Enhanced myocardial contractility but not tachycardia persists in isolated working hyperthyroid rat hearts

Summary It is generally believed that the increased contractility and tachycardia of the hyperthyroid heart are a result of thyroid hormone-induced alterations of the mechanical and electrical properties of the heart, respectively. We compared the contractility (dP/dt_max) and the spontaneous beating rate of hyperthyroid and euthyroid hearts perfused in vitro in either a non-working or a working mode. The dP/dt_max (4196±74 mm Hg s^–1) and beating rate (322±8 beats/min) of the non-working hyperthyroid hearts were significantly higher (p<0.001) than those of the euthyroid hearts (3267±115 mm Hg s^–1 and 260±6 beats/min at an external Ca²⁺ of 2.5 mM). At 2.5 mM Ca²⁺, the working hyperthyroid hearts again displayed enhanced contractility (5636±179 mm Hg s^–1 vs 4508±172 mm Hg s^–1; p<0.001) but the spontaneous beating rate (275±7 beats/min) was not significantly different from euthyroid (261±8 beats/min). When hearts were subjected to periods of alternate non-working and working perfusion, the beating rate of the hyperthyroid hearts was significantly higher than euthyroid during non-working (p<0.02) but not during working perfusion. Increasing the afterload on the non-working preparations in a stepwise fashion from 75 cm H₂O to 120 cm H₂O caused significant changes in left ventricular pressure and dP/dt_max in both heart types but the tachycardia in the hyperthyroid hearts persisted (at 120 cm H₂O; hyperthyroid, 294±9 beats/min; euthyroid, 224±10 beats/min; p<0.001). Alteration of the preload (10 to 25 cm H₂O) and afterload (75 to 105 cm H₂O) on working hyperthyroid and euthyroid hearts caused changes in both left ventricular pressure and dP/dt_max but the beating rates of both heart types were never significantly different. We conclude from our results that (i) the increased contractility of the hyperthyroid rat heart is due to thyroid hormone-induced alteration of the mechanical properties of the heart; (ii) the tachycardia of hyperthyroidism is not due to thyroid hormone-induced changes in the electrical properties of the heart, but probably involves some as yet unidentified chronotropic agent.     

Quantitative data on the afterload dependence of left ventricular dP/dtmax in isolated canine hearts

Summary In 15 canine heart-lung preparations the effect of an increase in aortic pressure on left ventricular dP/dt_max was tested. Abrupt elevation of aortic pressure by 20–80 mm Hg during diastole without change in enddiastolic pressure did not influence left ventricular dP/dt_max in the following heart beat. Left ventricular circumference increased slightly.Stepwise elevation of aortic pressure from 60 to 130 mm Hg (LVEDP maintained constant) resulted in an augmentation of the steady-state values of dP/dt_max by only 42 mm Hg/s per 10 mm Hg pressure rise.If the enddiastolic pressure was not maintained constant, the increase in dP/dt_max was 77 mm Hg/s per 10 mm Hg pressure rise.Aortic pressure alterations exhibit a slight but significant influence on left ventricular contractility in the steady-state phase, while an acute effect is not detectable, thus demonstrating that a sudden increase in coronary perfusion pressure is without immediate effect on the cardiac performance.A preliminary report was given at the 51st meeting of the German Physiological Society 1979.     

Time to dP/dtmax,a preload-independent index of contractility: open-chest dog study

A mathematical model of left ventricular pressure (LVP) during isovolumic contraction in the time domain shows the following predictions: 1) t_d, the time from onset of contraction to dP/dt_max and (dP/dt)/P, reflect only the time-dependent aspects of contraction, and are independent of preload; 2) dP/dt_max depends on both preload and the time-dependent aspects of contraction. To test preload independence we reduced filling volume (FV) by the method of ventricular volume clamps with a remote-controlled mitral valve in 7 anesthetized open-chest dogs. A decrease in FV of 80±15% produced a 29±12% (p<0.001) decrease in LVP, 34±13% (p<.001) decrease in dP/dt_max, 13±4% (p<0.001) decrease in t-dP/dt_neg, and no change in t_d(–3±5%, NS). The heart rate (HR) dependence on t_d was assessed in other 5 anesthetized open-chest dogs. HR was changed with atrial pacing (50–240 bpm). t_d was linearly and inversely related to HR in each dog, and at each HR: dobutamine lowered and propranolol elevated this relation when compared to control (p<.001, both). Since dP/dt_max occurs usually before the opening of the aortic valve, t_d is, thus, also afterload-independent. Conclusion: This study supports the theoretical predictions that t_d is independent of preload and that it can serve, at any given HR, as a reliable index of contractility, provided that dP/dt_max occurs before the opening of the aortic valve.     

