Reduced Left Ventricular Contractility Research Articles

Contractile Dysfunction of Left Ventricular Cardiomyocytes in Patients With Pulmonary Arterial Hypertension

BackgroundAfter lung transplantation, increased left ventricular (LV) filling can lead to LV failure, increasing the risk of post-operative complications and mortality. LV dysfunction in pulmonary arterial hypertension (PAH) is characterized by a reduced LV ejection fraction and impaired diastolic function. ObjectivesThe pathophysiology of LV dysfunction in PAH is incompletely understood. This study sought to assess the contribution of atrophy and contractility of cardiomyocytes to LV dysfunction in PAH patients. MethodsLV function was assessed by cardiac magnetic resonance imaging. In addition, LV biopsies were obtained in 9 PAH patients and 10 donors. The cross-sectional area (CSA) and force-generating capacity of isolated single cardiomyocytes was investigated. ResultsMagnetic resonance imaging analysis revealed a significant reduction in LV ejection fraction in PAH patients, indicating a reduction in LV contractility. The CSA of LV cardiomyocytes of PAH patients was significantly reduced (∼30%), indicating LV cardiomyocyte atrophy. The maximal force-generating capacity, normalized to cardiomyocyte CSA, was significantly reduced (∼25%). Also, a reduction in the number of available myosin-based cross-bridges was found to cause the contractile weakness of cardiomyocytes. This finding was supported by protein analyses, which showed an ∼30% reduction in the myosin/actin ratio in cardiomyocytes from PAH patients. Finally, the phosphorylation level of sarcomeric proteins was reduced in PAH patients, which was accompanied by increased calcium sensitivity of force generation. ConclusionsThe contractile function and the CSA of LV cardiomyocytes is substantially reduced in PAH patients. We propose that these changes contribute to the reduced in vivo contractility of the LV in PAH patients.

Long-term Cardiovascular Toxicity in Children, Adolescents, and Young Adults Who Receive Cancer Therapy: Pathophysiology, Course, Monitoring, Management, Prevention, and Research Directions

Cancer is diagnosed in >12 000 children and adolescents in the United States each year.1 Progress in cancer therapeutics over the past 40 years has remarkably improved survival rates for most childhood malignancies. For all pediatric cancers, 5-year survival increased from 58% for children diagnosed between 1975 and 1977 to 82% for those diagnosed between 1999 and 2006.2 In the United States, this success translates into >325 000 survivors of childhood cancer, of whom 24% are now >30 years from diagnosis.3 During this same period, the incidence of many histological subtypes of childhood cancer has increased, including acute lymphoblastic leukemia (ALL), acute myeloid leukemia, non-Hodgkin lymphoma, neuroblastoma, and soft-tissue and germ-cell tumors.3 Consequently, the number of childhood cancer survivors is expected to increase as a result of the rising pediatric cancer incidence and improved long-term survival rates.3 The increasing number of survivors soon revealed acute and delayed modality-specific toxicities and their impact on quality of life and early mortality. In their seminal 1974 publication, Meadows and D’Angio4 described the wide array of potential late effects of successful therapy for childhood cancer. In the past 2 decades, the Childhood Cancer Survivor Study has also improved our understanding of the long-term mortality and morbidity in this high-risk population. Among young adult survivors of childhood cancer diagnosed between 1970 and 1986, at least 1 of 6 domains of health status (general health, mental health, functional status, activity limitations, cancer-related pain, and cancer-related anxiety) declined moderately to severely in 44%.5 The cumulative incidence of a chronic health condition 30 years after cancer diagnosis is now 73%, with a cumulative incidence of 42% for severe, disabling, or life-threatening conditions or death attributable to a chronic condition.6 Also by 30 years after cancer diagnosis, the cumulative mortality rate from causes …

Prevalence, Clinical Characteristics, and Outcomes Associated With Eccentric Versus Concentric Left Ventricular Hypertrophy in Heart Failure With Preserved Ejection Fraction

