Preload Recruitable Stroke Work Relationship Research Articles

Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction

Background and aimsSodium–glucose linked cotransporter-2 (SGLT2) inhibitors reduce the likelihood of hospitalization for heart failure and cardiovascular death in both diabetic and non-diabetic individuals with reduced ejection fraction heart failure. Because SGLT2 inhibitors lead to volume contraction with reductions in both preload and afterload, these load-dependent factors are thought to be major contributors to the cardioprotective effects of the drug class. Beyond these effects, we hypothesized that SGLT2 inhibitors may also improve intrinsic cardiac function, independent of loading conditions.MethodsPressure–volume (P–V) relationship analysis was used to elucidate changes in intrinsic cardiac function, independent of alterations in loading conditions in animals with experimental myocardial infarction, a well-established model of HFrEF. Ten-week old, non-diabetic Fischer F344 rats underwent ligation of the left anterior descending (LAD) coronary artery to induce myocardial infarction (MI) of the left ventricle (LV). Following confirmation of infarct size with echocardiography 1-week post MI, animals were randomized to receive vehicle, or the SGLT2 inhibitor, empagliflozin. Cardiac function was assessed by conductance catheterization just prior to termination 6 weeks later.ResultsThe circumferential extent of MI in animals that were subsequently randomized to vehicle or empagliflozin groups was similar. Empagliflozin did not affect fractional shortening (FS) as assessed by echocardiography. In contrast, load-insensitive measures of cardiac function were substantially improved with empagliflozin. Load-independent measures of cardiac contractility, preload recruitable stroke work (PRSW) and end-systolic pressure volume relationship (ESPVR) were higher in rats that had received empagliflozin. Consistent with enhanced cardiac performance in the heart failure setting, systolic blood pressure (SBP) was higher in rats that had received empagliflozin despite its diuretic effects. A trend to improved diastolic function, as evidenced by reduction in left ventricular end-diastolic pressure (LVEDP) was also seen with empagliflozin. MI animals treated with vehicle demonstrated myocyte hypertrophy, interstitial fibrosis and evidence for changes in key calcium handling proteins (all p < 0.05) that were not affected by empagliflozin therapy.ConclusionEmpagliflozin therapy improves cardiac function independent of loading conditions. These findings suggest that its salutary effects are, at least in part, due to actions beyond a direct effect of reduced preload and afterload.

A Novel Large Animal Model of Thrombogenic Coronary Microembolization.

Coronary microembolization is one of the main causes of the “no-reflow” phenomenon, which commonly occurs after reperfusion of an occluded coronary artery. Given its high incidence and the fact that it has been proven to be an independent predictor of cardiac morbidity and mortality, there is an imperative need to study its underlying mechanisms and pathophysiology. Large animal models are essential to perform translational studies. Currently there is no animal model that recapitulates a clinical scenario of thrombogenic microembolism with preceding myocardial ischemia. Therefore, the goal of this study was to develop and characterize a novel pig model of coronary microembolization using autologous thrombus injection (CMET). Twenty-three pigs underwent myocardial infarction through percutaneous balloon occlusion of the left anterior descending artery (LAD). Each animal was enrolled in one of two groups: (1) the CMET group, in which the LAD occlusion was followed by delivery of autologous clotted blood in the LAD (distal to the balloon occlusion) and reperfusion; (2) the ischemic reperfusion (I/R) group, in which the LAD ischemia was followed by reperfusion. Surviving animals underwent functional and morphological characterization at 1-week post-procedure. Three sham operated animals were used as a control. CMET resulted in impaired left ventricular function compared to I/R pigs at 1 week. Three-dimensional echocardiography demonstrated reduced ejection fraction in the CMET group (CMET vs. I/R: 35.6 ± 4.2% vs. 47.6 ± 2.4%, p = 0.028). Invasive hemodynamic measurements by Swan-Ganz and left ventricular pressure-volume catheters revealed that CMET impaired left ventricular contractility and diastolic function. This was confirmed by both load-dependent indices including cardiac output (CMET vs. I/R: 2.7 ± 0.2 l/min, vs. 4.0 ± 0.1 l/min, p = 0.002) and load independent indices including preload-recruitable stroke work (CMET vs. I/R: 25.8 ± 4.0 vs. 47.5 ± 6.5 mmHg, p = 0.05) and end-diastolic pressure-volume relationship (slope, 0.68 ± 0.07 vs. 0.40 ± 0.11 mmHg/ml, p = 0.01). Our unique closed-chest model of coronary microembolization using autologous thrombus injection resembles the clinical condition of thrombogenic coronary microembolization in I/R injury. This model offers opportunities to conduct translational studies for understanding and treating coronary microembolization in myocardial infarction.