Maximal rate of pressure rise and time parameters in the right ventricle under isovolumic conditions

Summary In contrast to the left ventricle, the maximal rate of intraventricular pressure rise in the right ventricle does not occur within the isovolumic phase of the contraction. Occlusion of the pulmonary artery by inflation of a balloon during the diastole causes an isovolumic systole of the following heart beat. The canine heart-lung preparation was used to test whether dP/dt_max measured isovolumically and the peak ventricular pressure P_max as well as the parameters derived are useful indices for the contractile state of the right ventricle.Changes only of the aortic pressure influence neither dP/dt_max, P_max and the time values from the onset of contraction to dP/dt_max (t-dP/dt_max), nor the time to P_max (t-P_max). A rise in heart frequency leads to an increase in dP/dt_max and P_max at lowered enddiastolic pressure. It does not influence the time interval t-dP/dt_max and t-P_max. With augmented diastolic filling, dP/dt_max as well as P_max increase, and t-dP/dt_max and t-P_max are extended.The present study suggests that dP/dt_max and P_max measured isovolumically provide accurate and practical measurements of right ventricular contractility, provided that changes in enddiastolic pressure and heart frequency are taken into account. The time parameters are found to be not useful.

---

Maximale Druckanstiegsgeschwindigkeit und Zeitparameter beim rechten Ventrikel unter isovolumetrischen BedingungenUntersuchungen am Herz-Lungen-Präparat des Hundes

Zusammenfassung Im Gegensatz zum linken Ventrikel liegt die größte Druckanstiegsgeschwindigkeit im rechten Ventrikel gewöhnlich nicht innerhalb der isovolumetrischen Kontraktionsphase. Durch Verschluß der Pulmonalarterie (Aufblasen eines Ballons) innerhalb der Diastole kann ein isovolumetrischer Verlauf der folgenden Systole erzwungen werden.Am Herz-Lungen-Präparat des Hundes wird geprüft, inwieweit das isovolumetrisch gemessene dP/dt_max und der maximale Ventrikeldruck P_max sowie die Zeit vom Beginn der Kontraktion bis dP/dt_max (t-dP/dt_max) bzw. bis P_max (t-P_max) als Maß für die Kontraktilität des rechten Ventrikels brauchbar sind.Alleinige Änderung des Aortendrucks bleibt ohne Einfluß auf dP/dt_max und P_max sowie t-dP/dt_max bzw. t-P_max. Die Erhöhung der Herzfrequenz führt zu einer Vergrößerung von dP/dt_max und P_max bei sinkendem enddiastolischem Druck (EDP) und bleibt ohne Einfluß auf t-dP/dt_max und t-P_max.Mit Erhöhung der enddiastolischen Füllung nehmen sowohl dP/dt_max als auch P_max deutlich zu, und t-dP/dt_max und t-P_max werden im Mittel länger. Verbesserung (Strophanthin) oder Verschlechterung (Hypoxie) der Kontraktilität werden bei der isometrischen Kontraktion des rechten Ventrikels von dP/dt_max und P_max eindeutig wiedergegeben. Von den hier geprüften Parametern lassen nur dP/dt_max und P_max unter Berücksichtigung des enddiastolischen Drucks und der Herzfrequenz bei isovolumetrischer Kontraktion eindeutige Angaben über die Kontraktilität des rechten Ventrikels zu, während die Zeitparameter unbrauchbar sind.

---

---

With 5 figures

---

Protions of this study have been presented at the 40th, Meeting of the German Physiological Society; Pflügers Arch.335, R 14.     

Effects of pentobarbital on inotropic state of isolated canine left ventricle

Summary Although pentobarbital has been found to depress myocardial function, the magnitude of its direct effects on ventricular contraction at anesthetic concentrations has not been well quantified. The direct effects of pentobarbital on left ventricular function were measured by employing an isolated canine heart preparation with a blood oxygenator. Seven hearts were perfused with blood, dextran, and perfluorochemical artificial blood. Ventricular function was evaluated using the slope of the end-systolic pressure-volume relationship (E_es) and the maximal rate of pressure development (dP/dt_max) in ventricles contracting isovolumically in control, after a low dose (13 µg/ml), and after a high dose (48 µg/ml) of pentobarbital. These concentrations represent one-half and two times the typical value (25 µg/ml) found to produce anesthesia in canines (assessed by tail clamp or blink reflex). The low dose of pentobarbital did not produce clear-cut depression in contractile function. The high dose of pentobarbital produced significant reductions of E_es, and dP/dt_max:E_es decreased 29%, from a control of 4.30 ± 0.84 to 3.05 ± 0.49 mmHg/ml and dP/dt_max decreased 24%, from a control of 909 ± 148 to 695 ± 173 mmHg/s. Thus, the threshold for the direct depressant effect of pentobarbital on ventricular function falls within the range of half to double the typically-reported anesthetic concentrations.These studies were supported by United States NIH Research Grant HL 18912.Deceased August 22, 1989     

