measured. Furthermore, amiodarone was infused in prostaglandin F2 alpha (dinoprost)-preconstricted hand veins. RESULTS: Amiodarone produced dose-dependent venodilation (51% +/- 3% maximum). Maximum amiodarone-induced venodilation was lower in dinoprost compared with phenylephrine-preconstricted veins. Pretreatment with acetylsalicylic acid reduced the amiodarone-induced venodilation by 40% +/- 6%. L-NMMA reduced the amiodarone-induced venodilation after pretreatment with acetylsalicylic acid by 72% +/- 3%. Glyburide decreased the venodilatory response of amiodarone by 31% +/- 11%, whereas only a slight but not statistically significant additional reduction in venodilation was detected after pretreatment with acetylsalicylic acid. Infusion of the solvents of commercially available amiodarone (polysorbate 80 and benzyl alcohol) did not cause vasodilation in phenylephrine-preconstricted veins. CONCLUSIONS: Amiodarone dilates preconstricted human hand veins in vivo and acts as a venodilator through the cyclooxygenase pathway, activation of nitric oxide synthase, and blockade of alpha adrenergic mechanisms.     

Distribution and heterogeneity of mast cells in the human uterus

Mast cells (MCs) are widely distributed in most human tissues. Those cells that contain only tryptase are designated as T-MCs, while those that also contain chymase are referred to as TC-MCs. This study uses immunohistochemical staining for tryptase and chymase to assess the distribution and heterogeneity of these two types of MCs in the human uterus. The greatest number of MCs was found in the inner (i.e. luminal) half of the myometrium, with this area containing approximately equal proportions of T-MCs and TC-MCs. There were fewer MCs in the outer half of the myometrium and the cervix, but the proportion of TC-MCs in both of these areas was substantially higher. In contrast, the endometrium contained significantly fewer MCs, but proportionally more T-MCs. There was no change in the number of MCs between the proliferative and secretory phases of the menstrual cycle; however, there was a significantly lower number in all areas after menopause. Most of the MCs were observed in close association with uterine smooth muscle cells, as well as in the vicinity of fibroblasts and collagen, and it appears they may play an important role in the reconstruction of uterine tissues during the menstrual cycle.     

Nature of the molecular heterogeneity of human leukocyte interferon

The existence of two components of human leukocyte interferon has been recently reported. In the present study, the nature of this molecular heterogeneity was explored by affinity chromatography on immobilized micro- and macroligands, ion-exchange chromatography, and molecular sieving. Chromatography on a series of alkyl-agarose adsorbents shows, for the first time, the intrinsic hydrophobicity of human leukocyte interferon. Additionally, the separation of two interferon components is achieved by use of the alkyl-agarose as well as by the omega-aminoalkyl-agarose adsorbents. Clear-cut separation of the two components was also achieved by chromatography on BSA-CH-Sepharose and on DEAE-Bio Gel A. An important feature of these separations is that they do not require the use of denaturing conditions. The molecular weights of the leukocyte interferon components, as determined on Sephadex G-75, are quite similar or identical, approximately 26,000. Thus, the molecular heterogeneity of human leukocyte interferon can be attributed, at least in part, to differences in the hydrophobicity and ionic properties of its two components.     

Genetic heterogeneity of ischemic (coronary) heart disease

Results are presented on a study of the blood coagulation system and some indices of serum lipids and proteins in 133 normal individuals and probands with ischaemic heart disease and their 681 relatives. The examination of the relatives of probands with different types of biochemical disorders revealed a similar biochemical background in the probands and the members of their families. The disorders in blood biochemistry in the probands were most similar in the parents, the children of the probands' siblings, and less distinct in more distant relatives (cousins, nephews and nieces, etc.), biochemical disorders similar to those of the probands being found in young persons (14-16 years old) and reappearing in several generations. The author concludes on the genetic heterogeneity of ischaemic (coronary) heart disease and underlying coronary atherosclerosis.     