Perioperative changes of the slope in the preload recruitable stroke work relationship by a single-beat technique after mitral valve surgery in functional mitral regurgitation with non-ischemic dilated cardiomyopathy.

The slope in the preload recruitable stroke work relationship is a highly linear, load-insensitive contractile parameter. However, the perioperative change of the slope has not been reported before. We examined the perioperative slope from a steady-state single beat in patients with functional mitral regurgitation and assessed the correlation with brain natriuretic peptide (BNP) levels. The study included 16 patients with non-ischemic dilated cardiomyopathy and refractory heart failure: 10 patients underwent mitral valve plasty and left ventricular plasty (MVP + LVP group) and 6 patients who underwent mitral valve replacement and papillary muscle tugging approximation (MVR + PMTA group). The left ventricular ejection fraction was assessed by the modified Simpson method; the slope was assessed by the single-beat technique using transthoracic echocardiography. BNP levels were measured by chemiluminescent immunoassay. The left ventricular ejection fraction and slope did not significantly change from pre- to early post-surgery in the MVP + LVP group. Both the left ventricular ejection fraction and slope significantly increased 6months after surgery in the MVR + PMTA group. Postoperative BNP level was low in the MVR + PMTA group. While the postoperative left ventricular ejection fraction did not correlate with BNP levels, the postoperative slope significantly correlated with BNP level after surgery in the MVP + LVP group and in the total functional mitral regurgitation group. The change of slope was dependent on surgical procedures. In functional mitral regurgitation, the slope may be a more sensitive parameter in reflecting the left ventricular contractile function than the left ventricular ejection fraction.

Triple Contractile Imaging in the Stress Echo Lab: the Additive Prognostic Value of Pressure–Volume and Preload Recruitable Stroke Work Relationships

Introduccion: La positividad del ecoestres a traves de alteraciones de la motilidad parietal ha ido cediendo terreno frente a nuevas propuestas basadas en la reserva contractil del ventriculo izquierdo (indice stress/reposo de la elastancia ventricular izquierda). Por otra parte, la pendiente del trabajo latido reclutable por precarga, es decir, la pendiente de la relacion trabajo latido y volumen de fin de diastole proporciona una medida independiente de la precarga y la poscarga. Objetivo: El proposito de este estudio fue evaluar el valor pronostico adicional de la reserva contractil ventricular izquierda y la pendiente del trabajo latido reclutable por precarga. Metodos: Se seleccionaron 692 pacientes de la base de datos del estudio multicentrico de ecoestres del Consejo Nacional de Investigaciones (Consiglio Nazionale delle Ricerche, CNR), con edad media de 62 ± 12 anos, ecoestres negativo (ejercicio = 130; dipiridamol = 438; dobutamina n = 124) y sin dilatacion (n = 470) o miocardiopatia idiopatica dilatada (n = 22). Todos los pacientes fueron sometidos a triple imagen: 1) evaluacion de alteraciones de la motilidad parietal; 2) evaluacion de la reserva contractil ventricular izquierda; y 3) evaluacion de la pendiente del trabajo latido reclutable por precarga. Resultados: De acuerdo a la norma de seleccion, todos los pacientes tuvieron un estudio de ecoestres negativo segun el criterio de motilidad parietal alterada; la tasa de positividad global fue de 49% para la reserva contractil, 36% para la pendiente del trabajo latido reclutable por precarga (criterio de positividad ≤ 64 erg × cm−3 × 103), 19% para ambos criterios de positividad y 33% para ambos criterios de negatividad. En los 692 pacientes con una mediana de seguimiento de 20 meses, hubo 132 eventos. La tasa de eventos fue menor en pacientes con doble negatividad y mayor en aquellos con doble positividad (c2=51, p<0,001). Conclusiones: La tasa de positividad del ecoestres y el rendimiento pronostico aumentan marcadamente si la reserva contractil con estres y la pendiente del trabajo latido reclutable por precarga se suman a las alteraciones de motilidad parietal regional convencionales.

