Pattern of right ventricular pressure fall and its modulation by afterload

Pattern of right ventricular pressure (RVP) fall and its afterload dependence were examined by analyzing ventricular pressure curves and corresponding pressure dP/dt phase planes obtained in both ventricles in the rat heart in situ. Time and value of dP/dt(min), and the time constant tau were measured at baseline and during variable RV afterload elevations, induced by beat-to-beat pulmonary trunk constrictions. RVP and left ventricular pressure (LVP) decays were divided into initial accelerative and subsequent decelerative phases separated by corresponding dP/dt(min). At baseline, LVP fall was decelerative during 4/5 of its course, whereas only 1/3 of RVP decay occurred in a decelerative fashion. During RV afterload elevations, the absolute value of RV-dP/dt(min) and RV-tau increased, whilst time to RV dP/dt(min) decreased. Concomitantly, the proportion of RVP decay following a decelerative course increased, so that in highly RV afterloaded heartbeats RVP fall became more similar to LVP fall. In conclusion, RVP and LVP decline have distinct patterns, their major portion being decelerative in the LV and accelerative in the RV. In the RV, dP/dt(min), tau and the proportional contribution of accelerative and decelerative phases for ventricular pressure fall are afterload-dependent. Consequently, tau evaluates a relatively much shorter segment of RVP than LVP fall.     

Alveolar hypoxia induces left ventricular diastolic dysfunction and reduces phosphorylation of phospholamban in mice

Chronic obstructive pulmonary disease (COPD) may lead to pulmonary hypertension (PH) and reduced function of the right ventricle (RV). However, COPD patients may also develop left ventricular (LV) diastolic dysfunction. We hypothesized that alveolar hypoxia induces LV diastolic dysfunction and changes in proteins governing Ca(2+) removal from cytosol during diastole. Mice exposed to 10% oxygen for 1, 2, or 4 wk were compared with controls. Cardiac hemodynamics were assessed with Doppler echocardiography and a microtransducer catheter under general anesthesia. The pulmonary artery blood flow acceleration time was shorter and RV pressure was higher after 4 wk of hypoxia compared with controls (both P < 0.05). In the RV and LV, 4 wk of hypoxia induced a prolongation of the time constant of isovolumic pressure decay (51% RV, 43% LV) and a reduction in the maximum rate of decline in pressure compared with control (42% RV, 42% LV, all P < 0.05), indicating impaired relaxation and diastolic dysfunction. Alveolar hypoxia induced a 38%, 47%, and 27% reduction in Ser16-phosphorylated phospholamban (PLB) in the RV after 1, 2, and 4 wk of hypoxia, respectively, and at the same time points, Ser16-phosphorylated PLB in the LV was downregulated by 32%, 34%, and 25% (all P < 0.05). The amounts of PLB and sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) were not changed. In conclusion, chronic alveolar hypoxia induces hypophosphorylation of PLB at Ser16, which might be a mechanism for impaired relaxation and diastolic dysfunction in both the RV and LV.     

Acute changes of biventricular gene expression in volume and right ventricular pressure overload

OBJECTIVE: We investigated the effects of acute volume and RV pressure overload on biventricular function and gene expression of BNP, pro-inflammatory cytokines (IL-6 and TNF-alpha), iNOS, growth factors (IGF-1, ppET-1), ACE and Ca2+-handling proteins (SERCA2a, phospholamban and calsequestrin). METHODS: Male Wistar rats (n=45) instrumented with pressure tip micromanometers in right (RV) and left ventricular (LV) cavities were assigned to one of three protocols: i) Acute RV pressure overload induced by pulmonary trunk banding in order to double RV peak systolic pressure, during 120 or 360 min; ii) acute volume overload induced by dextran40 infusion (5 ml/h), during 120 or 360 min; iii) Sham. RV and LV samples were collected for mRNA quantification. RESULTS: BNP upregulation was restricted to the overloaded ventricles. TNF-alpha, IL-6, ppET-1, SERCA2a and phospholamban gene activation was higher in volume than in pressure overload. IGF-1 overexpression was similar in both types of overload, but was limited to the RV. TNF-alpha and CSQ mRNA levels were increased in the non-overloaded LV after pulmonary trunk banding. No significant changes were detected in ACE or iNOS expression. RV end-diastolic pressures positively correlated with local expression of BNP, TNF-alpha, IL-6, IGF-1, ppET-1 and SERCA2a, while RV peak systolic pressures correlated only with local expression of IL-6, IGF-1 and ppET-1. CONCLUSIONS: Acute cardiac overload alters myocardial gene expression profile, distinctly in volume and pressure overload. These changes correlate more closely with diastolic than with systolic load. Nonetheless, gene activation is also present in the non-overloaded LV of selectively RV overloaded hearts.     