Apoptosis in the failing human heart

BACKGROUND: Loss of myocytes is an important mechanism in the development of cardiac failure of either ischemic or nonischemic origin. However, whether programmed cell death (apoptosis) is implicated in the terminal stages of heart failure is not known. We therefore studied the magnitude of myocyte apoptosis in patients with intractable congestive heart failure. METHODS: Myocardial samples were obtained from the hearts of 36 patients who underwent cardiac transplantation and from the hearts of 3 patients who died soon after myocardial infarction. Samples from 11 normal hearts were used as controls. Apoptosis was evaluated histochemically, biochemically, and by a combination of histochemical analysis and confocal microscopy. The expression of two proto-oncogenes that influence apoptosis, BCL2 and BAX, was also determined. RESULTS: Heart failure was characterized morphologically by a 232-fold increase in myocyte apoptosis and biochemically by DNA laddering (an indicator of apoptosis). The histochemical demonstration of DNA-strand breaks in myocyte nuclei was coupled with the documentation of chromatin condensation and fragmentation by confocal microscopy. All these findings reflect apoptosis of myocytes. The percentage of myocytes labeled with BCL2 (which protects cells against apoptosis) was 1.8 times as high in the hearts of patients with cardiac failure as in the normal hearts, whereas labeling with BAX (which promotes apoptosis) remained constant. The near doubling of the expression of BCL2 in the cardiac tissue of patients with heart failure was confirmed by Western blotting. CONCLUSIONS: Programmed death of myocytes occurs in the decompensated human heart in spite of the enhanced expression of BCL2; this phenomenon may contribute to the progression of cardiac dysfunction.     

Mechano-electric feedback in the human heart

With the increasing popularity of using computer-aided design (CAD) in Hong Kong, it is time to look into the design of a suitable workplace for the CAD operators working in the industries. This can be achieved by applying anthropometric data into the design for enhancing performance and reducing musculoskeletal problems. In order to avoid any mismatches in anthropometric dimensions, which is believed to be one of the main causes of fatigue and occupational illness among workers, in the workplace design for them, eleven relevant body dimensions from a group of 150 Hong Kong male adults with ages ranging from 18 to 28 years were collected and analyzed to develop a computerized anthropometric database for Hong Kong CAD operators. The eleven anthropometric dimensions measured were: shoulder rest height, elbow-fingertip length, shoulder breadth, hip breadth, sitting eye height, elbow rest height, third lumbar disc-pan length, thigh clearance height, popliteal height, buttock-popliteal length, and stature. The computerized database can provide some useful statistics such as mean, standard deviation and relevant percentiles of all the measured dimensions. With the aid of these statistics, a new workplace for CAD operators was designed which improved performance substantially.     

Amiodarone affects membrane water permeability properties of human erythrocytes and rat mitochondria

Dose-dependent water exchange times and intracellular water contents were measured by NMR (nuclear magnetic resonance) in erythrocytes and mitochondria interacted with the anti-anginal and anti-arrhytmic agent, amiodarone. Addition of the drug up to 26 microM yielded 80% enhancement of the water exchange rate in erythrocytes at 37 degrees C and 41% enhancement at 22 degrees C with 40% and 9%, respectively, increases in the intracellular water content. Similar enhancements were obtained in mitochondria at 22 degrees C. The data suggests a somewhat higher affinity of amiodarone to mitochondrial than to erythrocyte membranes.     

The critical transmural pressure of the abirway

The critical transmural pressure (Ptm) is defined as the transmural pressure of the airway at the site where and when flow is limited during a forced expiration. According to the presented theory, the maximal expiratory flow (Vmax) can be calculated from the relation between Ptm and the corresponding cross-sectional area of the airway (A). By means of a pitot-static tube, Ptm-A curves were constructed for several locations in the elastic airway of a mechanical model. From these curves local Vmax was calculated at different values of Ptm and compared with actual flow, i.e. measured Vmax for the entire airway. In the downstream part of the airway, the actual flow equalled calculated Vmax at most Ptm values. The site of flow limitation, being the most upstream point where actual flow equals calculated local Vmax could therefore be located. Theory and experiments showed positive as well as negative Ptm not influenced by change in upstream or downstream resistance. Flow limitation could therefore be initiated at distending as well as compressing pressures across the wall of the airway. V was regarded as a function of Ptm and the elastic recoil pressure of the lung (Pel). Measured and calculated iso-Pel, Ptm-V curves agreed well with one major exception: when Ptm less than Ptm measured curves were distorted due to a concomitant downstrean compression of the collapsible airway.     