Single-Beat Estimation of Right Ventricular Contractility and Its Coupling to Pulmonary Arterial Load in Patients With Pulmonary Hypertension.

BackgroundAn accurate assessment of intrinsic right ventricular (RV) contractility and its relation to pulmonary arterial load is essential for the management of pulmonary hypertension. The pressure‐volume relationship with load manipulation is the gold standard assessment used for this purpose, but its clinical application has been hindered by the lack of a single‐beat method that is valid for the human RV. In the present study, we sought to validate a novel single‐beat method to estimate the preload recruitable stroke work (PRSW) and its derivative for ventriculoarterial coupling in the human RV.Methods and ResultsA novel single‐beat slope of the PRSW relationship (Msw) was derived by calculating the mean ejection pressure when the end‐systolic volume was equal to volume‐axis intercept of the PRSW relationship. In addition, by using a mathematical transformation of the equation representing the linearity of the PRSW relationship, a novel index for ventriculoarterial coupling, Msw/mean ejection pressure, was developed. RV pressure‐volume relationships were measured in 31 patients (including 23 patients with pulmonary hypertension) who were referred for right‐sided heart catheterization. In this cohort, the single‐beat Msw was strongly correlated with the multiple‐beat Msw (r=0.91, P<0.0001). Moreover, a significant correlation was observed between the single‐ and multiple‐beat Msw/mean ejection pressure (r=0.53, P=0.002), with a stronger correlation in those with greater RV systolic pressure (r=0.70, P=0.003).ConclusionsThe novel single‐beat approach provided an accurate estimation of indexes for the PRSW relationship and ventriculoarterial coupling. It may be particularly useful in assessing RV adaptation to increased pressure overload.

Inotropic Effects of Nicorandil on Cardiac Contractility Assessed by Left Ventricular Pressure-Volume Relationship Analyses in Anesthetized Monkeys.

Nicorandil is a representative antianginal drug that has dual properties of a nitrate and adenosine triphosphate-sensitive potassium (KATP) channel agonist; however, its effects on integrated cardiac function have not been fully understood. This study was conducted to clarify the functional, hemodynamic, and electrophysiological effects of nicorandil using ventricular pressure-volume loop analysis in isoflurane-anesthetized monkeys. Nicorandil was given intravenously at therapeutic doses of 0.2 and 2 mg/kg over 10 minutes to cynomolgus monkeys (n = 5) with a pause of 10 minutes between the 2 doses. Nicorandil at 0.2 mg/kg caused decreases in systemic blood pressure and left ventricular end-diastolic pressure by its vasodilating action. Nicorandil at 2 mg/kg also exhibited positive inotropic action demonstrated by increased slopes of preload recruitable stroke work relationship, which is a load-independent inotropic parameter. In load-dependent inotropic parameters, positive inotropy of nicorandil was also indicated by the shortened QA interval and increased contractility index; however, significant changes were not observed in the maximal upstroke velocity of left ventricular pressure. Moreover, reflex tachycardia accompanied by shortening of QT/QTc intervals was observed. Overall, the isoflurane-anesthetized monkey model with pressure-volume loop analysis revealed cardiac variables of nicorandil, including a positive inotropy contributable to cardiac performance in addition to its vasodilatory effect. These findings provide useful information when considering the prescription of nicorandil in patients.