Comparative analysis of parvalbumin and SERCA2a cardiac myocyte gene transfer in a large animal model of diastolic dysfunction

Diastolic dysfunction results from impaired ventricular relaxation and is an important component of human heart failure. Genetic modification of intracellular calcium-handling proteins may hold promise to redress diastolic dysfunction; however, it is unclear whether other important aspects of myocyte function would be compromised by this approach. Accordingly, a large animal model of humanlike diastolic dysfunction was established through 1 yr of left ventricular (LV) pressure overload by descending thoracic aortic coarctation in canines. Serial echocardiography documented a progressive increase in LV mass. Diastolic dysfunction with preserved systolic function was evident at the whole organ and myocyte levels in this model, as determined by hemispheric sonomicrometric piezoelectric crystals, pressure transducer catheterization, and isolated myocyte studies. Gene transfer of the sarco(endo)plasmic reticulum calcium-ATPase (SERCA2a) and parvalbumin (Parv), a fast-twitch skeletal muscle Ca(2+) buffer, restored cardiac myocyte relaxation in a dose-dependent manner under baseline conditions. At high Parv concentrations, sarcomere shortening was depressed. In contrast, during beta-adrenergic stimulation, the expected enhancement of myocyte contraction (inotropy) was abrogated by SERCA2a but not by Parv. The mechanism of this effect is unknown, but it could relate to the uncoupling of SERCA2a/phospholamban in SERCA2a myocytes. Considering that inotropy is vital to overall cardiac performance, the divergent effects of SERCA2a and Parv reported here could impact potential therapeutic strategies for human heart failure.     

The onset of left ventricular diastolic dysfunction in SHR rats is not related to hypertrophy or hypertension

Left ventricular (LV) diastolic dysfunction, particularly relaxation abnormalities, are known to be associated with the development of LV hypertrophy (LVH). Preliminary human and animal studies suggested that early LV diastolic dysfunction may be revealed independently of LVH. However, whether LV diastolic dysfunction is compromised before the onset of hypertension and LVH remains unknown. We therefore evaluated LV diastolic function in spontaneously hypertensive rats (SHR) at different ages and tested whether LV diastolic dysfunction is associated with abnormal intracellular calcium homeostasis. LV systolic and diastolic functions were evaluated by invasive and echocardiographic methods in 3-week-old (without hypertension) and 5-week-old (with hypertension) SHR and Wistar-Kyoto control rats. Basal intracytoplasmic calcium and sarcoplasmic reticulum (SR) Ca(2+) contents were measured in cardiomyocytes using fura-2 AM. Sarco(endo)plasmic Ca(2+)-ATPase isoform 2a (SERCA 2a) and phospholamban (PLB) expressions were quantified by Western blot and quantitative RT-PCR techniques. LV relaxation dysfunction was observed in 3-week-old SHR rats before onset of hypertension and LVH. An increase in basal intracytoplasmic Ca(2+) and a decrease in SR Ca(2+) release were demonstrated in SHR. Decreased expression of SERCA 2a and Ser16 PLB (p16-PLB) protein levels was also observed in SHR rats, whereas mRNA expression was not decreased. For the first time, we have shown that LV myocardial dysfunction precedes hypertension in 3-week-old SHR rats. This LV myocardial dysfunction was associated with high diastolic [Ca(2+)](i) possibly due to decreased SERCA 2a and p16-PLB protein levels. Diastolic dysfunction may be a potential predictive marker of arterial hypertension in genetic hypertension syndromes.     

