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R Coronel

Publications and source records attributed to R Coronel.

At least 19 recordsLinked to original sources
PubMed2003

Increased Na+/H+-exchange activity is the cause of increased [Na+]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model.

OBJECTIVE: Cytosolic sodium ([Na+]i) is increased in heart failure (HF). We hypothesize that up-regulation of Na+/H+-exchanger (NHE) in heart failure is causal to the increase of [Na+]i and underlies disturbance of cytosolic calcium ([Ca2+]i) handling. METHODS: Heart failure was induced in rabbits by combined volume and pressure overload. Age-matched animals served as control. [Na+]i, cytosolic calcium [Ca2+]i and cytosolic pH (pH(i)) were measured in isolated left ventricular midmural myocytes with SBFI, indo-1 and SNARF. SR calcium content was measured as the response of [Ca2+]i to rapid cooling (RC). Calcium after-transients were elicited by cessation of rapid stimulation (3 Hz) in the presence of 100 nmol/l noradrenalin. NHE and Na+/K+-ATPase activity were inhibited with 10 micromol/l cariporide and 100 micromol/l ouabain, respectively. RESULTS: At all stimulation rates (0-3 Hz) [Na+]i and diastolic [Ca2+]i were significantly higher in HF than in control. With increasing frequency [Na+]i and diastolic [Ca2+]i progressively increased in HF and control, and the calcium transient amplitude (measured as total calcium released from SR) decreased in HF and increased in control. In HF (at 2 Hz), SR calcium content was reduced by 40% and the calcium gradient across the SR membrane by 60%. Fractional systolic SR calcium release was 90% in HF and 60% in control. In HF the rate of pH(i) recovery following acid loading was much faster at all pH(i) and NHE dependent sodium influx was almost twice as high as in control. In HF cariporide (10 micromol/l, 5 min) reduced [Na+]i and end diastolic [Ca2+]i to almost control values, and reversed the relation between calcium transient amplitude and stimulation rate from negative to positive. It increased SR calcium content and SR membrane gradient and decreased fractional systolic SR depletion to 60%. Cariporide greatly reduced the susceptibility to develop calcium after-transients. In control animals, cariporide had only minor effects on all these parameters. Increase of [Na+]i with ouabain in control myocytes induced abnormal calcium handling as found in HF. CONCLUSIONS: In HF up-regulation of NHE activity is causal to increased [Na+]i and secondarily to disturbed diastolic, systolic and SR calcium handling. Specific inhibition of NHE partly normalized [Na+]i, end diastolic [Ca2+]i, and SR calcium handling and reduced the incidence of calcium after-transients. Chronic treatment with specific NHE inhibitors may provide a useful future therapeutic option in treatment of developing hypertrophy and heart failure.

Animals↗
PubMed2003

[Na+]i and the driving force of the Na+/Ca2+-exchanger in heart failure.

OBJECTIVE: Diastolic calcium is increased in myocytes from failing hearts despite up-regulation of the principal calcium extruding mechanism the Na+/Ca2+-exchanger (NCX). We hypothesize that increased diastolic calcium ([Ca2+]i) is secondary to increased cytosolic sodium ([Na+]i) and decreased driving force of NCX (DeltaG(exch)). METHODS: The stimulation rate dependence of simultaneously measured cytosolic sodium ([Na+]i), calcium transients ([Ca2+]i) and action potentials were determined with SBFI, indo-1 and the perforated patch technique in midmural left ventricular myocytes isolated from rabbits with pressure and volume overload induced heart failure (HF) and in age matched controls. Dynamic changes of DeltaG(exch) were calculated. RESULTS: With increasing stimulation frequency, 0.2-3 Hz (all data HF versus control): [Na+]i increased (6.4 to 10.8 versus 3.8 to 6.4 mmol/l), diastolic [Ca2+]i increased (142 to 219 versus 47 to 98 nmol/l), calcium transient amplitude decreased in HF (300 to 250 nmol/l) but increased in control (201 to 479 nmol/l), action potential duration (APD90) decreased (380 to 260 versus 325 to 205 ms) and time averaged DeltaG(exch) decreased (6.8 to 2.8 versus 8.7 to 6.4 kJ/mol. With increasing stimulation rate the forward mode time integral of DeltaG(exch) decreased in HF by about 30%, the reversed mode time integral increased about ninefold and the duration of reversed mode operation more than sixfold relative to control. CONCLUSIONS: [Na+]i is increased in HF and the driving force of NCX is decreased. NCX exerts thermodynamic control over diastolic calcium. Disturbed diastolic calcium handling in HF is due to decreased forward mode DeltaG(exch) secondary to increased [Na+]i and prolongation of the action potential. Enhanced reversed mode DeltaG(exch) may account for increased contribution of NCX to e-c coupling in HF.