Feasibility and limitations of mitral valve repair, with or without left ventricular reconstruction in non-ischemic dilated cardiomyopathy

BackgroundAlthough non-transplant surgical interventions for non-ischemic dilated cardiomyopathy (NIDCM) are relatively effective, their feasibility and limitations have not been fully elucidated. The aim of this study was to define the feasibility and limitations of mitral valve repair, with or without surgical ventricular reconstruction for patients with NIDCM in terms of postoperative low cardiac output syndrome (LOS). MethodsTwenty non-transplant candidates (aged 57±13 years) with NIDCM and significant mitral regurgitation had undergone mitral valve repair combined with submitral procedures. Using a 72-mL plastic ellipsoidal sizer, left ventricular reconstruction was performed concomitantly in 14/20 (70%) patients with extremely large ventricles. Total stroke volume, deceleration time of early trans-mitral flow wave, and the slope (Mw) in the preload recruitable stroke-work relationship were assessed using transthoracic echocardiography. LOS was defined as in-hospital death due to heart failure or a cardiac index less than 2.2L/min/m2 before discharge. ResultsThere were three in-hospital deaths and four patients with postoperative cardiac index less than 2.2L/min/m2 [n=7 (35%), LOS group]. Preoperative total stroke volume, deceleration time, and the Mw were significantly lower in the LOS group compared to those in the non-LOS group; the predicted cut-off values for LOS were 84mL/beat (p=0.008), 133ms (p=0.015), and 45ergcm−3×103 (p=0.036), respectively. Preoperative left ventricular ejection fraction and ventricular size could not predict postoperative LOS. The one-year survival rate was 0% in the LOS group and 84% in the non-LOS group (p<0.001). ConclusionsMitral valve repair, with or without left ventricular reconstruction, could be contraindicated for NIDCM patients with low total stroke volume, deceleration time, and Mw in terms of high postoperative incidence of LOS. For high-risk patients, other therapeutic strategies might be necessary.

Novel, single-beat approach for determining both end-systolic pressure–dimension relationship and preload recruitable stroke work

ObjectiveThe end-systolic pressure–dimension relationship (ESPDR) and the preload recruitable stroke work (PRSW) relationship are load-insensitive measures of contractility, but their clinical application has been limited by the need to record...

Carvedilol-Enriched Cold Oxygenated Blood Cardioplegia Improves Left Ventricular Diastolic Function After Weaning From Cardiopulmonary Bypass.

To investigate whether adding carvedilol, a nonselective β- and selective α1-receptor blocking agent with antioxidant properties, to oxygenated blood cardioplegia improves myocardial function after weaning from bypass. A randomized controlled study. A university laboratory. Twenty anesthetized pigs, Norwegian Landrace. On cardiopulmonary bypass, cardiac arrest was induced with cold (12°C), oxygenated blood cardioplegia, enriched with carvedilol or vehicle, and repeated every 20 minutes. After 100 minutes, the heart was reperfused and weaned. Left ventricular function was evaluated with pressure-volume loops, local myocardial systolic strain, and strain rate from Speckle tracking analysis and multilayer short-axis tissue Doppler Imaging. In the carvedilol group, the load-independent logarithmic end-diastolic pressure volume relationship, β, decreased from 1 to 3 hours of reperfusion and was low, 0.028±0.004 v 0.042±0.007 (p<0.05) in controls at 3 hours, demonstrating improved left ventricular compliance. The diastolic relaxation constant τ was decreased, 28.9±0.6 ms v 34.6±1.3 ms (pg<0.035), and dP/dtmin was more negative,-1,462±145 mmHg/s v-1,105±105 mmHg/s (pg = 0.024), for carvedilol v control group. The systolic variables, preload recruitable stroke work and end-systolic pressure-volume relationship, did not differ between groups, neither did left ventricular systolic strain and strain rate. Myocardial oxidative stress, measured as tissue levels of malondialdehyde, was reduced by carvedilol, 0.19±0.01 compared to 0.24±0.01 nmol/mg (p = 0.004) in controls. Carvedilol added to blood cardioplegia improved diastolic cardiac function and reduced oxidative stress during the first 3 hours after reperfusion in a porcine model, with 100 minutes of cardioplegic arrest.