Independent mechanisms for the chronotropic and inotropic responses in hyperthyroidism

Summary We established a hyperthyroid rat model and compared the hemodynamic responses of the hypertrophied rat heartin vivo andin vitro. Heart rate (557±26 beats/min), systolic blood pressure (162±5 mm Hg) and dry heart mass (230±11 mg) in hyperthyroid rats were significantly greater than in control animals (408±12 beats/min, 140±5 mm Hg and 193±4 mg respectively).In vitro studies were performed in order to eliminate neurohumoral and peripheral circulatory factors which are presentin vivo. In thein vitro working heart preparation, there was no significant difference between the heart rates of L-thyroxine-treated (263±9 beats/min) and control (258±10 beats/min) animals, implying that the tachycardia of hyperthyroidism is partly mediated byin vivo factors. Consistent with this hypothesis was the observation that the hyperthyroid heart was more sensitive to the chronotropic effects of physiological concentrations of the synthetic catecholamine, isoproterenol (10^–8M, 10^–7 M) than the control heart. The maximum rate of left ventricular pressure rise (dP/dt_max) was used as an index of myocardial contractility.In vitro values for dP/dt_max were significantly greater in hearts from hyperthyroid rats (5338±228 mm Hg/s) than in control hearts (4583±158 mm Hg/s), suggesting that the increased contractile response of hyperthyroidism is intrinsic to the heart itself. Although persistence of the inotropic response of the hyperthyroid heartin vitro was associated with an increase in heart mass, this factor alone did not account entirely for the enhanced contractility. It appears that intrinsicfunctional changes also contribute to the inotropic response of the hyperthyroid heart.     

Noninvasive evaluation of contractile state by left ventricular dP/dtmax divided by end-diastolic volume using continuous-wave doppler and M-mode echocardiography

The maximum rate of left ventricular (LV) pressure rise (dP/dt_max) is commonly used in the assessment of directional change in LV contractility and, recently, estimated by analyzing continuous-wave Doppler ultrasound velocity curve of mitral regurgitation. As an alteration in ventricular preload is known to affect dP/dt_max, normalized dP/dt_max for preload might be more reliable to assess LV contractile state. To investigate the usefulness of a new index of LV contractile state determined by continuous-wave Doppler analysis of mitral regurgitation and M-mode echocardiogram-derived LV end-diastolic volume, we studied 18 patients with mild mitral regurgitation. The continuous-wave Doppler velocity curves of mitral regurgitation were digitized and converted to instantaneous pressure gradient between the LV and left atrium using the simplified Bernoulli equation. The maximum value of its first derivative (Doppler-derived dP/dt_max) correlated well with LV dP/dt_maxusing simultaneously recorded LV pressures by manometer-tipped catheter (n = 20, r = 0.97, p < 0.001). Corrected Doppler-derived dP/dt_max for LV end-diastolic volume using Teichholz's method significantly increased by inotropic stimulation with dobutamine (p < 0.01); however, it remained unchanged by augmentation of afterload with angioteasin II. Thus, the LV dP/dt_max can be accurately estimated in humans by analyzing the continuous wave Doppler velocity curve of mitral regurgitation, and corrected Doppler-derived dP/dt_max for LV end-diastolic volume is relatively independent of loading alteration and sensitive to inotropic stimulation. We concluded that echocardiographic assessment by combined Doppler- and M-mode measurements provides a useful and sensitive index of LV contractile state noninvasively.     

Effects of different inotropic interventions on myocardial function in the developing rabbit heart