Action Potentials↗
PubMed2001

Activation delay after premature stimulation in chronically diseased human myocardium relates to the architecture of interstitial fibrosis.

BACKGROUND: Progressive activation delay starting at long coupling intervals of premature stimuli has been shown to correlate with sudden cardiac death in patients with hypertrophic cardiomyopathy. The purpose of this study was to elucidate the mechanism of increased activation delay in chronically diseased myocardium. METHODS AND RESULTS: High-resolution unipolar mapping (105, 208, or 247 recording sites with interelectrode distances of 0.8, 0.5, or 0.3 mm, respectively) of epicardial electrical activity was carried out during premature stimulation in 11 explanted human hearts. The hearts came from patients who underwent heart transplantation and were in the end stage of heart failure (coronary artery disease, 4; hypertrophic cardiomyopathy, 1; and dilated cardiomyopathy, 6). Eight hearts were Langendorff-perfused. Epicardial sheets were taken from the remaining hearts and studied in a tissue bath. Activation maps and conduction curves were constructed and correlated with histology. Conduction curves revealing prominent increase of activation delay were associated with zones of dense, patchy fibrosis with long fibrotic strands. Dense, diffuse fibrosis with short fibrotic strands only marginally affected conduction curves. The course of conduction curves in patchy fibrotic areas greatly depended on the direction of propagation relative to fiber direction. CONCLUSIONS: The study demonstrates that in chronically diseased human myocardium, nonuniform anisotropic characteristics imposed by long fibrotic strands cause a progressive increase of activation delay, starting at long coupling intervals of premature stimuli. The increase strongly depends on the direction of the wave front with respect to fiber direction and the architecture of fibrosis.

Adult↗
PubMed2001

Late ventricular arrhythmias during acute regional ischemia in the isolated blood perfused pig heart. Role of electrical cellular coupling.

OBJECTIVE: Acute ischemia comes with two phases of life-threatening arrhythmias, early (within 10 minutes, 1A) and late (after about 15 minutes, 1B). The mechanism of the latter is unknown and in this paper, we test the hypothesis that a phase of intermediate coupling between surviving epicardium and inexcitable midmyocardium underlies 1B arrhythmias. METHODS: Pig hearts (n=26) were retrogradely perfused with a blood Tyrode's mixture. The left anterior descending artery was occluded. We investigated (1) inducibility of ventricular fibrillation (VF) with programmed stimulation, (2) tissue impedance (Rt) heterogeneity within the ischemic zone, (3) multiple subepicardial and midmyocardial electrograms, (4) subepicardial lactate dehydrogenase (LDH) and glycogen content. RESULTS: In nine of ten hearts, one--three premature stimuli caused VF between 14 and 53 min of ischemia. This typically happened when the Rt of the ischemic zone had increased up to 40% of its final value. More uncoupling terminated the period of VF inducibility. The excitability of the surviving subepicardial layer was depressed during the same period with partial uncoupling, but recovered when the uncoupling from the midmyocardium had progressed further. CONCLUSIONS: We show that 1B-VF can be induced within a distinct time window and coincides with a distinct range of Rt rise. Subepicardium is electrically depressed, presumably through coupling with midmyocardium, complete uncoupling causes subepicardial recovery and terminates the substrate for 1B-VF. Hence, we suggest that the substrate for 1B-VF consists of intermediate coupling of subepicardium and midmyocardium.

Animals↗
PubMed2001

Transmural repolarisation in the left ventricle in humans during normoxia and ischaemia.

