Influence of right ventricular pre- and afterload on right ventricular ejection fraction and preload recruitable stroke work relation.

When right ventricular (RV) afterload is abnormally increased, it correlates inversely with right ventricular ejection fraction (RVEF). We tested, whether this would be different with normal afterload. Additionally, we investigated whether previous studies on the slope of RV preload recruitable stroke work (SW) relation, which used rather non-physiological measures to change RV preload, could be transferred to more physiological loading conditions. RV volumes were determined by thermodilution in 16 patients with stable coronary artery disease and normal pulmonary artery pressure (PAP) at rest. Pre- and afterload were varied by body posture, nitroglycerin (NTG) application and by exercise at different body positions. At rest, the change from recumbent to sitting position decreased PAP, cardiac index (Ci), RV diastolic and systolic volumes, and RVEF. Additionally, mean pulmonary artery pressure (MPAP) correlated positively with both RVEF and cardiac index. After correction for mathematical coupling, the RV preload recruitable SW relation was: right ventricular stroke work index (RVSWi) (103 erg m-2)= 8.1 x (RV end-diastolic volume index -4.9), with n=96, r=0.57, P< or =0.001. Exercise abolished this correlation and led to an inverse correlation between RV end-systolic volume (ESV) and RVSW. In conclusion, (i) RVEF correlates positively with RV afterload when afterload varies within normal range; (ii) the slope of the RV preload recruitable SW relation, which is obtained at steady state under normal loading conditions, is substantially flatter than previously described for dynamic changes of RV preload. With increasing afterload, preload loses its determining effect on RV performance, while afterload becomes more important. This puts earlier assumptions of an afterload independent RV preload recruitable SW relation into question.     

Performance of the hypertrophied left ventricle in spontaneously hypertensive rat. Effects of changes in preload and afterload.

Isolated hearts from adult spontaneously hypertensive rats (SHR; Okamoto 1969), with established hypertension, were investigated in an antegrade perfusion apparatus where preload and afterload could be varied independently. Frank-Starling curves were constructed at constant afterloads ranging from 50 mmHg to 150 mmHg. As earlier reported, the SHR hearts exhibited a rightward shift of their Frank-Startling relationships compared to those from the normotensive control hearts, though visible only at afterloads up to about 100 mmHg. At higher afterloads the SHR hearts performed significantly better then the NCR ones as their maximal stroke volume was significantly greater compared to that of controls. Thus, left ventricular hypertrophy obviously increases the work capacity of the heart, though at the cost of an altered Frank-Startling relation dependent on the reduced diastolic compliance. For such reasons the myocardial hypertrophy in established SHR hypertension must be considered a physiologic adaptation and not a degenerative phenomenon, though naturally degenerative processes may later become superimposed.     

链霉素对兔左心室后负荷增加所致电生理变化的影响

目的:探讨左心室后负荷增加引起的心脏电生理变化及链霉素和维拉帕米对其的影响。方法:采用部分夹闭家兔升主动脉根部以增加左室后负荷的在体心脏模型,观察后负荷增加前后心肌相对不应期(RRP)、有效不应期(ERP)、单相动作电位时程(MAPD₉₀)和室颤阈(VFT)的变化,并比较了链霉素和维拉帕米对这些电生理参数变化的影响。结果:后负荷上升引起RRP、ERP和MAPD₉₀缩短,VFT下降(P<0.01);链霉素可有效抑制后负荷增加引起的心脏电生理变化;而维拉帕米除可提高VFT外(P<0.01),对后负荷增加引起RRP、ERP和MAPD90的缩短没有明显影响(P＞0.05)。结论:结果提示牵张激活性离子通道的活化可能参与后负荷增加引起的心脏电生理变化过程,且链霉素通过抑制这种离子通道的活化而发挥作用。     