Distinct load dependence of relaxation rate and diastolic function in<Emphasis Type="Italic"> Oryctolagus cuniculus</Emphasis> and<Emphasis Type="Italic"> Ratus norvegicus</Emphasis>

This study investigated potential differences on load dependence of relaxation rate and diastolic function between Oryctolagus cuniculus and Ratus norvegicus, which have constitutive differences in the mechanisms involved in myocardial inactivation. Load dependence of relaxation rate and diastolic function were evaluated with the response of left ventricular time constant tau and diastolic pressure-dimension relation to beat-to-beat aortic constrictions in open-chest rabbits and rats. Afterload levels were normalized, being expressed as a percentage of peak isovolumetric pressure (relative load). In control heartbeats, relaxation rate and diastolic function were similar in the two animal species. They presented, however, distinct responses to afterload elevations. In rabbits, time constant decreased approximately 7% and diastolic pressure-dimension relation remained unchanged when afterload was elevated to a relative load of 73-76%. Above this afterload level, a significant deceleration of relaxation rate (increase of time constant) and an upward shift of diastolic pressure-dimension relation were observed. In rats, afterload elevations accelerated pressure fall up to a relative load of 97-100% and no afterload-induced shift of the diastolic pressure-dimension relation was observed. This study provides, therefore, evidence that Oryctolagus cuniculus has lower afterload reserve of myocardial relaxation and diastolic function than Ratus norvegicus.     

Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles

Thyroid hormone exerts positive inotropic effects on the heart mediated in part by its regulation of calcium transporter proteins, including sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2), phospholamban (PLB), and Na(+)/Ca(2+) exchanger (NCX). To further understand the potential cardiac chamber-specific effects of thyroid hormone action, we compared the triiodo-L-thyronine (T(3)) responsiveness of calcium transporter proteins in atrial versus ventricular tissues. Rats were rendered hypothyroid by ingestion of propylthiouracil, and a subgroup of animals was treated with T(3) for 7 days (7 microg/day by constant infusion). Atrial and left ventricular (LV) tissue homogenates were analyzed for expression of SERCA2, PLB, and NCX proteins by Western blot analysis. SERCA2 protein significantly decreased by 50% in hypothyroid LV and was normalized by T(3) treatment. In contrast, SERCA2 protein in atria was unaltered in the hypothyroid state. PLB protein expression significantly increased by 1.6- and 5-fold in the hypothyroid LV and atria, respectively, and returned to euthyroid levels with T(3) treatment. Expression of NCX protein showed a greater response to T(3) treatment in atria tissue than in ventricular tissue. Sarcoplasmic reticulum calcium cycling is determined in part by the ratio of SERCA2 to PLB. This ratio was sixfold higher in the atria compared with LV, suggesting that PLB may play a minor role in the regulation of SERCA2 function in normal atria. We conclude that calcium transporter proteins are responsive to thyroid hormone in a chamber-specific manner, with atria showing a greater change in protein content in response to T(3). The differential effect on atria may account for the occurrence of atrial rather than ventricular arrhythmias in response to even mild degrees of thyrotoxicosis.     

Mechanistic basis of differences in Ca2+ -handling properties of sarcoplasmic reticulum in right and left ventricles of normal rat myocardium

This study investigated Ca2+ -cycling properties of sarcoplasmic reticulum (SR) in right ventricle (RV) and left ventricle (LV) of normal rat myocardium. Intracellular Ca2+ transients and contractile function were monitored in freshly isolated myocytes from RV and LV. SR in RV displayed nearly fourfold lower rates of ATP-energized Ca2+ uptake in vitro than SR of LV. The Ca2+ concentration required for half-maximal activation of Ca2+ transport was nearly twofold higher in SR of RV. The lower Ca2+ -sequestering activity of SR in RV was accompanied by a matching decrement in Ca2+ -induced phosphoenzyme formation during the catalytic cycle of the Ca2+ -pumping ATPase (SERCA2). Western immunoblot analysis showed that protein levels of Ca2+ -ATPase and its inhibitor phospholamban (PLN) were only approximately 15% lower in SR of RV than in SR of LV. Coimmunoprecipitation experiments revealed that PLN-bound, functionally inert Ca2+ -ATPase molecules in SR of RV greatly exceed (> 50%) that in SR of LV. Endogenous Ca2+/calmodulin-dependent protein kinase-mediated phosphorylation of SR substrates did not abolish the huge disparity in SR Ca2+ pump function between RV and LV. Intracellular Ca2+ transients, evoked by electrical field stimulation, were significantly prolonged in RV myocytes compared with LV myocytes, mainly because of slow decay of intracellular Ca2+ concentration. The slow decay of intracellular Ca2+ concentration in RV and consequent decrease in the speed of RV relaxation may promote temporal synchrony of the end of diastole in RV and LV. The preponderance of functionally silent SR Ca2+ pumps in RV reflects a higher diastolic reserve required to protect and maintain RV function in the face of a sudden rise in afterload or resistance in the pulmonary circulation.     