Although concentric remodeling (CR) and concentric hypertrophy (CH) are common forms of left ventricular (LV) remodeling in heart failure with preserved ejection fraction (HFpEF), eccentric hypertrophy (EH) can also occur in these patients. However, clinical characteristics and outcomes of EH have not been well described in HFpEF. We prospectively studied 402 patients with HFpEF, divided into 4 groups based on LV structure: normal geometry (no LV hypertrophy [LVH] and relative wall thickness [RWT] ≤0.42); CR (no LVH and RWT >0.42); CH (LVH and RWT >0.42); and EH (LVH and RWT ≤0.42). We compared clinical, laboratory, echocardiographic, invasive hemodynamic, and outcome data among groups. Of 402 patients, 48 (12%) had EH. Compared with CH, patients with EH had lower systolic blood pressure and less renal impairment despite similar rates of hypertension. After adjustment for covariates, EH was associated with reduced LV contractility compared with CH: lower LVEF (β coefficient=-3.2; 95% confidence interval [CI]-5.4 to-1.1%) and ratio of systolic blood pressure to end-systolic volume (βcoefficient=-1.0; 95% CI-1.5 to-0.5 mmHg/ml). EH was also associated with increased LV compliance compared with CH (LV end-diastolic volume at an idealized LV end-diastolic pressure of 20 mmHg β coefficient= 14.2; 95% CI 9.4 to 19.1 ml). Despite these differences, EH and CH had similarly elevated cardiac filling pressures and equivalent adverse outcomes. In conclusion, the presence of EH denotes a distinct subset of HFpEF that is pathophysiologically similar to HF with reduced EF (HFrEF) and may benefit from HFrEF therapy.

Taurine attenuates oxidative stress and alleviates cardiac failure in type I diabetic rats

AimTo investigate cardioprotective effect of taurine in diabetic rats.MethodsMale Sprague-Dawley rats were assigned randomly into four groups of 15 rats: control group, control + taurine group, streptozotocin (STZ) group, and STZ + taurine group. Rats in STZ and STZ+ taurine groups were treated by a single injection of STZ (70 mg kg-1, intraperitoneally) dissolved in 0.01 M citrate buffer (pH 4.5) for induction of diabetes, and rats in control and control + taurine groups were treated with the same volume citrate buffer. Taurine was orally administered to rats in control + taurine and STZ + taurine groups daily for 8 weeks. Rats were examined for diabetic cardiomyopathy by left ventricular (LV) hemodynamic analysis. Myocardial oxidative stress was assessed by measuring the activity of superoxide dismutase (SOD) and the level of malondialdehyde (MDA). Myocardial protein kinase B (Akt/PKB) phosphorylation and heme oxygenase-1 (HO-1) protein levels were measured by Western blot in all rats at the end of the study.ResultsIn untreated diabetic rats, LV systolic pressure, rate of pressure rise, and rate of pressure fall were decreased, while LV end-diastolic pressure was increased, indicating reduced LV contractility and slowing of LV relaxation. The levels of Akt/PKB phosphorylation and SOD activity were decreased and HO-1 protein expression and MDA content increased. Taurine treatment significantly improved LV systolic and diastolic function, and there were persistent increases in activities of Akt/PKB and SOD, and the level of HO-1 protein.ConclusionTaurine treatment ameliorates myocardial function and heart oxidant status, while increasing myocardial Akt/PKB phosphorylation, and HO-1 levels have beneficial effects on diabetic cardiomyopathy.

Phytochemical screening and evaluation of cardioprotective activity of ethanolic extract of Ocimum basilicum L. (basil) against isoproterenol induced myocardial infarction in rats.

Background and the purpose of the studyThe objectives of the present study were phytochemical screening and study of the effects of ethanolic extract of aerial parts of Ocimum basilicum (basil) on cardiac functions and histopathological changes in isoproterenol-induced myocardial infarction (MI).MethodsThe leaves of the plant were extracted with ethanol by maceration and subjected to colorimetry to determine flavonoids and phenolic compounds. High-performance TLC analysis and subsequent CAMAG's TLC scanning were performed to quantify rosmarinic acid content. Wistar rats were assigned to 6 groups of normal control, sham, isoproterenol, and treatment with 10, 20, and 40 mg/kg of the extract two times per day concurrent with MI induction. A subcutaneous injection of isoproterenol (100 mg/kg/day) for 2 consecutive days was used to induce MI.ResultsPhytochemical screening indicated the presence of phenolic compounds (5.36%) and flavonoids (1.86%). Rosmarinic acid was the principal phenolic compound with a 15.74% existence. The ST-segment elevation induced by isoproterenol was significantly suppressed by all doses of the extract. A severe myocardial necrosis and fibrosis with a sharp reduction in left ventricular contractility and a marked increase in left ventricular end-diastolic pressure were seen in the isoproterenol group, all of which were significantly improved by the extract treatment. In addition to in-vitro antioxidant activity, the extract significantly suppressed the elevation of malondialdehyde levels both in the serum and the myocardium.ConclusionThe results of the study demonstrate that Ocimum basilicum strongly protected the myocardium against isoproterenol-induced infarction and suggest that the cardioprotective effects could be related to antioxidative activities.