The development of the mammalian heart is characterized by substantial changes in myocardial performance. We studied the ontogeny of myocardial function with and without various inotropic interventions in the developing isolated, antegrade-perfused rabbit heart (2d, 8d, 14d, 28d, n = 96). Myocardial function was related to the protein expression of the sarcolemmal Na⁺-Ca²⁺ exchanger and to the sarcoplasmic Ca²⁺-ATPase. In neonatal hearts an age-dependent increase in maximal developed pressure velocity (dP/dt_max) by 45 % and peak negative pressure velocity (dP/dt_min) by 75 % within days 2 to 8 were observed. In response to inotropic intervention with isoproterenol, ouabain, calcium and the Na⁺-channel modulator BDF 9148, dP/dt_max and dP/dt_min increased in a concentration dependent manner. Significant differences between neonatal, juvenile and adult hearts could be demonstrated in a repeated measurement ANOVA model on the concentration-response curves for BDF 9148 (dP/dt_max and dP/dt_min), ouabain (dP/dt_min) and calcium (dP/dt_min), but not for isoproterenol. At the maximum isoproterenol concentration of 1 μmol/l, the increase in dP/dt_max and dP/dt_min was significantly higher in adult compared to neonatal hearts (t-test, p < 0.01). The significant decline of the Na⁺-Ca²⁺ exchanger protein expression from neonatal (1822 ± 171) to adult hearts (411 ± 96 S.E.M. [units per 20 μg protein], p < 0.01) was related to an increase in myocardial function (dP/dt_max r = 0.63, p < 0.01, dP/dt_min r = 0.62, p < 0.01). Contractility, relaxation and the observed positive inotropic effects were in general significantly lower in neonatal compared to adult hearts. In the individual heart an increase in contractility and relaxation was related to a decrease in Na⁺-Ca²⁺ exchanger expression. Received: 22 May 2000, Returned for 1. revision: 21 June 2000, 1. Revision received: 27 November 2000, Returned for 2. revision: 19 December 2000, 2. Revision received: 2 January 2001, Returned for 3. revision: 17 January 2001, 3. Revision received: 25 May 2001, Accepted: 11 June 2001     

Role of force – frequency relation during AV–block,sinus node block and betaadrenoceptor block in conscious animals

Objective Myocardial contractility is regulated by adrenergic stimulation, the strength–length relationship and the force–frequency relationship or Bowditch effect. The latter mechanism was clearly demonstrated in muscle strips, in the isolated heart as well as in in–vivo experiments. The aim of this study was to further investigate the role of the force–frequency effect on the contractile response to exercise or isoproterenol infusion in conditions of restricted increases in heart rate i.e., AV–block, sinus node block and beta–adrenoceptor block. Methods Nineteen dogs were instrumented with a left ventricular miniature pressure gauge, catheters in the aorta, pulmonary artery and left atrium and pacing leads on the left atrium and left ventricle. In order to control the chronotropic response during sympathetic stimulation, permanent AV–block was induced in nine dogs, sinus node block using UL–FS 49 and beta–adrenoceptor block using propranolol was studied in ten dogs. Results Adrenergic stimulation (isoproterenol 0.4 µg/kg or exercise) after total AV–block failed to increase LVdP/dt. However, increasing LV pacing rate (from 50 up to 200 bpm) prior to adrenergic stimulation elicited a significant increase in LVdP/dt (4762 ± 166 mmHg/s vs. 6485 ± 381 mmHg/s, p < 0.05). In dogs in sinus rhythm, heart rate and LVdP/dt response to isoproterenol and exercise following pre–treatment with UL-FS 49 is significantly reduced, with heart rate increasing from 103 ± 7 up to 154 ± 5 bpm and LV dP/dt_max from 2925 ± 171 mmHg/s to 6249 ± 400 mmHg/s compared to the response in control conditions (HR 220 ± 3 bpm and LV dP/dt_max 7473 ± 616 mmHg/s) (p < 0.05). When heart rate is matched using atrial pacing, the LVdP/dt_max response reached comparable values as observed in control conditions (7310 ± 550 mmHg/s). Similar responses were obtained during exercise. Beta–adrenoceptor blockade attenuates considerably the heart rate and LVdP/dt response to sympathetic stimulation. Adjusting heart rate with atrial pacing restores only partially LVdP/dt_max. Conclusion During sympathetic stimulation, the chronotropic response plays a major role for the concomitant full expression of the inotropic response. In conditions where increases in heart rate are absent or severely restricted such as in permanent AV–block, sinus node block and beta–adrenoceptor block, the inotropic response will also be impaired.     

Maximum derivative of left ventricular pressure predicts cardiac mortality after cardiac resynchronization therapy

Background

Cardiac resynchronization therapy (CRT) has been reported to improve cardiac performance. However, CRT in patients with advanced heart failure is not always accompanied by an improvement in survival rates. We investigated the association between hemodynamic studies and long‐term prognosis after CRT.

Methods

A total of 68 consecutive patients receiving CRT devices due to advanced heart failure were assessed by hemodynamic study and long‐term outcome after implantation of the device. Hemodynamic parameters were measured both with the CRT on and off.