Mechanisms of left ventricular filling during increased preload and inotropy

To examine the factors contributing to left ventricular filling, experiments were performed in anesthetized, open-chest dogs with intact or mechanically constricted mitral ostium. Stroke volume was raised either by increasing left ventricular end-diastolic volume (preload) by blood volume expansion or by infusing isoproterenol, a beta-adrenergic agonist. In all experimental settings, stroke volume rose in proportion (r greater than 0.9) to the pressure time product (PTP = integral of the diastolic atrio-ventricular (A-V) pressure difference). During saline infusion atrial distention and contraction increased atrial pressure more than ventricular pressure whereas diastolic filling time (DFT) was not lengthened. Peak mitral and peak aortic flow rose almost equally. During isoproterenol infusion at constant heart rate (atrial pacing), the increase in PTP was mainly caused by a longer DFT. When heart rate was allowed to rise, DFT was reduced and the A-V pressure difference increased because of a greater reduction in ventricular than in atrial pressure in early diastole. Thus, the A-V pressure difference is generated in different ways by raising preload and inotropy with and without changes in heart rate.     

Sympathoadrenal system under conditions of increased left and right ventricular afterload

Adrenergic plexuses in the myocardium and adrenal medulla were studied histochemically under conditions of increased left or right ventricular afterload. Under conditions of high afterload not accompanied by heart failure the density of sympathetic myocardial innervation remained unchanged in the loaded ventricle, but increased in the intact ventricle. Comparison of the state of the sympathoadrenal system under conditions of increased afterload complicated or uncomplicated by heart failure revealed common prognostically unfavorable changes: sharp decrease in the density of adrenergic nerve plexuses in the ventricular myocardium and activation of adrenal chromaffin cells.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 11, pp. 597–600, November, 2004     

Discrepancy between left ventricular mechanoenergetics and mitochondrial respiratory function in canine acute failing hearts

In canine excised cross-circulated hearts, we induced three different types of acute failure (time-dependently deteriorated, calcium (Ca²⁺) overloaded, and capsaicin-induced) to investigate the relation between left ventricular mechanoenergetics and myocardial subcellular (mitochondrial) energetics. First, we measured left ventricular pressure and volume and coronary arteriovenous oxygen content difference and blood flow. We analyzed these data by using the framework of the E_max (a contractility index)-PVA (pressure-volume area; total mechanical energy)-V_O2 (oxygen consumption per beat) relation. All acute failing hearts demonstrated similar changes in mechanoenergetics, that is, decreased E_max and decreasedV_O2 for the excitation-contraction coupling (presumably Ca²⁺ handling). We then examined the mitochondrial respiratory function by measuring their oxygen consumption for ATP synthesis polarographically. As indexes of the function, respiratory control index (RCI) and State III O₂ consumption were obtained with succinate as substrate. RCI and State III O₂ consumption behaved differently among the three different types of acute cardiac failure. We conclude that the left ventricular mechanoenergetics do not directly reflect changes in mitochondrial energetics in different types of acute failing.     

Changes in binucleation and cellular dimensions of rat left atrial myocytes after induced left ventricular infarction

The left atrium of young rats has previously been demonstrated to respond with DNA synthesis and binucleation 11 days after left ventricular infarction. This investigation was designed to examine the hypertrophic response of the left atrial myocyte of the rat at 20 and 60 days after ventricular infarction. Male Sprague-Dawley rats were subjected to left coronary artery ligation (CAL) or sham operation. Following enzymatic separation, left atrial myocytes were examined at 20 and 60 days postoperation for number of nuclei and cellular dimensions (cell length, width and area, and nuclear area). Results demonstrated that the level of binucleation at 20 days (77.3%) and 60 days (71.3%) was nearly twice that observed in sham-operated animals, which were 33.1% binucleated at 20 days and 43.5% binucleated at 60 days. In both mononu-cleated and binucleated myocytes, the mean lengths, widths, and cell areas from CAL hearts were significantly greater than those of corresponding sham-operated animals. In all cases, these values were larger in binucleated myocytes than in mononucleated cells. The mean area of CAL cells was approximately twice that of sham-operated myocytes. With regard to mean lengths and widths, although both were greater in the CAL animals, there was a decrease in length and increase in width between 20 and 60 days in the CAL group. Mean nuclear areas were significantly greater in CAL myocytes than in those from the sham-operated group. These increases in nuclear number and cellular dimensions of the atrial myocyte are prominent features of the response to the stress imposed by left ventricular infarction.     