The value of novel invasive hemodynamic parameters added to the TIMI risk score for short-term prognosis assessment in patients with ST segment elevation myocardial infarction

BackgroundWe compared the prognostic capacity of conventional and novel invasive parameters derived from the slope of the preload recruitable stroke work relationship (PRSW) in STEMI patients and assessed their contribution to the TIMI risk score. MethodsLeft ventricular end-diastolic pressure (EDP), ejection fraction (EF), pressure adjusted maximum rate of pressure change in the left ventricle (dP/dt/P), aortic systolic pressure to EDP ratio (SBP/EDP) and end-diastolic volume adjusted stroke work (EW), derived from the slope of the PRSW relationship, were obtained during the emergency cardiac catheterization in 523 STEMI patients. The predictive power of the analyzed parameters for 30-day and 1-year mortality was evaluated using C-statistics and reclassification analysis was adopted to assess the improvement in TIMI score. ResultsThe highest area under the curve (AUC) values for 30-day mortality were observed for EW (0.872(95% confidence interval 0.801–0.943)), SBP/EDP (0.843(0.758–0.928)) and EF (0.833(0.735–0.931)); p<0.001 for all values. For 1-year mortality the best predictive value was found for EW (0.806(0.724–0.887) and EF (0.793(0.703–0.883)); p<0.001 for both. The addition of EDP, SBP/EDP ratio and EW to TIMI score significantly increased the AUC according to De Long's test. For 30-day mortality, increased discriminative power following addition to the TIMI score was observed for EW and SBP/EDP (Integrated Discrimination Improvement was 0.086(0.033–0.140), p=0.002 and 0.078(0.028–0.128), p=0.002, respectively). ConclusionsEW and SBP/EDP are prognostic markers with high predictive value for 30-day and 1-year mortality. Both parameters, easily obtained during emergency catheterization, improve the discriminatory capacity of the TIMI score for 30-day mortality.

Outcomes of lung cancer surgery after neo-adjuvant treatment: a National Surgical Quality Improvement Program analysis

METHODS: 26 dogs underwent bypass; temperature was raised to 42 C in 14 dogs (heat-shocked HS) or maintained at 37 C in 12 dogs (nonheat-shocked NHS). After 12 or 24 hours, heart rate (HR), left ventricular pressure (LVP), and peak +dP/dT were measured, as well as preload recruitable stroke work relationship (PRWA) throughout reperfusion. Myocardial expression of hsp70i was quantified by Western blots.

Slope in preload recruitable stroke work relationship predicts survival after left ventriculoplasty and mitral repair in patients with idiopathic cardiomyopathy

BackgroundLeft ventriculoplasty (LVP) and mitral valve plasty (MVP) are sometimes effective for patients with idiopathic dilated cardiomyopathy (DCM) who are not eligible for heart transplantation. Strict patient selection is warranted for these controversial procedures. Methods and resultsThe subjects were 18 patients with idiopathic DCM and mitral regurgitation who had not been indicated for heart transplantation due to either older age or patient refusal, and who underwent LVP and MVP. Their mean age was 57±14 years and 50% were dependent on catecholamine infusion. The preload recruitable stroke work (PRSW) relationship and its slope (Mw) were estimated by a single-beat technique using transthoracic echocardiography. There were one 30-day mortality and six (33%) hospital deaths due to heart failure. The one-year survival rate was 50%. Left ventricular end-diastolic dimension (LVDd) decreased from 77±11 to 68±11mm (p=0.001) whereas the ejection fraction did not change. Preoperative Mw was significantly higher in one-year survivors than that in non-survivors (54±17ergcm−3103 vs. 31±10ergcm−3103, p=0.005). Preoperative LVDd was not different between the groups. The cut-off value of 42ergcm−3103 for Mw predicted one-year survival with high sensitivity (100%) and specificity (77%). ConclusionsMw, the slope in the PRSW relationship, may predict survival after LVP and MVP in patients with idiopathic DCM.