BACKGROUND: Studies in isolated tissues and myocytes show different repolarisation properties in subepicardium, midmyocardium and subendocardium. Whether these differences are present in vivo and are relevant to humans has been the subject of controversy. Our objectives were (1) to ascertain whether transmural repolarisation gradients are present in humans, (2) to determine whether the greater sensitivity of subepicardial cells to ischaemia in vitro is manifest during early ischaemia in humans in vivo. METHODS AND RESULTS: We studied 21 patients during routine coronary artery surgery. Unipolar activation recovery intervals (ARI) were recorded from five transmural locations between subepicardium and subendocardium in the left ventricular wall. A pacing protocol spanned a range of cycle lengths from a cycle length of 300 ms to the maximum permitted by the intrinsic atrial activity. Following the onset of cardiopulmonary bypass recordings were obtained before (control) and during a 3-min period of global ischaemia. During control transmural ARIs were homogeneous between 300 and 1500 ms (ventricular pacing) and 750 and 1500 ms (atrial spontaneous beats). During ischaemia, ARIs shortened similarly at all transmural electrode sites and transmural homogeneity was maintained. CONCLUSIONS: Transmural repolarisation differences within the ventricular wall of the human heart were absent at cycle lengths within the physiological range but also during prolonged cycles. During early (global) ischaemia repolarisation changed equally in subepicardial and subendocardial regions and transmural homogeneity of repolarisation was preserved.

Adult↗
PubMed2001

Effects of cell-to-cell uncoupling and catecholamines on Purkinje and ventricular action potentials: implications for phase-1b arrhythmias.

OBJECTIVE: The delayed phase of ventricular arrhythmias during acute ischemia (phase-1b arrhythmia) is associated with depletion of catecholamines and cell-to-cell uncoupling between depressed depolarized intramural ischemic region and surviving cells in subepicardium and subendocardium. In the present study we determined the effects of uncoupling and catecholamines on development of proarrhythmic afterdepolarizations. METHODS: Depressed depolarized ischemic region was simulated by a passive electronic circuit with a potential of -73, -53, -33 or -13 mV. Using patch-clamp methodology, single sheep Purkinje and ventricular cells were coupled to the simulated ischemic region via a variable conductance. By varying coupling conductance, we were able to selectively study the effects of various degrees of uncoupling. RESULTS: At strong coupling, cells were inexcitable and depolarized to potentials near those of the simulated ischemic region. Excitability, action potential duration and resting potential increased with progressive uncoupling. In a critical range of uncoupling, ventricular and "high-plateau" Purkinje cells developed early afterdepolarizations when the potential of the simulated ischemic region was -13 mV. Norepinephrine (1 microM) frequently induced early and delayed afterdepolarizations in both ventricular and Purkinje cells, but these afterdepolarizations were only present during uncoupling when the potential of the simulated ischemic region was -33 mV or more positive. CONCLUSIONS: In a critical range of uncoupling, afterdepolarizations were present when the potential of the simulated ischemic region was -33 or -13 mV, suggesting that triggered activity plays a role in phase-1b arrhythmias when surviving layers uncouple from a highly depolarized intramural ischemic region.

Action Potentials↗
PubMed2001

Arrhythmogenesis in heart failure.

In a rabbit model of heart failure produced by combined pressure and volume overload, nonsustained ventricular tachycardias developed in 15 of 23 failing rabbits. Sinus rate was increased in rabbits dying suddenly, but was decreased in survivors. This also was true in isolated preparations. Microelectrode recordings from ventricular trabeculae both from patients with end-stage failure and from failing rabbits showed that in half of the preparations, delayed afterdepolarizations and triggered activity occurred, but only in the presence of norepinephrine and a lowered extracellular K+ concentration of 3 mM. This was due to spontaneous release of Ca2+ from the sarcoplasmic reticulum.

Animals↗
PubMed2001

K(ATP) channel opening during ischemia: effects on myocardial noradrenaline release and ventricular arrhythmias.

Cardioprotection by K(ATP) channel openers during ischemia is well documented although ill understood. Proarrhythmic effects may be an important drawback. K(ATP) channel modulation influences neurotransmitter release during ischemia in brain synaptosomes. Therefore, we studied the effects of K(ATP) channel modulation on myocardial noradrenaline release and arrhythmias in ischemic rabbit hearts. Isolated rabbit hearts were perfused according to Langendorff and stimulated. Local electrograms were recorded and K+-selective electrodes were inserted in the left ventricular free wall. Cromakalim (3 microM) or glibenclamide (3 microM) was added 20 min prior to induction of global ischemia. After 15, 20, or 30 min of ischemia, hearts were reperfused and noradrenaline content of the first 100 ml of reperfusate was measured. Cromakalim (n = 16) prevented the second rise of extracellular [K(+)] in accordance with its cardioprotective effect. Cromakalim significantly reduced noradrenaline release after 15 min (mean, 169 +/- SEM 97 pmol/gr dry weight vs. control 941 +/- 278; p < 0.05) and 20 min of ischemia (230 +/- 125 pmol/gr dry wt vs. control 1,460 +/- 433; p < 0.05), but after 30 min of ischemia, the difference in noradrenaline release was no longer significant (cromakalim 2,703 +/- 1,195 pmol/gr dry wt vs. control 5,413 +/- 1,310; p = 0.08). Ventricular fibrillation or ventricular tachycardia occurred in 10 of 13 control hearts (77%) (n = 19), in six of 10 glibenclamide-treated hearts (60%) (n = 15), and in six of 14 cromakalim-treated hearts (43%) (p = NS). Cromakalim significantly accelerated onset of ventricular tachycardia or fibrillation (mean +/- SEM onset after 12.5 +/- 1.6 min ischemia vs. control 16.2 +/- 0.7 min; p < 0.05). Noradrenaline release occurred only in cromakalim-treated hearts with early-onset arrhythmias whereas no noradrenaline release was observed in cromakalim-treated hearts without ventricular tachycardia or fibrillation. Our results show that activation of the K(ATP) channel by cromakalim during ischemia reduces myocardial noradrenaline release and postpones the onset of irreversible damage, contributing to the cardioprotective potential of K(ATP) openers during myocardial ischemia.