O pré-condicionamento isquêmico influencia a contratilidade ventricular na cirurgia sem extracorpórea

Ischemic preconditioning is a method that prepares and protects cells to tolerate a long period of ischemia with the least possible injury. Evaluate the influence of ischemic preconditioning over left ventricular function during off-pump myocardial revascularization. Forty patients with clinical indication for off-pump myocardial revascularization were randomized in two groups, with or without ischemic preconditioning. Ischemic preconditioning was carried out by performing coronary occlusion for two minutes and releasing blood flow for one minute; two cycles were performed. Left ventricular contractility was evaluated through transesophageal Doppler by measuring blood flow acceleration in the descending aorta - Hemosonic 100. The acceleration measurements were performed at the start of the surgery, after heart positioning and five and ten minutes after coronary occlusion. There was no significant difference in left ventricular contractility between the two groups. At the beginning of the procedure flow acceleration was 9.37 +/- 2.9m/s(2) in the preconditioning group and 12.5 +/- 3.1 m/s(2) in no-preconditioning group (p = 0.23); after positioning of heart, it was 8.47 +/- 3.3 and 8.31 +/- 3.6 m/s(2) (p = 0.96); after five minutes - 8.7 +/- 4.1 and 7.94 +/- 2.9 m/s(2) (p = 0.80); and after ten minutes - 9.2 +/- 4.5 and 7.98 +/- 3.4 m/s(2) (p = 0.71). However, contractility evolution was different throughout time in each group. The preconditioning group maintained left ventricular contractility during the entire procedure, since the beginning (0.52), while the group without ischemic preconditioning presented reduction in left ventricular contractility (p = 0.0034). Ischemic preconditioning prevented the decrease in left ventricular contractility during off-pump myocardial revascularization surgery.

Left Ventricular Septal and Left Ventricular Apical Pacing Chronically Maintain Cardiac Contractile Coordination, Pump Function and Efficiency

Conventional right ventricular (RV) apex pacing can lead to adverse clinical outcome associated with asynchronous activation and reduced left ventricular (LV) pump function. We investigated to what extent alternate RV (septum) and LV (septum, apex) pacing sites improve LV electric activation, mechanics, hemodynamic performance, and efficiency over 4 months of pacing. After AV nodal ablation, mongrel dogs were randomized to receive 16 weeks of VDD pacing at the RV apex, RV septum, LV apex, or LV septum (transventricular septal approach). Electric activation maps (combined epicardial contact and endocardial noncontact) showed that RV apical and RV septal pacing induced significantly greater electric desynchronization than LV apical and LV septal pacing. RV apex and RV septal pacing also significantly increased mechanical dyssynchrony, discoordination (MRI tagging) and blood flow redistribution (microspheres) and reduced LV contractility, relaxation, and myocardial efficiency (stroke work/myocardial oxygen consumption). In contrast, LV apical and LV septal pacing did not significantly alter these parameters as compared with the values during intrinsic conduction. At 16 weeks, acute intrasubject comparison showed that single-site LV apical and LV septal pacing generally resulted in similar or better contractility, relaxation, and efficiency as compared with acute biventricular pacing. Acute and chronic LV apical and LV septal pacing maintain regional cardiac mechanics, contractility, relaxation, and efficiency near native levels, whereas RV apical or RV septal pacing diminish these variables. Acute LV apical and LV septal pacing tend to maintain or improve contractility and efficiency compared with biventricular pacing.

Mitral valve regurgitation and left ventricular systolic dysfunction: Corrective surgery or cardiac resynchronization therapy?