Effects of Antegrade and Retrograde Machine Perfusion Preservation on Cardiac Function After Transplantation in Canines

IntroductionMost studies investigating machine perfusion preservation for heart transplantation perfuse through the aortic root (antegrade), but the coronary sinus (retrograde) is a potential option. We hypothesized that retrograde machine perfusion provides better functional protection than static storage, while avoiding the potential irregular perfusion seen when aortic insufficiency occurs with antegrade perfusion. Materials and MethodsEighteen canine donor hearts were arrested, procured, and stored in modified Celsior solution for 4 hours by using either static storage at 0°C to 4°C (n = 6) or machine perfusion preservation at 5°C via the aortic root (antegrade, n = 6) or coronary sinus (retrograde, n = 6). Lactate and myocardial oxygen consumption were measured in perfused hearts. Hearts were reimplanted and reperfused for 6 hours with hourly function calculated by using the preload recruitable stroke work (PRSW) relation. Myocardial water content was determined at the end of the experiment. ResultsStorage lactate levels and myocardial oxygen consumption were comparable in both perfused groups. The PRSW was increased immediately after bypass in the antegrade group (120.6 ± 19.1 mm Hg) compared with the retrograde (75.0 ± 11.3 mm Hg) and static (78.1 ± 10.5 mm Hg) storage groups (P < .05). At the end of reperfusion, PRSW was higher in the retrograde group (69.8 ± 7.4 mm Hg) compared with the antegrade (40.1 ± 6.8 mm Hg) and static (39.9 ± 10.9 mm Hg) storage groups (P < .05). Myocardial water content was similar among groups. ConclusionsBoth antegrade and retrograde perfusion demonstrated excellent functional preservation, at least equivalent to static storage. Initial function was superior in the antegrade group, but the retrograde hearts displayed better function late after reperfusion. Neither perfused group developed significant edema. Machine perfusion preservation is a promising technique for improving results of cardiac transplantation.

Preload‐adjusted left ventricular dP/dtmax: a sensitive, continuous, load‐independent contractility index

The classical indicators of left ventricular (LV) performances have been derived from pressure-volume (PV) and stroke work-volume plots obtained during various loading or pharmacological interventions. More recently, the preload-adjusted maximal change in pressure over time (PAdP/dtmax), derived from single beat PV analysis, has been shown to reflect the LV systolic performance accurately in varying conditions of inotropy and afterload. The objective of this study was to address whether PAdP/dtmax is a valid indicator of LV function in the setting of large preload variations, compared with the classical dP/dtmax-end-diastolic volume (EDV) and stroke work-EDV (preload recruitable stroke work) relationships. Nine anaesthetized and mechanically ventilated rats were instrumented with a ventricular conductance catheter. Stepwise preload reduction was achieved by repeated blood withdrawals (up to a total of 5 ml). Steady-state and dynamic PV loops were recorded during brief occlusion of the inferior vena cava, and LV function parameters were derived from these recordings. Our results demonstrate that PAdP/dtmax behaved in a similar manner to preload recruitable stroke work, reflecting well-maintained LV contractility during controlled haemorrhage until mean arterial pressure decreased below 40 mmHg. In contrast, dP/dtmax-EDV increased significantly and exhibited a curvilinear response that was associated with a large inter- and intra-animal variability. In a model of acute preload reduction, PAdP/dtmax was found to be the best indicator of systolic LV function. Given its simplicity, this real-time index derived from single beat analysis should be tested further in clinical settings.