Adenosine Triphosphate↗
PubMed2000

Changes in sinus node function in a rabbit model of heart failure with ventricular arrhythmias and sudden death.

BACKGROUND: Heart failure is associated with profound changes in the balance of the autonomic nervous system, such as vagal withdrawal and increased catecholamine levels. It is not known whether the intrinsic sinus node function changes during the progression of heart failure. METHODS AND RESULTS: We implanted transmitters for Holter recording in an established rabbit model of heart failure (n=9) and observed changes in sinus cycle length and the occurrence of arrhythmias during the progression of heart failure. The in vitro sinus cycle length and the responses to acetylcholine and norepinephrine in the isolated right atria were analyzed in 12 rabbits with heart failure and in 6 control rabbits. In vivo cycle length increased in some animals and decreased in others. Sudden death occurred in 3 of 9 rabbits. These rabbits had developed a shorter cycle length than the surviving rabbits. Ventricular tachycardias developed in all but 1 rabbit. The in vitro sinus cycle length increased in heart failure. The response to acetylcholine also increased in heart failure, whereas the response to norepinephrine was unchanged. CONCLUSIONS: Changes in intrinsic sinus node function during the progression of heart failure cannot explain the observed decreases in heart rate variability and/or baroreflex sensitivity in this disease, because increased responsiveness to acetylcholine would be expected to cause the opposite.

Animals↗
PubMed2000

Inhomogeneous transmural conduction during early ischaemia in patients with coronary artery disease.

Electrical inhomogeneity and conduction slowing are critical factors in the initiation and maintenance of ventricular arrhythmias during early ischaemia. Studies in animal models have shown delay in epicardial activation compared to endocardial activation. Epicardial activation delay has been attributed to either enhanced sensitivity of epicardium to ischaemia or to mid-myocardial conduction delay. No information is available in humans and in particular in patients with chronic ischaemia due to coronary artery disease who may have altered electrophysiological properties. Twenty-three patients undergoing routine coronary surgery were studied. All had severe two or three vessel coronary artery disease and a documented history of angina for a mean of 2.4 years. On cardiopulmonary bypass a 3 min period of ischaemia was created by cross clamping the aorta between the input from the pump oxygenator and the coronary arteries. During atrial pacing (normal endocardial to epicardial activation) intramyocardial activation time within the left ventricular free wall between subendocardial and subepicardial plunge electrode terminals, increased from 12.7+/-1.5 ms (control) to 28.2+/-3.2 ms after 3 min ischaemia at the base. At the apex, the activation time increase (over the same distance) was less (19.5+/-2 ms at 3 min ischaemia). This difference in increase in activation time at the base and apex was significant (P<0.05). At the apex the ischaemia induced activation delay occurred primarily over the endocardial half of the wall, whereas the opposite was observed at the base of the heart. Using an epicardial electrode array stimulation along the long axis of the epicardial fibres showed minimal conduction delay during ischaemia whereas stimulation transverse to the epicardial fibres resulted in substantial conduction time prolongation, as was the case with intramural conduction. Intramural conduction during ischaemia was similar in non-infarcted regions of infarcted hearts compared to hearts with no previous MI. To conclude, in patients with coronary artery disease epicardial activation delay early during ischaemia is caused primarily by intramural delay and not by delay along the epicardium. Moreover, the ischaemia-induced transmural activation delay is inhomogeneous.

Aged↗