Cardiac dysfunction in terms of left ventricular mechanical work and energetics in hypothyroid rats

We hypothesized that cardiac dysfunction in hypothyroidism is mainly caused by the impairment of Ca(2+) handling in excitation-contraction coupling. To prove this hypothesis, we investigated left ventricular (LV) mechanical work and energetics without interference of preload and afterload in an excised, blood-perfused whole heart preparation from hypothyroid rats. We found that LV inotropism and lusitropism were significantly depressed, and these depressions were causally related to decreased myocardial oxygen consumption for Ca(2+) handling and for basal metabolism. The oxygen costs of LV contractility for Ca(2+) and for dobutamine in the hypothyroid rats did not differ from those in age-matched normal rats. The expression of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2) significantly decreased and that of phospholamban significantly increased. The present results revealed that changes in LV energetics associated with decreased mechanical work in hypothyroid rats are mainly caused by the impairment of Ca(2+) uptake via SERCA2. We conclude that the impairment of Ca(2+) uptake plays an important role in the pathogenesis of cardiac dysfunction in hypothyroidism.     

Early calcium handling imbalance in pressure overload-induced heart failure with nearly normal left ventricular ejection fraction

Heart failure with preserved ejection fraction (HFpEF) is a common clinical syndrome associated with high morbidity and mortality. Therapeutic options are limited due to a lack of knowledge of the pathology and its evolution. We investigated the cellular phenotype and Ca²⁺ handling in hearts recapitulating HFpEF criteria. HFpEF was induced in a portion of male Wistar rats four weeks after abdominal aortic banding. These animals had nearly normal ejection fraction and presented elevated blood pressure, lung congestion, concentric hypertrophy, increased LV mass, wall stiffness, impaired active relaxation and passive filling of the left ventricle, enlarged left atrium, and cardiomyocyte hypertrophy. Left ventricular cell contraction was stronger and the Ca²⁺ transient larger. Ca²⁺ cycling was modified with a RyR2 mediated Ca²⁺ leak from the sarcoplasmic reticulum and impaired Ca²⁺ extrusion through the Sodium/Calcium exchanger (NCX), which promoted an increase in diastolic Ca²⁺. The Sarcoplasmic/endoplasmic reticulum Ca²⁺ ATPase (SERCA2a) and NCX protein levels were unchanged. The phospholamban (PLN) to SERCA2a ratio was augmented in favor of an inhibitory effect on the SERCA2a activity. Conversely, PLN phosphorylation at the calmodulin-dependent kinase II (CaMKII)-specific site (PLN-Thr17), which promotes SERCA2A activity, was increased as well, suggesting an adaptive compensation of Ca²⁺ cycling. Altogether our findings show that cardiac remodeling in hearts with a HFpEF status differs from that known for heart failure with reduced ejection fraction. These data also underscore the interdependence between systolic and diastolic “adaptations” of Ca²⁺ cycling with complex compensative interactions between Ca²⁺ handling partner and regulatory proteins.     

Cardiac overexpression of alcohol dehydrogenase (ADH) alleviates aging-associated cardiomyocyte contractile dysfunction: role of intracellular Ca2+ cycling proteins

Aging is a complex biological process with contributions from a wide variety of genes including insulin-like growth factor I and alcohol dehydrogenase (ADH), which decline with advanced age. The goal of this study was to examine if ADH enzyme plays any role in cardiac aging. Ventricular myocytes were isolated from young (2-3 months old) or aged (26-28 months old) male FVB wild-type and cardiac-specific ADH (class I, isozyme type 1) transgenic mice. Mechanical properties were measured using an IonOptix system. Aged FVB myocytes displayed significantly reduced ADH activity compared with young ones, which was restored by the ADH transgene. Compared with young cardiomyocytes, aged FVB myocytes exhibited prolonged relengthening duration and a steaper decline in peak shortening amplitude in response to elevated electrical stimuli. Although ADH transgene itself did not alter mechanical properties in young mice, it rescued aging-associated diastolic dysfunction without affecting dampened contractile response to high stimulus frequency. Immunoblot analysis revealed reduced sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA2a) and Na(+)-Ca(2+) exchanger (NCX) levels in conjunction with enhanced phospholamban expression in aged FVB hearts. ADH transgene prevented aging-induced reduction in SERCA2a and NCX without affecting up-regulated phospholamban. Our data suggest that aging is associated with a reduced ADH enzymatic activity and diastolic dysfunction, which may be corrected with cardiac overexpression of the ADH enzyme. Alteration in cardiac Ca(2+) cycling proteins including SERCA2a and NCX may play a role in both pathogenesis of cardiac aging and the beneficial effect of ADH enzyme.     