Results

Patients demonstrated significant improvement in the maximum first derivative of left ventricular (LV) pressure (LV dP/dt_max) and QRS duration after periods with the CRT on. During the follow‐up period of 34.9 ± 17.6 months, basal LV dP/dt_max and isovolemic LV pressure half‐time (T_1/2), but not percent change in LV dP/dt_max, were independent predictors of cardiac mortality or hospitalization due to heart failure after multivariate Cox regression analysis. The Kaplan‐Meier survival analysis revealed that patients in the lowest basal LV dP/dt_max tertile or the longest basal T_1/2 tertile exhibited a significantly higher cardiac‐caused mortality or heart failure hospitalization.

Conclusions

Lower LV dP/dt_max or longer T_1/2 independently predicts cardiac mortality or heart failure hospitalization in patients receiving CRT. The assessment of the basal LV dP/dt_max and T_1/2 could provide useful information in long‐term prognosis after CRT. Copyright © 2010 Wiley Periodicals, Inc. This work was supported by grant from the Grant‐in‐Aid for Young Scientists, the Nakashima Foundation, and the Kowa Life Science Foundation to RS. Hirohiko Suzuki, MD and Masayuki Shimano, MD equally contributed to the work.     

Tolerance of myocardium of aged animals to repeated oxygen deficiency

Summary Hemodynamic and metabolic effects of three times 4 min of oxygen deficiency were investigated in 18-month-old rats in comparison to 4-month-old Wistar rats. Left-ventricular isovolumicpressure-generating capacity and dp/dt_max during isovolumic conditions and hemodynamic indices during intact circulation were determined in open-chest rats. Additionally, high-energy phosphates were measured at the end of the experiments after 20 min of postasphyxial recovery.Older rats had a significantly reduced isovolumic left-ventricular pressure generating capacity (236±9 vs 269±5 mm Hg; p<0.05) and a low cardiac index (55±9 vs 117±8 ml×min^–1×kg^–1). The effects of the oxygen deficiency were comparable in both groups. The isovolumic pressure generating capacity was reduced for 11% vs 14%, and dp/dt_max for 13% vs 13%. The myocardial ATP-content was also decreased for the same extent in both groups (0.6 vs 1.0 mol/gww). Both hemodynamic and biochemical results indicate that aged myocardium does not have a reduced tolerance to repeated periods of oxygen deficiency.Supported in part by the Deutsche Forschungsgemeinschaft, Bonn, FRG (HO 1003/1-2)Parts of the results were presented at the 10th meeting of the Internat. Soc. for Heart Research (Europ. Section), Rotterdam, 1989     

Attenuation of the systemic and coronary hemodynamic effects of cocaine in conscious dogs: propranolol versus labetalol

Summary The interaction of cocaine with myocardial and vascular adrenoceptors is incompletely understood. The systemic and coronary hemodynamic effects of intravenous cocaine (1.5 mg/kg) were examined in dogs with and without pretreatment with propranolol (2 mg/kg i.v.) or labelatol (5 mg/kg i.v.) on different days. A total of 24 experiments was completed (three sets of experiments) using eight dogs chronically instrumented for measurement of aortic and left-ventricular pressure, left-ventricular dP/dt, subendocardial segment length, coronary blood flow, and cardiac output. Myocardial oxygen consumption was estimated from the pressure work index (PWI). Cocaine significantly (p<0.05) increased heart rate (+51±17 bpm), mean arterial pressure (+72±10 mm Hg), left-ventricular systolic and end-diastolic pressures (+56±9 and +14±6 mm Hg, respectively), coronary blood flow (+32±10 ml/min) and the PWI (+10.0±2.3 ml O₂/min/100 g). Significant reductions in stroke volume (–9±5 ml) and percent segment shortening (–7.1±1.7) were observed. These changes returned to control after 30 min. After pretreatment with propranolol, the cocaine-mediated increases in mean arterial pressure, left-ventricular systolic pressure, rate-pressure product, and the pressure work index (4.4±0.7 ml O₂/min/100 g) were significantly (p<0.05) less than those observed with cocaine alone. Cocaine also reduced contractility [dP/dt₅₀ (–341±80 mm Hg/s)] and increased systemic vascular resistance (+2703±339 dyn·s·cm^–5) in the resence of propranolol. Labetalol abolished the cocainemediated increases in heart rate and coronary blood flow and significantly attenuated the increases in mean arterial pressure, left-ventricular systolic pressure, cardiac output, rate-pressure product, and calculated myocardial oxygen consumption when compared to results obtained with cocaine alone. The results demonstrate that a portion of the basic dynamic effects of cocaine is mediated by stimulation of alpha and beta adrenoceptors. Combined alpha and beta adrenergic blockade reduces the hemodynamic effects of cocaine more than beta blockade alone. During antagonism of the sympathomimetic response of cocaine, direct negative inotropic actions of this drug are unmasked.This work was supported by US PHS grants HL 36144 and HL 32911, Anesthesiology Research Training Grant GM 08377, and VA Medical Research Funds.     