Changes in atrial natriuretic factor during preload reduction with nitroglycerin in patients with congestive heart failure

Nine patients with congestive heart failure, New York Heart Association class II-III, were evaluated with right heart catheterization. Plasma atrial natriuretic factor (ANF) was determined in blood samples from the pulmonary artery simultaneously with recordings of right atrial, pulmonary arterial, pulmonary capillary wedge and systemic arterial pressures and heart rate during preload reduction with 0.5 mg nitroglycerin sublingually. Basal plasma ANF levels were higher in patients with congestive heart failure compared to normal controls, and correlated to right atrial, pulmonary arterial, and pulmonary capillary wedge pressures. After nitroglycerin all patients had reductions in right atrial, pulmonary arterial, and pulmonary capillary wedge pressures and a simultaneous decrease in plasma ANF concentrations, reaching lowest values after 10 min. Central pressures and plasma ANF rose to baseline values within 30 min. After nitroglycerin plasma ANF concentrations correlated to pulmonary arterial and pulmonary capillary wedge pressures, while changes in plasma ANF correlated to changes in right atrial and pulmonary arterial pressures. These results provide further evidence that ANF is released by a pressure-sensitive mechanism and demonstrates that ANF secretion in relation to central pressure variations is preserved in patients with congestive heart failure and that the response is rapid.     

Myocardial structural changes in acute left ventricular overload in an experiment

Acute left ventricular (LV) overload was simulated in rabbits, by applying a metal spiral to narrow the ascending aorta by one third of its baseline diameter. A control group comprised intact animals. Studies were conducted 1, 3, and 5 days after surgery for simulation of LV overload in parallel series. In the first series of the experiment, semifine LV sections were examined by light microscopy and morphometry. The rate of cardiomyocyte (CMC) apoptosis was estimated calculating the free lying nuclei--the morphologically unchanged nuclei that were present in the extracellular space. In the second series, CMC apoptosis underwent immunohistochemical assessment, by running the TUNEL test. During its acute hemodynamic overload, the LV myocardium showed significant tissue destruction and a substantially lower number of viable myofibrils, and an increase in the count of apoptotically altered CMCs.     

Left ventricular and myocardial perfusion responses to volume unloading and afterload reduction in a computer simulation

Ventricular assist devices (VADs) have been used successfully as a bridge to transplant in heart failure patients by unloading ventricular volume and restoring the circulation. In a few cases, patients have been successfully weaned from these devices after myocardial recovery. To promote myocardial recovery and alleviate the demand for donor organs, we are developing an artificial vasculature device (AVD) that is designed to allow the heart to fill to its normal volume but eject against a lower afterload. Using this approach, the heart ejects its stroke volume (SV) into an AVD anastomosed to the aortic arch, which has been programmed to produce any desired afterload condition defined by an input impedance profile. During diastole, the AVD returns this SV to the aorta, providing counterpulsation. Dynamic computer models of each of the assist devices (AVD, continuous, and pulsatile flow pumps) were developed and coupled to a model of the cardiovascular system. Computer simulations of these assist techniques were conducted to predict physiologic responses. Hemodynamic parameters, ventricular pressure-volume loops, and vascular impedance characteristics were calculated with AVD, continuous VAD, and asynchronous pulsatile VAD support for a range of clinical cardiac conditions (normal, failing, and recovering left ventricle). These simulation results indicate that the AVD may provide better coronary perfusion, as well as lower vascular resistance and elastance seen by the native heart during ejection compared with continuous and pulsatile VAD. Our working hypothesis is that by controlling afterload using the AVD approach, ventricular cannulation can be eliminated, myocardial perfusion improved, myocardial compliance and resistance restored, and effective weaning protocols developed that promote myocardial recovery.     