Load as an acute determinant of end-diastolic pressure-volume relation

Afterload-induced changes in myocardial relaxation are a mechanism for diastolic dysfunction when afterload is elevated beyond certain limits. The present study investigated the effects of acute afterload and preload changes on the position of the end-diastolic (ED) pressure-volume (P-V) relation. Beat-to-beat afterload elevations were induced in seven open-chest rabbits by gradually occluding the ascending aorta to increase peak left ventricular pressure (LVP) from baseline to isovolumetric level. Afterload elevations were performed at three ED LVP: 2.0 +/- 0.2 (low), 5.7 +/- 0.2 (mid), and 9.6 +/- 0.6 (high) mmHg. Preload was altered with caval occlusions and/or intravenous dextran. Afterload elevations induced an upward shift of the diastolic P-V relation, which became more important as afterload and/or preload increased. For instance, maximal afterload elevations shifted this relation upward 2.2 +/- 0. 5, 5.1 +/- 0.8, and 12.1 +/- 1.7 mmHg at low, mid, and high preload, respectively. These effects were partially due to changes in relaxation rate and time available to relax. In conclusion, load is an acute determinant of the ED P-V relation, which, therefore, does not provide a load-independent assessment of diastolic function.     

Unequal effects of renin-angiotensin system inhibitors in acute cardiac dysfunction induced by isoproterenol

Several clinical trials have demonstrated that angiotensin-converting enzyme inhibitor (ACEI) and angiotensin II type 1 receptor blocker (ARB) are equally effective in the treatment of chronic heart failure. However, this has not been confirmed for acute cardiac dysfunction. We examined whether ACEI or ARB prevents isoproterenol-induced acute left ventricular (LV) dysfunction in dogs. LV dysfunction induced by a large dose of isoproterenol (1 microg.kg(-1).min(-1), 3-h infusion) was compared in dogs treated with ACEI (temocaprilat) or ARB (olmesartan). Atrial pacing induced a constant heart rate and use of adjustable aortic banding provided a nearly constant afterload. LV systolic function (LV dP/dt, fractional shortening, and ejection fraction) and diastolic function (tau and LV end-diastolic pressure) were significantly deteriorated after isoproterenol infusion. The LV dysfunction was almost totally prevented by ARB but was only partially prevented by ACEI. The partial effect of ACEI was complemented by cotreatment with HOE-140, a bradykinin B2 receptor antagonist. At baseline, the response to low doses of isoproterenol was significantly attenuated by ACEI but not by ARB, and the ACEI-induced attenuation was totally abolished by cotreatment with HOE-140. The response to isoproterenol was significantly attenuated after 3 h of excess isoproterenol loading, and it was almost completely preserved by ARB but not by ACEI. In conclusion, acute LV dysfunction and beta-adrenergic desensitization induced by excess isoproterenol administration were almost totally prevented by ARB but only partially prevented by ACEI. These differences were attributable at least in part to bradykinin pathways activated by ACEI administration in acute LV dysfunction.     