Novel Means to Monitor Cardiac Performance: The Impact of the Force-frequency and Force-interval Relationships on Recirculation Fraction and Potentiation Ratio

Insights into intracellular calcium regulation and contractile state can be accomplished by changing pacing rate. Steady-state increases in heart rate (HR) (force-frequency relationship, FFR), and introduction of extrasystoles (ES) (force-interval relationship, FIR) have been used to investigate this relationship. This study focused on the recirculation fraction (RF) and potentiation ratio (PR), obtained from the recovery of the FFR and FIR. These parameters may provide insight on intracellular Ca²⁺ regulation. Left ventricular (LV) pressures and HR were assessed in anesthetized canines (n = 7). Intrinsic data were collected prior to and following HR increases to 150, 180, and 200 bpm, as well as following delivery of an ES at 280 ms. The RF was calculated as the slope of dP/dt_{max(n + 1)} vs. dP/dt_max(n), where n = beat number. The PR was calculated by normalizing dP/dt_max from the first beat following the ES (or the last paced beat) to the steady-state dP/dt_max. The RF due to an ES was not significantly different than that from a HR of 200 bpm. The PR from an ES was not significantly different than from a HR of 150 bpm. The impact of an ES delivered at an interval of 280 ms produces a PR similar to that from a HR of 150 bpm; yet, it recovers similarly to the termination of pacing at 200 bpm, eliciting a similar RF value. The method of measuring RF by an ES versus an increased HR may provide a safer and more feasible approach to collecting diagnostic information.     

The role of calcium in the enhanced myocardial contractility of the hyperthyroid rat heart

Summary The hyperthyroid rat myocardium exhibits enhanced contractility. There is evidence that altered calcium handling by the myocardium may be responsible for this enhanced state. To investigate this, isolated hyperthyroid and cuthyroid hearts were perfused in the working mode and exposed to alterations in external calcium concentration. Heart rate was not significantly different in either group of hearts, nor was it altered by the change in calcium. The concentration of calcium needed to elicit half-maximal contractility (dP/dt_max) was lower in the hyperthyroid (0.81±0.07 mM) than in the cuthyroid hearts (1.12±0.09 mM, p<0.05). This increase in calcium sensitivity was unlikely to be at the site of the sarcolemma as verapamil exerted equal negative inotropic effects on both groups of hearts. Dantrolene, which blocks calcium release from the sarcoplasmic reticulum, exerted a significantly greater (p<0.01) depression in dP/dt_max after 12 min in the hyperthyroid (50±7%) than in the cuthyroid heart (15±2%). We conclude from our results that the enhanced contractile state of the hyperthyroid rat heart is likely to involve an altered mechanical response to calcium which is possibly at the level of enhanced calcium release from the sarcoplasmic reticulum.     

Left Ventricular Function by Pressure‐Volume Loop Analysis before and after Percutaneous Repair of Large Atrial Septal Defects

Aim

The intent of the present study was to evaluate changes in ventricular function with percutaneous closure of atrial septal defect (ASD), as it is associated with alterations in ventricular loading and function. Transcatheter occlusion of ASD imparts acute changes in volume loading of the left ventricle (LV) that obscures measurement of ventricular function by load‐dependent indices. To differentiate between changes in ventricular loading and function, load‐independent indices of ventricular function must be utilized.

Methods

During transcatheter occlusion of ASD, subjects underwent measurement of LV pressure and volume by the conductance catheter method. Load‐dependent indices of ventricular function included: systolic and diastolic pressures, +dP/dt_max, and ?dP/dt_max. Load‐independent indices included: elastance and tau, the preload‐independent time constant ofisovolumic relaxation. To obtain elastance, afterload was augmented by phenylephrine bolus pre‐ and post‐device occlusion.

Results

In total, 29 patients (age 2–79 years) underwent ASD device occlusion (device size 12–38 mm, median 28 mm). Load‐dependent indices were obtained in all, and satisfactory pressure‐volume loops in 11. At baseline, LV end‐diastolic pressure was 5–23 mmHg (13 ± 5 mmHg) and tau was 31 ± 6 ms. Postclosure of the ASD, LV systolic and diastolic pressures rose by 10 ± 11 mmHg and 5 ± 3 mmHg, respectively (P < 0.05), and +dP/dt_max rose from 1,288 ± 313 mmHg/sec to 1,415 ± 465 mmHg/sec (P < 0.05), but ?dP/dt_max was unchanged. Elastance significantly improved (9.4 ± 8.3 mmHg/mL vs. 13.0 ± 7.3 mmHg/mL, P < 0.05) and tau was unchanged.