Control of breathing during acute change in cardiac preload in a patient with partial cardiopulmonary bypass

We recently had the opportunity to investigate the ventilatory effects of changing the rate of venous return to the heart (and thus pulmonary gas exchange) in a patient equipped with a venous-arterial oxygenated shunt (extracorporeal membrane oxygenation (ECMO) support). The presence of the ECMO support provided a condition wherein venous return to the right heart could be increased or decreased while maintaining total aortic blood flow and arterial blood pressure (ABP) constant. The patient, who had received a heart transplant 12 years ago, was admitted for acute cardiac failure related to graft rejection. The clinical symptomatology was that of right heart failure. We studied the patient on the 4th day of ECMO support, while she was breathing spontaneously. The blood flow diverted through the ECMO system represented 2/3 of the total aortic flow (4 l min⁻¹). With these ECMO settings, the baseline level of ventilation was low (3.89 ± 0.99 l min⁻¹), but PET_CO2$\text{PE}{\text{T}}_{\text{C}{\text{O}}_2}$ was not elevated (37 ± 2 mmHg). When Pa_CO2$\text{P}{\text{a}}_{\text{C}{\text{O}}_2}$ in the blood coming from the ECMO was increased, no stimulatory effect on ventilation was observed. However, when the diversion of the venous return to the ECMO was stopped then restored, minute ventilation respectively increased then decreased by more than twofold with opposite changes in PET_CO2$\text{PE}{\text{T}}_{\text{C}{\text{O}}_2}$. These maneuvers were associated with large changes in the size of the right atrium and ventricle and of the left atrium. This observation suggests that the change in venous return affects breathing by encoding some of the consequences of the changes in cardiac preload. The possible sites of mediation are discussed.     

Comparative pathomorphological study of contractile myocardium under conditions of increased left and right ventricular afterload

Structural changes in the myocardium under conditions of increased left and right ventricular afterload were studied using polarization microscopy and histological, histochemical, and stereological methods. Increased afterload not complicated by heart failure was characterized by low number of damaged cardiomyocytes (3.3–6.5%) and moderate structural changes in the ventricular myocardium (contractures of different severity). Increased afterload complicated by heart failure was characterized by high ratio of damaged cardiomyocytes (5.6–19.2%) and severe reversible (grade I and II contractures) and irreversible (grade III contractures and lump degradation of myofibrils) structural changes. Irreversible damage to most cardiomyocytes included plasmatic impregnation, which was most pronounced in the sub-endocardial layer of ventricles operating under conditions of increased afterload. Comparative study showed that increased left and right ventricular afterload induces similar pathomorphological changes in the contractile myocardium. Our results indicate that increased afterload to the right or left ventricle is accompanied by the development of stereotypical structural changes in the myocardium. Profound and severe disturbances can cause heart failure.Translated from Byulleten Eksperimentalnoi Biologii i Meditsiny, Vol. 138, No. 12, pp. 693–697, December, 2004This revised version was published online in April 2005 with a corrected cover date.     

Changes in heart rate recovery in response to acute changes in training load

Heart rate recovery is an indirect marker of autonomic function and changes therein may offer a practical way of quantifying the physiological effects of training. We assessed whether per cent heart rate recovery (HRr%) after a standardized sub-maximal running (Heart rate Interval Monitoring System: HIMS) test, changed with acute changes in training load. A total of 28 men and women (mean age 30 ± 5 years) trained ad libitum for 2 weeks during which their heart rate (HR) was recorded. Training load was quantified using Training Impulse (TRIMPs). The participants were grouped based on whether they increased (Group I, n = 9), decreased (Group D, n = 8) or kept their training load constant (Group S, n = 11) from week 1 to week 2. Each week, the subjects completed a HIMS test. Changes between weeks in HR at the end of the test and HRr% were compared between groups. Mean per cent change in TRIMPs from week 1 to week 2 was significantly different among the groups (Group I, 55 ± 21% vs Group S, −6 ± 6% vs Group D, −42 ± 16%; P < 0.05). Group I had a slower HRr% and Group D tended to have a slightly faster HRr% after HIMS 2 than after HIMS 1 (mean per cent change 5.6 ± 8.7 vs −2.6 ± 3.9; P = 0.03). Thus a negative effect on HRr was observed with increases in training load. Sub-maximal HR was not affected by acute changes in training load. Whereas HR during exercise measures cardiac load, HRr may reflect the state of the autonomic nervous system, indicating the body’s capacity to respond to exercise.     