Mitral regurgitation (MR) can be found in a sizeable percentage of patients with chronic congestive heart failure (CHF) and systolic left ventricular (LV) dysfunction despite a structurally normal valve. This functional or secondary regurgitation results from a dysbalance between closing and opening forces on the mitral leaflets due to reduced LV contractility, geometric distortion of the subvalvular apparatus, and global dilatation of the left ventricle and the mitral annulus. MR in LV dysfunction has a negative impact on both symptoms and prognosis. Surgical correction of secondary MR remained controversial although it was found to be technically feasible and to provide symptomatic benefit in some (mostly) mono-center series. Cardiac resynchronization therapy (CRT) was also found to improve secondary mitral regurgitation. However, the prediction in which patient significant secondary MR will improve with CRT is largely unresolved. The following paper reviews the available data concerning the two major interventional options for significant secondary MR in patients with CHF and systolic LV dysfunction, i.e. mitral valve surgery vs. CRT, and describes our institutional approach to this problem.

Left ventricular contractile function is preserved during prolonged exercise in middle-aged men

We examined left ventricular (LV) performance before, during, and following prolonged exercise (EX) in 12 healthy middle-aged men [means +/- SE: age = 43.5 +/- 1.9 yr; maximal O(2) uptake (Vo(2max)) = 51.7 +/- 1.5 ml.kg(-1).min(-1)]. Subjects cycled for 120 min at 65% Vo(2max) (75% of maximal heart rate). Two-dimensional echocardiography (ECHO) to determine tissue-Doppler longitudinal myocardial strain and strain rate, LV ejection fraction (EF), end-diastolic (EDV), end-systolic (ESV), and stroke volume (SV) at baseline and after 5, 30, and 120 min of EX and following 30 min of recovery. In addition, hematocrit and plasma norepinephrine (NE) were measured. From baseline to 5 min of EX, there were significant increases in LV longitudinal strain (-23.20 +/- 0.87 to -27.63 +/- 1.07%; P < 0.01), strain rate (-1.50 +/- 0.15 to -2.08 +/- 0.14 s(-1); P < 0.01), and EF (56.3 +/- 2.2 to 77.1 +/- 1.0%; P < 0.05) with continued increases by both at 30 min of exercise vs. SV, EDV, and ESV, which remained constant. After 120 min of EX, HR and NE increased further with reductions in SV, cardiac output, and systolic blood pressure without changes in strain or strain rate. EDV decreased after 120 min of EX (-9.2- vs. 30-min value; P = 0.05) along with a hemoconcentration (baseline = 41.3 +/- 1.0 vs. EX = 45.1 +/- 1.2%; P < 0001) and significant reduction in body mass despite a mean fluid consumption of 1.8 +/- 0.2 liters throughout EX. After 30 min of recovery, LV longitudinal strain was depressed relative to baseline (-23.20 +/- 0.87 to -19.57 +/- 1.21%; P < 0.01). The reduction in LV SV during prolonged EX occurred without changes in the LV contractile state and is likely secondary to reduced LV preload. A reduction in LV contractility despite a reduced afterload following exercise may be due to factors unique to the recovery period and do not appear to contribute to a reduction in SV during prolonged exercise.

Altered expression of connexin43 contributes to the arrhythmogenic substrate during the development of heart failure in cardiomyopathic hamster

Heart failure is known to predispose to life-threatening ventricular tachyarrhythmias even before compromising the systemic circulation, but the underlying mechanism is not well understood. The aim of this study was to clarify the connexin43 (Cx43) gap junction remodeling and its potential role in the pathogenesis of arrhythmias during the development of heart failure. We investigated stage-dependent changes in Cx43 expression in UM-X7.1 cardiomyopathic hamster hearts and associated alterations in the electrophysiological properties using a high-resolution optical mapping system. UM-X7.1 hamsters developed left ventricular (LV) hypertrophy by ages 6 approximately 10 wk and showed a moderate reduction in LV contractility at age 20 wk. Appreciable interstitial fibrosis was recognized at these stages. LV mRNA and protein levels of Cx43 in UM-X7.1 were unaffected at age 10 wk but significantly reduced at 20 wk. The expression level of Ser255-phosphorylated Cx43 in UM-X7.1 at age 20 wk was significantly greater than that in control golden hamsters at the same age. In UM-X7.1 at age 10 wk, almost normal LV conduction was preserved, whereas the dispersion of action potential duration was significantly increased. UM-X7.1 at age 20 wk showed significant reduction of cardiac space constant, significant decrease in conduction velocity, marked distortion of activation fronts, and pronounced increase in action potential duration dispersion. Programmed stimulation resulted in sustained ventricular tachycardia or fibrillation in UM-X7.1. LV activation during polymorphic ventricular tachycardia was characterized by multiple phase singularities or wavebreaks. During the development of heart failure in the cardiomyopathic hamster, alterations of Cx43 expression and phosphorylation in concert with interstitial fibrosis may create serious arrhythmogenic substrate through an inhibition of cell-to-cell coupling.