Conclusions

Transcatheter occlusion of ASD is associated with acute improvement in load‐independent indices of systolic function in this cohort, without significant worsening of the preload‐independent index of diastolic function. (J Interven Cardiol 2014;27:204–211)

     

Electrocardiographic and hemodynamic effects of cisapride alone and combined with erythromycin in anesthetized dogs

The cardiovascular effects of cisapride administered intravenously at escalating doses with and without pretreatment with erythromycin were evaluated in morphine/chloralose anesthetized dogs. Dogs were instrumented to permit simultaneous recording of ECGs, left ventricular (LVP) and aortic (AoP) pressures, as well as programmed electrical stimulation (PES). Escalating intravenous doses of cisapride from 2 to 8 mg/kg (four times the recommended therapeutic dose) increased the heart rate (HR) and prolonged the corrected QT interval (QTc) (p<0.05) compared to controls. Pretreatment with erythromycin failed to enhance the effect of cisapride on either HR or QTc. Cisapride with or without erythromycin pretreatment had no effect on AoP, but depressed indices of left ventricular contractility (dP/dt _max decreased while PEP/ET increased) compared to controls. No dogs developed spontaneous arrhythmias, and arrhythmias were not inducible by PES. Cisapride with or without erythromycin pretreatment altered the orientation of the T-wave vector (p<0.05) compared to controls, indicating a primary effect of cisapride on ventricular repolarization. The QTc and T wave changes observed were consistent with the known action of cisapride on canine l_Kr channels.     

Effects of physical training on the myocardium of streptozotocin-induced diabetic rats

Summary Effects of endurance swimming training on myocardial contractility and left ventricular myosin isoenzymes were examined in diabetic rats. A diabetic condition was induced in 15-weck-old male Wistar rats, by intravenous injection of streptozotocin (50 mg/kg). Swimming training was carried out for five to six weeks (90 min/day, 6 days/week). In order to estimate myocardial contractility, the isometric developed tension of the isolated left ventricular papillary muscle was measured. Myosin isoenzymes were obtained by pyrophosphate gel electrophoresis. Fasting blood glucose of the trained group was significantly lower than that of the sedentary group (sedentary vs. trained=409.6±25.9 vs. 266.3±20.5 mg/dl, p<0.001). There was no significant difference in isometric developed tension (T) between the two groups, and the dT/dt_max of the trained group showed a tendency to increase (sedentary vs. trained, T: 2.8±0.8 vs. 2.9±0.8 g/mm², dT/dt_max: 23.1±3.6 vs. 26.2±3.5 g/mm² · 2, p<0.1). Myocardial mechanical responses to isoproterenol and dibutyryl cAMP were increased in the trained group. Left ventricular myosin isoenzyme pattern was shifted towards VM-1 by endurance swimming (sedentary vs. trained, VM-1: 5.6±4.5 vs. 19.6±8.8%, p<0.001, VM-3: 75.1±10.0 vs. 54.9±14.7%, p<0.001). These results indicate that endurance swimming can improve disordered glucose metabolism and also influence myocardial contractility, myocardial catecholamine responsiveness, and energetics in myocardial contraction.     

The use of impedance cardiography for optimizing the interventricular stimulation interval in cardiac resynchronization therapy—a comparison with left ventricular contractility

The present study aimed to assess whether impedance cardiography (IC) can correctly identify the optimal interventricular (VV) pacing interval in cardiac resynchronization therapy (CRT). Twenty four patients received a biventricular pacemaker and underwent IC for cardiac output (CO) measurements to identify the optimal VV interval. Invasive measurements of left ventricular (LV) dP/dt_max were used as a reference. During optimization the VV interval was changed with 20 ms steps from +80 (LV pre-excitation) to−80 ms (RV pre-excitation). The optimal VV interval was defined as the one that resulted in the highest LV dP/dt_max value and the highest CO obtained by IC, respectively. During simultaneous biventricular pacing both LV dP/dt_max and CO increased (mean 16.6% and 16.2%, respectively) as compared to baseline. Biventricular pacing with optimized VV intervals resulted in a further absolute increase of LV dP/dt _max and CO (5.6% and 41.3%, respectively). The average decrease in LV dP/dt_max was 79.6 ± 51.6 mmHg/s when the optimal VV interval was programmed according to the IC measurements. Cross spectral analysis showed no correlation between the optimal VV intervals identified by the two methods (p > 0.05) and identical optimal VV intervals were identified in only six of the 24 patients. When broader VV time intervals were compared the correlation between the two methods was statistically significant (p = 0,0166). In conclusion, the use of IC for VV interval optimization is questionable since these optimized time intervals do not seem to correlate well with those obtained by measuring LV dP/dt.     