Volume loading reduces pulmonary vascular resistance in ventilated animals with acute lung injury: evaluation of RV afterload

During mechanical ventilation, increased pulmonary vascular resistance (PVR) may decrease right ventricular (RV) performance. We hypothesized that volume loading, by reducing PVR, and, therefore, RV afterload, can limit this effect. Deep anesthesia was induced in 16 mongrel dogs (8 oleic acid-induced acute lung injury and 8 controls). We measured ventricular pressures, dimensions, and stroke volumes during positive end-expiratory pressures of 0, 6, 12, and 18 cmH(2)O at three left ventricular (LV) end-diastolic pressures (5, 12, and 18 mmHg). Oleic acid infusion (0.07 ml/kg) increased PVR and reduced respiratory system compliance (P < 0.05). With positive end-expiratory pressure, PVR was greater at a lower LV end-diastolic pressure. Increased PVR was associated with a decreased transseptal pressure gradient, suggesting that leftward septal shift contributed to decreased LV preload, in addition to that caused by external constraint. Volume loading reduced PVR; this was associated with improved RV output and an increased transseptal pressure gradient, which suggests that rightward septal shift contributed to the increased LV preload. If PVR is used to reflect RV afterload, volume loading appeared to reduce PVR, thereby improving RV and LV performance. The improvement in cardiac output was also associated with reduced external constraint to LV filling; since calculated PVR is inversely related to cardiac output, increased LV output would reduce PVR. In conclusion, our results, which suggest that PVR is an independent determinant of cardiac performance, but is also dependent on cardiac output, improve our understanding of the hemodynamic effects of volume loading in acute lung injury.     

Timing of valve replacement in chronic aortic regurgitation. A pathophysiological approach

Timing of valve replacement (AVR) in chronic aortic regurgitation remains a difficult problem in clinical practice. When the disease takes a favorable natural course, this may be attributed to excellent compensatory mechanisms - especially an increase in left ventricular end-diastolic volume (LVEDV) in relation to regurgitant volume (RV) - whereas a rapid clinical and hemodynamic deterioration may usually be ascribed to a vicious circle consisting in a marked increase in afterload leading to an increase in LVEDV and so on. 54 patients with aortic regurgitation underwent pre- and postoperative as well as long-term follow-up radionuclide ventriculographic (RNV) studies in order to determine LVEDV and RV and to measure left ventricular ejection fraction (LVEF). These measures were expected to provide information on 'physiologic' LVEDV elevation in relation to RV. Our results indicate that if LVEDV exceeds 300-400 ml there may be an increase in afterload for LV. Factors counteracting this increased afterload (LV hypertrophy, increased diastolic stretching) will eventually preserve LVEF and keep LVEDV/RV within the normal range, but are accompanied by an elevation of LV filling pressure leading to dyspnea on exertion. With an LVEDV exceeding 400-500 ml these factors generally cannot prevent the initiation of the above mentioned vicious circle. Hence, in these severely symptomatic cases LVEDV/RV exceeds the normal range and LVEF becomes markedly depressed. An unfavorable postoperative result must be expected in these patients, while the postoperative result will be good in cases with an LVEDV/RV within the normal range. Hence, we conclude that AVR should ideally be performed in those patients with an EDV exceeding 300 ml, who still have an LVEDV/RV within the normal range, but who show clinical symptoms and/or an only moderately depressed LVEF, indicating that the limits of the compensatory mechanism are reached. The indications for AVR in other conditions characterized by the clinical status, the level of the LVEDV and LVEDV/RV are discussed.     

Right ventricular dysfunction following acute myocardial infarction in the absence of pulmonary hypertension in the mouse

Background

Cardiac remodelling after AMI is characterized by molecular and cellular mechanisms involving both the ischemic and non-ischemic myocardium. The extent of right ventricular (RV) dilatation and dysfunction and its relation to pulmonary hypertension (PH) following AMI are unknown. The aim of the current study was to evaluate changes in dimensions and function of the RV following acute myocardial infarction (AMI) involving the left ventricle (LV).

Methods

We assessed changes in RV dimensions and function 1 week following experimental AMI involving the LV free wall in 10 mice and assessed for LV and RV dimensions and function and for the presence and degree of PH.

Results

RV fractional area change and tricuspidal annular plane systolic excursion significantly declined by 33% (P = 0.021) and 28% (P = 0.001) respectively. Right ventricular systolic pressure measured invasively in the mouse was within the normal values and unchanged following AMI.

Conclusion

AMI involving the LV and sparing the RV induces a significant acute decline in RV systolic function in the absence of pulmonary hypertension in the mouse indicating that RV dysfunction developed independent of changes in RV afterload.     