Non-invasive Determination of the Preload Recruitable Stroke Work Relationship in Patients with Heart Failure

Non-invasive Determination of the Preload Recruitable Stroke Work Relationship in Patients with Heart Failure

FT011, a new anti‐fibrotic drug, attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy

Cardiac remodelling in diabetes includes pathological accumulation of extracellular matrix and myocyte hypertrophy that contribute to heart dysfunction. Attenuation of remodelling represents a potential therapeutic target. We tested this hypothesis using a new anti-fibrotic drug, FT011 (Fibrotech Therapeutics Pty Ltd), on diabetic Ren-2 rats, a model which replicates many of the structural and functional manifestations of diabetic cardiomyopathy in humans. Homozygous Ren-2 rats were randomized to receive streptozotocin or vehicle then further randomized to FT011 (200 mg/kg/day) or vehicle treatment for 6 weeks. Prior to tissue collection, cardiac function was assessed via echocardiography and cardiac catheterization. Total collagen deposition and cardiomyocyte hypertrophy were assessed by picrosirius red and haematoxylin and eosin staining, respectively. Macrophage interstitial infiltration and type I and III collagen were quantitated by immunostaining. Without affecting blood pressure or hyperglycaemia, treatment of diabetic rats with FT011 significantly attenuated interstitial fibrosis (total collagen, 5.09 ±1.28 vs, 2.42 ±0.43%/area; type I collagen, 4.09 ±1.16 vs. 1.42 ±0.38%/area; type III collagen, 1.52 ±0.33 vs. 0.71 ±0.14 %/area; P < 0.05), cardiomyocyte hypertrophy (882 ±38 vs. 659 ±28 µm(2); P < 0.05), and interstitial macrophage influx (66 ±5.3 vs, 44 ±7.9 number/section; P < 0.05). Cardiac myopathic dilatation was normalized, as evidenced by reduced left ventricular inner diameter at diastole (0.642 ±0.016 vs. 0.577 ±0.024 cm), increased ejection fraction (75 ±1.1 vs. 83 ±1.2%) and preload recruitable stroke work relationship (44 ±6.7 vs. 77 ±6.3 slope-mmHg; P < 0.05), and reduced end-diastolic pressure-volume relationship (0.059 ±0.011 vs. 0.02 ±0.003 slope-mmHg/μL; P < 0.05). A direct anti-fibrotic agent, FT011, attenuates cardiac remodelling and dysfunction in experimental diabetic cardiomyopathy. This represents a novel therapy for the treatment of diabetic cardiomyopathy associated with cardiac fibrosis and hypertrophy.

Does left ventricular size impact on intrinsic right ventricular function in hypoplastic left heart syndrome?

BackgroundThe size of the remnant left ventricle (LV) may influence right ventricular function and thus long-term outcome in palliated hypoplastic left heart syndrome (HLHS). We therefore sought to assess the impact of the size of the hypoplastic LV on intrinsic RV function in HLHS patients after Fontan surgery. MethodsFifty-seven HLHS patients were studied 2.5 (range: 0.8-12.6) years after Fontan-type palliation with the pressure-volume conductance system. The patient cohort was divided into two groups according to the median LV area index (group 1: LV area index≤1.33cm2/m2, n=29; group 2: LV area index>1.33cm2/m2, n=28). ResultsThe slopes of the end systolic elastance (Ees) and the preload recruitable stroke work relation (Mw) were not different between group 1 and 2 (Ees: 2.70±1.92 vs. 3.68±2.68mmHg/ml; Mw: 52.75±14.98 vs. 51.09±16.63mmHg x ml; P=NS for all). Furthermore, the systolic responses to dobutamine were not statistically different between groups. However, the slope of the end diastolic stiffness (Eed) was higher in group 2 and catecholaminergic stimulation resulted in a decrease in Eed in group 2 (group 1: 0.40±0.26 vs. 0.52±0.45; group 2: 0.68±0.44 vs. 0.47±0.38mmHg/ml, P<0.01). Furthermore Eed was lowest in patients with mitral atresia/aortic atresia, the anatomic subgroup with the smallest LV remnant. ConclusionsIntrinsic systolic RV function is not affected by the size of the hypoplastic LV in survivors of surgical palliation of HLHS. Diastolic stiffness, however, was higher in patients with a larger LV remnant.