The inotropic reactions of the human heart muscle in ischemic heart disease

The investigation were performed on trabeculae extracted from right auricle of IHD patients aged 40-55 years during aortocoronary bypass. In transitory increase of stimulation frequency from 0.5 up to 1 Hz, a significant decrease of developed tension (Tmax), of the rate of its increase (T'max) and decrease (T'min) by 37% on the average were observed. On the contrary, stimulation frequency decrease up to 0.1 Hz caused, Tmax, T'min and T'max increase, by 20 + 4, 16 + 3 and 13 + 4 respectively (p < 0.05). The effect of hypercalcium (4 mM Ca2+) solution led to Tmax increase by 324%, T'max--by 254% and T'min by 383%, meanwhile the T'min/T'max ratio being initially equal to 0.3, increased to 0.4. Adrenalin caused not only the same Tmax increase (by 322%) as did Ca2+ but the same response of the rate parameters (T'min/T'max, 0.4--fold). The decrease of stimulation frequency to 0.1 Hz associated with Ca2+ or adrenalin effects resulted in additional increase of contractile activity. It was concluded that the contractile apparatus of myocardium in IHD patients retained sufficient functional reverse, accompanied by changes in the regulation of Ca(2+)-transporting systems.     

Differential responses to transmural stimulation and vasopressin in isolated strips of artery and vein of human mesoappendix

Responses to exogenous norepinephrine (NE), transmural electrical stimulation, 5-hydroxytryptamine (5-HT) and lysine vasopressin were studied in isolated helical strips of the small artery and vein from the mesoappendix of patients undergoing incidental appendectomy at the time of cholecystectomy. Responses to NE and 5-HT were similar in each vessel. Arterial strips were unresponsive to electrical stimulation and responses to vasopressin were greater than those to NE in this tissue. Venous strips were unresponsive to vasopressin. Relaxation of exogenous NE responses following oil immersion of arterial strips was unaffected by cocaine whereas relaxation of similarly treated venous strips was markedly prolonged. The data suggest: (1) that the artery of human mesoappendix is poorly innervated and (2) that vasopressin is clearly more active on human mesoappendix artery than it is on human mexoappendix vein. The latter observation may help to explain the efficacy of vasopressin infusion in gastrointestinal hemorrhage secondary to portal hypertension.     

The role of cytokines in the failing human heart

Despite repeated attempts to develop a unifying hypothesis that explains the clinical syndrome of heart failure, no single conceptual paradigm has withstood the test of time. In this regard, recent studies have shown that a class of biologically active molecules, generically referred to as cytokines, are overexposed in heart failure. This article will review recent clinical and experimental material that suggest proinflammatory (stress activated) cytokines such as tumor necrosis factor-alpha (TFN-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) may play a role in the pathogenesis of congestive heart failure. The scope of this article includes an overview of the biology of cytokines in the heart, as well as review of the clinical studies that have documented elevated levels of cytokines and cytokine receptors in patients with heart failure.     

Evidence for heterogeneity of endothelin receptor distribution in human coronary artery

1. The receptors mediating endothelin-evoked contraction of human coronary artery have been investigated in isolated segments of the left anterior descending coronary artery (LAD). 2. Endothelin-1 (ET-1) was 10 times more potent in distal than in proximal segments but the potency ratio between ET-1 and ET-3 (endothelin-3) was similar and close to 100 in any segment of the artery. 3. BQ-123, an ETA receptor antagonist, competitively antagonized the response to ET-1 of distal segments (pA2 equal to 7.47). In the proximal segments, part of the contractile response was BQ123 sensitive, but the antagonism was non-competitive. In both groups of segments, the response to ET-3 could be completely blocked by BQ-123. 4. These observations indicate that ETA receptors mediate the contractile response to ET-1 in distal, pre-resistant coronary arteries, but that other ET receptors are also involved in the contractile response of proximal segments.