Inhibition of nitric oxide synthesis improves left ventricular contractility in neonatal pigs late after cardiopulmonary bypass

BACKGROUND—Following neonatal open heart surgery a nadir occurs in left ventricular function six to 12 hours after cardiopulmonary bypass. Although initiated by intraoperative events, little is known about the mechanisms involved.
OBJECTIVE—To evaluate the involvement of nitric oxide in this late phase dysfunction in piglets.
DESIGN—Piglets aged 2 to 3 weeks (4-5 kg) underwent cardiopulmonary bypass (1 h) and cardioplegic arrest (0.5 h) and then remained ventilated with inotropic support. Twelve hours after bypass, while receiving dobutamine (5 µg/kg/min), the left ventricular response to non-selective nitric oxide synthase inhibition (l-N^G-monomethylarginine (l-NMMA)) was evaluated using load dependent and load independent indices (E_es, the slope of the end systolic pressure-volume relation; M_w, the slope of the stroke work-end diastolic volume relation; [dP/dt_max]_edv, the slope of the dP/dt_max-end diastolic volume relation), derived from left ventricular pressure-volume loops generated by conductance and microtip pressure catheters.
RESULTS—10 pigs received 7.5 mg l-NMMA intravenously and six of these received two additional doses (37.5 mg and 75 mg). E_es (mean (SD)) increased with all three doses, from 54.9 (40.1) mm Hg/ml (control) to 86.3 (69.5) at 7.5 mg, 117.9 (65.1) at 37.5 mg, and 119 (80.4) at 75 mg (p < 0.05). At the two highest doses, [dP/dt_max]_edv increased from 260.8 (209.3) (control) to 470.5 (22.8) at 37.5 mg and 474.1 (296.6) at 75 mg (p < 0.05); and end diastolic pressure decreased from 16.5 (5.6) mm Hg (control) to 11.3 (5.0) at 37.5 mg and 11.4 (4.9) at 75 mg (p < 0.05).
CONCLUSIONS—In neonatal pigs 12 hours after cardiopulmonary bypass with ischaemic arrest, low dose l-NMMA improved left ventricular function, implying that there is a net deleterious cardiac action of nitric oxide at this time.


Keywords: ventricular function; nitric oxide; neonatal pigs; cardiovascular surgery; paediatric cardiology     

Effects of a sinus node inhibitor on the normal and failing rabbit heart

The effects on cardiac function of slowed frequency produced by a sinus node inhibitor (zatebradine, or UL-FS 49) were studied in the conscious rabbit under control conditions (n=16) and after heart failure was produced by rapid atrial pacing for an average of 18.5 days (n=8). Echocardiography was used to verify severe left ventricular (LV) dysfunction, and high-fidelity micromanometry and cardiac output measurements (Doppler echo) were performed. Echocardiographic fractional shortening was 40.3±4.1% (SD) in controls; in heart failure it was 18.0±1.6%, and the LV was enlarged. In controls, as heart rate (HR) was decreased from 279 beats per minute (bpm) by incremental doses of zatebradine (up to 0.75 mg/kg), maximal changes occurred when the heart reached 218 bpm with a maximum decrease of the first derivative of LV pressure (LV dP/dt_max) of 15.9%; LV enddiastolic pressure (EDP) increased from 4.3 to 8.4 mmHg along with a significant decrease in cardiac index (CI) of 15.2%, while LV systolic pressure (SP) was stable. In heart failure, LV dP/dt_max and CI were markedly reduced compared to controls and with reduction of HR from 257 to 221 with reduction of HR from 257 to 221 bpm LV dP/dt_max was unchanged, LVEDP increased slightly (NS), LVSP was unchanged and CI fell by 13.5% at the highest dose. In subgroups (control n=9, failure n=6), in order to eliminate the hemodynamic effects of cardiac slowing by zatebradine the sinus rate present before zatebradine was matched by atrial pacing; this procedure eliminated all hemodynamic abnormalities accompanying cardiac slowing in both groups. In conclusion, slowed HR due to a sinus node inhibitor was well tolerated in severe heart failure, and all negative hemodynamic responses in both controls and in heart failure were due entirely to a negative forcefrequency effect, without a direct depressant action of zatebradine on the myocardium.Supported in part by grand HL-53733 awarded by the National Heart, Lung and Blood Institute and an endowed chair awarded to Dr. Ross by the San Diego County Affiliate of the American Heart Association.