Dietary Supplementation With Vitamin E Ameliorates Cardiac Failure in Type I Diabetic Cardiomyopathy by Suppressing Myocardial Generation of 8- iso-Prostaglandin F 2α and Oxidized Glutathione

Background Diabetic cardiomyopathy has been documented as an underlying cause of heart failure in diabetic patients. Although oxidative stress has been implicated in diabetic cardiomyopathy, much of the current evidence lacks specificity. Furthermore, studies investigating antioxidant protection with vitamin E in this unique cardiac phenomenon have yet to be performed. In the present study, we sought to determine whether vitamin E supplementation can confer cardioprotective effects against diabetic cardiomyopathy in relation to specific and quantitative markers of myocardial oxidative stress. Methods and Results Diabetes was induced in rats by a single injection of streptozotocin. Animals were fed either a basal diet or a diet enriched with 2000 IU of vitamin E per kilogram beginning immediately after induction of diabetes and continued for 8 weeks. Rats were examined for diabetic cardiomyopathy by left ventricular (LV) hemodynamic analysis. Myocardial oxidative stress was assessed by measuring the formation of 8- iso-prostaglandin F 2α and oxidized glutathione. In the unsupplemented streptozotocin-diabetic rats, LV systolic pressure, rate of pressure increase (+dP/dt), and rate of pressure decay (−dP/dt) were depressed, whereas LV end-diastolic pressure was increased, indicating reduced LV contractility and slowing of LV relaxation. These hemodynamic alterations were accompanied by increased myocardial formation of 8- iso-prostaglandin F 2α and oxidized glutathione. Vitamin E supplementation improved LV function and significantly attenuated myocardial 8- iso-prostaglandin F 2α and oxidized glutathione accumulation in streptozotocin-diabetic rats. Conclusions These findings demonstrate the usefulness of vitamin E supplementation during the early phases of type I diabetes for the prophylaxis of cardiomyopathy and subsequent heart failure.

Abstract 867: The Longevity Factor Sirt1 Exacerbates LV Dysfunction and Energy Depletion in Response to Pressure Overload

Sirt1, a class III histone deacetylase, extends the lifespan of many organisms. Longevity mechanisms usually confer stress resistance to organisms, and accumulation of stress resistance leads to lifespan extension. We have shown previously that Sirt1 is upregulated by stress up to 10 fold in the heart, and heart specific overexpression (up to 7.5 fold) of Sirt1 in mice not only suppresses histological/biochemical markers of aging, but also induces resistance to oxidative stress in the heart. We examined whether Sirt1 is protective against another pathologically relevant stimulus, namely pressure overload. Cardiac specific Sirt1 transgenic mice (Tg-Sirt1) from line #40, the line which has been shown to be protected against aging and oxidative stress, were subjected to transverse aortic constriction (TAC). Unexpectedly, at 10 days, the left ventricular (LV) ejection fraction (EF) in Tg-Sirt1 was significantly reduced (46 vs 71%, p&lt;0.01), the LV end diastolic dimension was significantly increased (4.1 vs 3.4 mm, p&lt;0.05), and the pressure gradient was reduced (92 vs 57 mmHg, p&lt;0.05), possibly due to reduced LV contractility, in Tg-Sirt1 compared with non-transgenic (NTg) controls. At 4 weeks, LV weight/body weight (BW) (6.4 vs 4.7, p&lt;0.05) and lung weight/BW (18.8 vs 7.0, p&lt;0.05) were significantly increased in Tg-Sirt1, LV +dP/dt was significantly reduced (4617 vs 7513, p&lt;0.05), and the LV end diastolic pressure was significantly elevated (13.6 vs 1.4 mmHg, p&lt;0.05) in Tg-Sirt1 compared with NTg. These results suggest that Tg-Sirt1 mice develop more severe LV dysfunction than NTg in response to TAC. Tg-Sirt1 mice exhibited significantly less apoptosis (−50%, p&lt;0.05) than NTg however, despite the development of LV dysfunction, suggesting that the LV dysfunction may be caused by apoptosis-independent mechanisms. The myocardial ATP content in Tg-Sirt1 was significantly less (−41%, p&lt;0.05) than that in NTg after TAC. These results suggest that the cardioprotective effect of Sirt1 depends on the type of stress: although modest expression of Sirt1 confers resistance to aging and oxidative stress, it exacerbates heart failure in response to TAC through apoptosis-independent mechanisms possibly involving energy depletion.