Short-Term Hemodynamic Effects of Cardiac Resynchronization Therapy in Patients With Heart Failure, a Narrow QRS Duration, and No Dyssynchrony

Cardiac resynchronization therapy produces both short-term hemodynamic and long-term symptomatic/mortality benefits in symptomatic heart failure patients with a QRS duration >120 ms. This is conventionally believed to be due principally to relief of dyssynchrony, although we recently showed that relief of external constraint to left ventricular filling may also play a role. In this study, we evaluated the short-term hemodynamic effects in symptomatic patients with a QRS duration <120 ms and no evidence of dyssynchrony on conventional criteria and assessed the effects on contractility and external constraint. Thirty heart failure patients (New York Heart Association class III/IV) with a left ventricular ejection fraction < or =35% who were in sinus rhythm underwent pressure-volume studies at the time of pacemaker implantation. External constraint, left ventricular stroke work, dP/dtmax, and the slope of the preload recruitable stroke work relation were measured from the end-diastolic pressure-volume relation before and during delivery of biventricular and left ventricular pacing. The following changes were observed during delivery of cardiac resynchronization therapy: Cardiac output increased by 25+/-5% (P<0.05), absolute left ventricular stroke work increased by 26+/-5% (P<0.05), the slope of the preload recruitable stroke work relation increased by 51+/-15% (P<0.05), and dP/dtmax increased by 9+/-2% (P<0.05). External constraint was present in 15 patients and was completely abolished by both biventricular and left ventricular pacing (P<0.05). Cardiac resynchronization therapy results in an improvement in short-term hemodynamic variables in patients with a QRS <120 ms related to both contractile improvement and relief of external constraint. These findings provide a potential physiological basis for cardiac resynchronization therapy in this patient population.

Inhibition of Protein Kinase C–β by Ruboxistaurin Preserves Cardiac Function and Reduces Extracellular Matrix Production in Diabetic Cardiomyopathy

Background— Heart failure is a common cause of morbidity and mortality in diabetic patients that frequently manifests in the absence of impaired left ventricular systolic function. In contrast to the strong evidence base for the treatment of systolic heart failure, the treatment of heart failure with preserved left ventricular function is uncertain, and therapeutic targets beyond blockade of the renin-angiotensin-aldosterone and β-adrenergic systems are being sought. One such target is the β-isoform of protein kinase C (PKC), implicated in both the complications of diabetes and in cardiac dysfunction in the nondiabetic setting. Methods and Results— Using a hemodynamically validated rodent model of diabetic diastolic heart failure, the (mRen-2)27 transgenic rat, we sought to determine whether selective inhibition of PKC-β would preserve cardiac function and reduce structural injury. Diabetic rats were randomized to receive either vehicle or the PKC-β inhibitor, ruboxistaurin (20 mg/kg per d) and followed for 6 weeks. Compared with untreated animals, ruboxistaurin-treated diabetic rats demonstrated preserved systolic and diastolic function, as measured by the slope of preload recruitable stroke work relationship ( P &lt;0.05) and the slope of the end-diastolic pressure volume relationship ( P &lt;0.01). Collagen I deposition and cardiomyocyte hypertrophy were both reduced in diabetic animals treated with ruboxistaurin ( P &lt;0.01), as was phosphorylated-Smad2, an index of transforming growth factor-β activity ( P &lt;0.01 for all, versus untreated diabetic rats). Conclusions— PKC-� inhibition attenuated diastolic dysfunction, myocyte hypertrophy, and collagen deposition and preserved cardiac contractility. PKC-β inhibition may represent a novel therapeutic strategy for the prevention of diabetes-associated cardiac dysfunction.

Non-invasive Assessment of Preload Recruitable Stroke Work Relations in Preclinical Cardiomyopathy

Non-invasive Assessment of Preload Recruitable Stroke Work Relations in Preclinical Cardiomyopathy