Left ventricular assist device support induces acute changes in myocardial electrolytes in heart failure

The regulation of myocardial electrolyte concentrations is critical to proper cardiac function. Myocardial ischemia is associated with deranged ion transport. Left ventricular assist device (LVAD) therapy improves myocyte bioenergetics in chronic heart failure (CHF), which may manifest as electrolyte alterations; however, rapid electrolyte shifts may place critically ill patients at risk for arrhythmias upon initiation of LVAD support. We examine the effect of incremental increases in LVAD support on acute changes in myocardial arteriovenous electrolytes in CHF. CHF was induced in sheep via coronary microembolization. Four months later, sheep underwent acute LVAD implantation. LVAD support was incrementally increased (0%, 25%, 50%, 75% support). Paired arterial and coronary sinus blood samples were obtained at each increment and analyzed for K+, Ca2+, and Na+ concentrations. Arteriovenous electrolyte concentrations (mmol/l) were inverted in CHF before LVAD support: K+ (-0.08), Ca2+ (-0.04), and Na+ (0.04). These imbalances were corrected within 20 minutes and with as little as 25% LVAD support: K+ (0.06), Ca2+ (0.012), and Na+ (-0.80). The arteriovenous differences further widened as LVAD support was increased. In conclusion, LVAD support in CHF induces acute alterations in myocardial electrolytes. Rapid shifts myocardial arteriovenous electrolyte balances during LVAD support may in part explain the incidence of post-LVAD arrhythmias observed clinically in humans.     

Calcium channel heterogeneity in canine left ventricular myocytes

Regional variations in the electrophysiological properties of myocytes across the left ventricular wall play an important role in both the normal physiology of the heart and the genesis of arrhythmias. To investigate the possible contributions of calcium channels to transmural electrical heterogeneity, whole-cell patch-clamp recordings were made from isolated canine epicardial and endocardial left ventricular myocytes. Two major differences in Ca²⁺ channel properties were found between epi- and endocardial cells. First, the L-type Ca²⁺ current was larger in endocardial than in epicardial myocytes. The average peak current density at +10 mV in endocardial myocytes was  3.4 ± 0.2 pA pF⁻¹  , and was 45 % higher than that in epicardium (  2.3 ± 0.1 pA pF⁻¹  ). The kinetic properties of the L-type current in epi- and endocardial cells were not significantly different. Second, a low-threshold, rapidly activating and inactivating Ca²⁺ current that resembled the T-type current was present in all endocardial myocytes but was small or absent in epicardial myocytes. This T-like current had an average peak density of  0.5 pA pF⁻¹  at −40 mV in endocardial cells. In most endocardial cells the T-like Ca²⁺ current comprised two components: a Ni²⁺-sensitive T-type current and a tetrodotoxin-sensitive Ca²⁺ current. We conclude that there are considerable regional variations in the density and properties of Ca²⁺ channels across the canine left ventricular wall. These variations may contribute to the overall transmural electrical heterogeneity.     

改变左心室后负荷和离体兔心脏对阈下条件串刺激引起的心室不应期变化的影响

目的:探讨改变左心室后负荷和兔离体灌注心脏对阈下条件串刺激引起的心室不应期变化的影响。方法:采用阈下条件刺激(S_t)法心室不应期测定技术,测定改变左心室后负荷和去除神经,体液因素作用时,S_t法心室不应期强度间期关系特征。结果:减小左室后负荷,可使S_t法测定的心室不应期延长(P＜ 0.05, P＜ 0.01);且在各刺激强度的S_t,S_t(200 Hz,100 ms)和S_t(50 ms, 100 Hz)测定的心室不应期最长(P＜ 0.05,P＜0.01)。结论:改变左心室后负荷和去除神经体液因素作用可使S_t法心室不应期强度间期关系特征发生改变。