When and how does cardiac resynchronization therapy reduce dynamic mitral regurgitation?

Cardiac resynchronization therapy (CRT) improves clinical status, quality of life, and exercise capacity, promotes reverse left ventricular (LV) remodelling, and prolongs survival of selected heart failure patients with intraventricular conduction delay.1,2 However, 30% of patients do not respond to CRT. Response to CRT largely depends on the extent of LV dyssynchrony, but also on the severity of functional mitral regurgitation (MR). Responders are characterized by a decrease in LV dyssynchrony—restoration of a more normal ventricular activation pattern—and in MR degree. Functional MR results from an imbalance between tethering forces—annular dilatation, LV dilatation, papillary muscle displacement, and LV sphericity—and closing forces—reduction of LV contractility, global LV dyssynchrony, papillary muscle asynchrony, and altered mitral systolic annular contraction.3 CRT acutely reduces functional MR by increasing closing forces with an improvement in LV d P /d t 4 and by improving co-ordinated timing of mechanical activation of papillary muscle insertion sites.5 This benefit appeared to be dependent on continued pacing because withholding pacing resulted in an immediate loss of effect and recurrence of MR.6 Functional MR is characteristically dynamic during exercise. The magnitude of exercise-induced changes in MR … *Corresponding authors. Tel. +32-4-366-71-94; fax +32-4-366-71-95. E-mail address : lpierard{at}chu.ulg.ac.be and plancellotti{at}chu.ulg.ac.be

Development of Right Ventricular Dysfunction in Acute Myocardial Infarction and Chronic Heart Failure

Objective: to evaluate the structural and functional state of the right cardiac cavities in acute left ventricular myocardial infarction and in progressive chronic heart failure (CHF) in patients with coronary heart disease. Materials and methods. 20 patients with acute myocardial infarction and 48 with postinfarct cardiosclerosis with NYHA functional classes I to IV CHF were examined. The structural and functional state of the right heart was evaluated in progressive left ventricular systolic and diastolic dysfunction by echocardiography. Results. In the acute period of infarction, remodeling processes occur in the left ventricle, with normal postload values, volumetric indices and right ventricular contractility are in the normal range. There is right cardiac dilatation at the early stage of left ventricular systolic and diastolic dysfunction in postinfarct remodeling and evolving CHF, normal pulmonary arterial and right atrial pressures. With a significant reduction in left ventricular contractility and its pronounced filling impairment, increases in post- and preload for the right ventricle occur with a just considerable change in its structural and functional state. Conclusion. In impaired myocardial relaxation in the presence of CHF, remodeling of the right cardiac cavities takes place without the influence of a hemodynamic factor. There is a close relationship of remodeling of both ventricles from the very early CHF stages, which suggests that there are common pathogenetic mechanisms responsible for the development of myocardial dysfunction.

Abstract 566: Altered Expression of Connexin43 Contributes to the Arrhythmogenic Substrate in Early Stage Heart Failure of Cardiomyopathic Hamster