Functional alterations after cardiac sodium-calcium exchanger overexpression in heart failure

The sodium-calcium exchanger (NCX) is discussed as one of the key proteins involved in heart failure. However, the causal role and the extent to which NCX contributes to contractile dysfunction during heart failure are poorly understood. NCX overexpression was induced by infection with an adenovirus coding for NCX, which coexpressed green fluorescence protein (GFP) (AdNCX) by ex vivo gene transfer to nonfailing and failing rabbit cardiomyocytes. Myocardial gene transfer in rabbits in vivo was achieved by adenoviral delivery via aortic cross-clamping. Peak cell shortening of cardiomyocytes was determined photo-optically. Hemodynamic parameters in vivo were determined by echocardiography (fractional shortening) and tip catheter [maximal first derivative of left ventricular (LV) pressure (dP/dt(max)); maximal negative derivative of LV pressure (-dP/dt(max))]. Peak cell shortening was depressed after NCX gene delivery in isolated nonfailing and in failing cardiomyocytes. In nonfailing rabbits in vivo, basal systolic contractility (fractional shortening and dP/dt(max)) and maximum rate of LV relaxation (-dP/dt(max)) in vivo were largely unaffected after NCX overexpression. However, during heart failure, long-term NCX overexpression over 2 wk significantly improved fractional shortening and dP/dt(max) compared with AdGFP-infected rabbits, both without inotropic stimulation and after beta-adrenergic stimulation with isoproterenol. -dP/dt(max) was also improved after NCX overexpression in the failing rabbits group. These results indicate that short-term effects of NCX overexpression impair contractility of isolated failing and nonfailing rabbit cardiomyocytes. NCX overexpression over 2 wk in vivo does not seem to affect myocardial contractility in nonfailing rabbits. Interestingly, in vivo overexpression of NCX decreased the progression of systolic and diastolic contractile dysfunction and improved beta-adrenoceptor-mediated contractile reserve in heart failure in rabbits in vivo.     

Load-insensitive measurements from an isolated perfused biventricular working rat heart

To determine whether a rat heart model can provide load-insensitive measurements of cardiac function, a recently developed biventricular perfused preparation was tested. Using 29 Sprague-Dawley rat hearts perfused with modified Krebs-Henseleit buffer, ventricles functioned simultaneously with adjustable independent preload (venous reservoirs) and afterload (compliance chambers). Ultrasonic crystal pairs provided continuous left (LV) and right ventricular (RV) short-axis dimensions. LV and RV pressure-length loops (loop area = work) were generated from paired intraventricular pressure and short-axis dimensions. Load-insensitive measurements were obtained from the slopes (elastance) and x-intercepts (L₀) of regression lines generated from the end-systolic coordinates of these pressure-length loops over ranges of RV and LV preloads. Measurements were made after 15 min of stable function and after 20 min of warm (37°C) ischemia. During perturbations in LV afterload, there were linear changes in dP/dt, but loop work remained relatively unchanged. RV dP/dt and work varied little with physiologic ranges of afterload. Increased RV afterload had little effect on LV function. Ischemia affected LV function more than RV function using these measurements. Elastance, however, increased after ischemia with diastolic creep (increased L₀) for both ventricles. Load-insensitive and other sophisticated hemodynamic measurements are possible with this new preparation.     

Indexes of diastolic RV function: load dependence and changes after chronic RV pressure overload in lambs

Diastolic function is a major determinant of ventricular performance, especially when loading conditions are altered. We evaluated biventricular diastolic function in lambs and studied possible load dependence of diastolic parameters [minimum first derivative of pressure vs. time (dP/dt(min)) and time constant of isovolumic relaxation (tau)] in normal (n = 5) and chronic right ventricular (RV) pressure-overloaded (n = 5) hearts by using an adjustable band on the pulmonary artery (PAB). Pressure-volume relations were measured during preload reduction to obtain the end-diastolic pressure-volume relationship (EDPVR). In normal lambs, absolute dP/dt(min) and tau were lower in the RV than in the left ventricle whereas the chamber stiffness constant (b) was roughly the same. After PAB, RV tau and dP/dt(min) were significantly higher compared with control. The RV EDPVR indicated impaired diastolic function. During acute pressure reduction, both dP/dt(min) and tau showed a relationship with end-systolic pressure. These relationships could explain the increased dP/dt(min) but not the increased tau-value after banding. Therefore, the increased tau after banding reflects intrinsic myocardial changes. We conclude that after chronic RV pressure overload, RV early relaxation is prolonged and diastolic stiffness is increased, both indicative of impaired diastolic function.