Background: Heart failure is known to predispose life-threatening ventricular tachyarrhythmias even before compromising the systemic circulation, but the underlying mechanism is not well understood. Methods and Results : We investigated stage-dependent changes in connexin43 (Cx43) expression and consequent electrophysiological properties in UM-X7.1 cardiomyopathic hamster hearts. UM-X7.1 hamsters develop left ventricular (LV) hypertrophy by age 6~10w, and show more pronounced LV hypertrophy and a moderate reduction in LV contractility at age 20w. Appreciable interstitial fibrosis is recognized at these stages. LV mRNA and protein levels of Cx43 in UM-X7.1 were unaffected at 10w, but significantly reduced at 20w (by 33% and 55%, respectively from controls). The relative expression level of serin255-phosphorylated Cx43 was markedly increased in UM-X7.1 at age 20w (by 175%). Electrophysiological properties were examined by optical mapping. In UM-X7.1 at 10w, almost normal LV conduction was preserved, whereas the dispersion of action potential duration (APD) was significantly increased. UM-X7.1 at 20w showed significant reduction of conduction velocity (by 35~40%), significant prolongation of APD (by 68%), marked distortion of activation fronts and a pronounced increase in APD dispersion. Programmed stimulation resulted in no arrhythmias in controls, but sustained ventricular tachycardia or fibrillation (VT/VF &gt;5s) in UM-X7.1 (1/11 at 10w and 5/6 at 20w). LV activation during polymorphic VT was characterized by multiple phase singularities or wavebreaks. Conclusions : In the early stage heart failure of cardiomyopathy, down-regulation and serine255-phosphorylation of Cx43 in addition to the interstitial fibrosis may contribute to the arrhythmogenic substrate through the inhibition of cell-to-cell communication.

Functional mitral regurgitation in acute coronary syndrome: what determines its prognostic impact?

Functional mitral regurgitation (MR) is frequently present in patients with acute coronary syndrome and can be observed by contrast ventriculography or Doppler echocardiography.1–5 It is, however, poorly detected by auscultation.1,6 Ischaemic MR results from either tethering force that restricts the ability of the mitral leaflets to close, reduced left ventricular (LV)-generated closing force, or both.7 Tethering is produced by global LV remodelling—increased LV sphericity and annular dilation—or more frequently by mitral valve distortion, characterized by systolic valvular tenting due to apical and outward displacement of the posterior papillary muscle or of both papillary muscles. Reduced closing force can be determined by reduced LV contractility or LV regional dyssynchrony. In the acute phase of myocardial infarction (MI), MR may pre-exist or result from the acute event through regional LV dilation and loss of contraction. Most studies have shown that functional MR in early MI is associated with a worse prognosis and is an important, independent predictor of cardiovascular mortality. The incidence of functional MR in the prospective studies is highly dependent on the method used to document it. The lowest frequency (9%) is observed when the detection of the MR relies only on cardiac auscultation.8 The frequency varies from 13 to 19% when MR is diagnosed by contrast ventriculography.1–3 The highest incidence is found, not surprisingly, in the trials using Doppler echocardiography.4,5 Several clinical parameters characterize patients with acute MI and MR when compared with patients without MR. The patients with MR … Corresponding author. Tel: +32 4 366 71 94; fax: +32 4 366 71 95. E-mail address : lpierard{at}chu.ulg.ac.be

313: Quantification of left ventricular mechanical dyssynchrony by conductance catheter in the failing heart: Effect of biventricular pacing

Mechanical dyssynchrony is important codeterminant of cardiac dysfunction in heart failure. We evaluated new indexes to quantify temporal and spatial aspects of mechanical dyssynchrony derived from on-line segmental conductance catheter signals. To test the feasibility and usefulness of our approach, we determined cardiac function and left ventricular (LV) dyssynchrony in normal (n=6) and failing canine hearts (rapid pacing: 180 min-1, 12 weeks, n=7) before and after biventricular pacing. Segmental signals were defined as dyssynchronous at each time point if its change were opposite to the simultaneous change in the total LV volume. Overall dyssynchrony was calculated as the mean of the segmental dyssynchronies during systole (DYSsys) and diastole (DYSdias). Ineffective blood shifting within the LV (IBF) was calculated as the sum of the absolute volume changes of all segments and subtracting the total absolute total volume change and expressed as percent fraction of total effective flow. Mechanical dispersion (DISP) was assessed by segmental lag times. LV contractility was described by the slope of the endsystolic pressure-volume relationships (Ees). Pacing induced heart failure led to significantly reduced Ees. Indexes of LV dyssynchrony were increased in the heart failure group. Biventricular pacing improved Ees by reduction of mechanical dyssynchrony (Table 1). Pacing induced heart failure in canines leads to reduced LV contractility and significant LV mechanical dyssynchrony which can be improved by biventricular pacing. The proposed indexes provide additional, new and quantitative information on temporal and spatial aspects of mechanical dyssynchrony and may refine diagnosis of cardiac dysfunction and evaluation of interventions. Table 1 Control Heart Failure Biventricular pacing Ees 6.9 ± 1.0 2.3 ± 0.3 3.7 ± 0.2† DYSsys 9 ± 8 39 ± 7 12 ± 7† DYSdias 3 ± 2 41 ± 7 13 ± 6† DISP 18 ± 7 70 ± 15 27 ± 7† IBF 11 ± 4 66 ± 12 23 ± 7† p < 0.05 vs control †p < 0.05 vs heart failure Open table in a new tab

Cardiac Resynchronization Therapy

Left ventricular (LV) dysynchrony, generally defined as the effect of intraventricular conduction defects or bundle branch block to produce nonsynchronous ventricular activation, places the failing heart at a further mechanical disadvantage. The deleterious effects of ventricular dysynchrony include suboptimal ventricular filling, paradoxical septal wall motion, reduced LV contractility, increased mitral regurgitation, and poor clinical outcomes (eg, increased hospitalization and mortality). The clinical and mechanical manifestations of ventricular dysynchrony can be treated by simultaneously pacing both the right and left ventricles usually in association with right atrial sensing, resulting in atrial-synchronized biventricular pacing or cardiac resynchronization therapy (CRT). The weight of evidence supporting the routine use of CRT in patients with heart failure with ventricular dysynchrony is now quite substantial. More than 4000 patients have been evaluated in randomized controlled trials of CRT, and several thousand additional patients have been assessed in observational studies and in registries. Data from these studies have consistently demonstrated the safety and efficacy of CRT in patients with New York Heart Association class III and IV heart failure. Cardiac resynchronization therapy has been shown to significantly improve LV structure and function, New York Heart Association functional class, exercise tolerance, quality of life, and morbidity and mortality.

Compensated hypertrophy of cardiac ventricles in aged transgenic FVB/N mice overexpressing calsequestrin.

Cardiac-specific overexpression of murine cardiac calsequestrin results in depressed contractile parameters and hypertrophy in transgenic mice. To determine the long-term consequences of calsequestrin overexpression, the cardiac phenotype of young (2-3-months old) and aged (17 months old) transgenic FVB/N mice was characterized. Ventricular/body weight ratios, which were increased in young transgenics compared with wild-types, were unaltered with age. Left atria of aged transgenics exhibited enlargement and mineralization, but their ventricles did not display fibrosis, mineralization and other injuries. Although echocardiography suggested a time-dependent change in ventricular geometry and loading conditions in vivo, as well as an age-dependent reduction of left ventricular fractional shortening in transgenic mice, Langendorff-perfused hearts of young and aged transgenics indicated that there were no age-related reductions of contractile parameters (+/-dP/dt). Furthermore, neither genotype nor age altered lung/body weight ratios. Thus, our findings suggest that left ventricular performance in calsequestrin overexpressing mice becomes apparently depressed with age, but this depression is not associated with progressive reduction of left ventricular contractility and heart failure.

The left ventricular stress-velocity relation in transgenic mice expressing a dominant negative CREB transgene in the heart

Objective: CREBA133 transgenic mice that express a dominant negative CREB transcription factor in cardiomyocytes develop a dilated cardiomyopathy that is anatomically, physiologically, and clinically similar to human idiopathic dilated cardiomyopathy. The goals of this study were to quantitate left ventricular (LV) contractility and measure cardiac reserve in CREBA133 mice by using the relation of end-systolic wall stress to the velocity of fiber shortening. Methods: A total of 37 adult CD-1 mice (including both nontransgenic and CREBA133 transgenic mice) were studied with simultaneously acquired high-fidelity instantaneous aortic pressures and 2-dimensionally targeted M-mode echocardiograms. Results: CREBA133 mice displayed significantly lower values of LV fiber shortening velocities over a wide range of afterloads, and they displayed smaller dobutamine-induced shifts from baseline contractility relations. Counterbalancing effects of differences in LV geometry and aortic pressures resulted in comparable levels of LV wall stress during ejection in both groups. Conclusion: These results demonstrate directly that CREBA133 mice display reduced LV contractility at baseline and decreased cardiac reserve. (J Am Soc Echocardiogr 2001;14:209-18.)