Left Ventricular End-systolic Wall Stress Research Articles

Hemodynamic evaluation of extremely low birth weight infants during the first 7 days of life

Background and aimWe aimed to investigate the hemodynamic status of extremely low birth weight (ELBW) infants during the transitional period under intensive management. MethodsThis retrospective cohort study analyzed left ventricular ejection fraction (LVEF), left ventricular end-systolic wall stress (ESWS), left ventricular internal dimension in diastole (LVIDd), and mean arterial pressure (MAP) of ELBW infants during their first week of life. Small for gestational age (SGA), histological chorioamnionitis (hCAM), severe intraventricular hemorrhage (IVH), and non-survival to discharge infants were compared to their counterparts. ResultsSixty-two infants (25.7 ± 2.1 weeks, 700.7 ± 165.4 g) were analyzed. MAP gradually increased. Median LVEF was 69.8 % on day 1, decreased to 62.7 % on day 2, then increased throughout the week. ESWS was lowest at birth, rose to 28.2 g/cm2 on day 2, and decreased on day 6. There were no significant changes in LVIDd. SGA infants had higher MAP throughout, higher LVEF on day 2 and 3, but lower LVEF on day 5 to 7. LVIDd was lower in hCAM group. Severe IVH group had a more significant drop in LVEF on day 2, higher ESWS, and a higher incidence of hemodynamic significant patent ductus arteriosus (hsPDA). Non-survival had lower LVIDd. ConclusionsMAP increased gradually. Hemodynamic instability was observed in the first two days, with decreased LVEF and increased ESWS before stabilization. We observed an alteration in hemodynamic adaptation in SGA and hCAM infants. Severe IVH group experienced early hemodynamic instability and a higher incidence of hsPDA.

Carvedilol for prevention of heart failure in anthracycline-exposed survivors of childhood cancer: Results from COG ALTE1621.

10013 Background: Carvedilol improves cardiac function in patients with heart failure (HF), but remains untested as cardioprotective therapy in long-term childhood cancer survivors at risk for HF due to high-dose anthracycline exposure. We hypothesized that low-dose carvedilol would be safe and efficacious in reducing anthracycline-related heart failure risk in long-term survivors without evidence of HF. Methods: This was a randomized, double-blind, placebo-controlled phase 2B trial (NCT02717507) conducted at 28 sites. Eligibility included ≥250 mg/m2 cumulative anthracycline exposure by age 21 years (y), ≥2y from completion of cancer treatment, and preserved systolic function (ejection fraction [EF] ≥55% and/or fractional shortening [FS] ≥28%) at enrollment. Patients were randomized 1:1 to take low-dose carvedilol (12.5 mg/day) or placebo for 2y; dose up-titration started at 3.125 mg/day. The primary objective was to determine the impact of carvedilol on echocardiographic indices of HF risk: standardized left ventricular (LV) wall thickness/dimension ratio (LVWT/Dz; primary endpoint), LV end-systolic wall stress (ESWS), LV chamber diameters, systolic and diastolic function. These indices were obtained every 6 months and measured centrally in a blinded fashion. Common Terminology Criteria for Adverse Events (CTCAE v4.0) was used to assess toxicity. Cardiac event was defined as relative EF/FS decline < 20% from baseline or both < 55% [EF] and < 28% [FS]. Treatment effects were analyzed using the Generalized Estimating Equation for normally distributed data, assuming linear time-trend. Group differences were evaluated by treatment*time interaction. Results: Of 196 participants enrolled, 182 were eligible and randomized. Characteristics (median, range): age at enrollment, 24.7y (10.4-53.9); time from cancer diagnosis, 13.4y (2.9-43.6); anthracycline dose, 374 mg/m2 (250-1760); 19% had received chest-directed radiotherapy. There were no group differences in baseline participant demographics, cardiotoxic treatment exposure, or cardiac endpoints. LVWT/Dz was similar (+0.053, p = 0.15) between arms at 2y. However, treatment effects varied by time since diagnosis (p = 0.008) suggesting greater efficacy among longer-term survivors. Compared to placebo, carvedilol arm participants had significantly better LV end-diastolic diameter (-0.16 cm, p = 0.005) and LVESWS (-7.53, p = 0.027) at 2y. There were no CTCAE grade ≥3 events; all except 2 participants tolerated full dose escalation. Six out of eight cardiac events occurred on the placebo arm; longer-term follow-up of study participants is ongoing. Conclusions: In this randomized trial of long-term survivors of childhood cancer treated with high-dose anthracyclines, low-dose carvedilol was safe and effective in reducing established biomarkers of HF risk and could serve as a risk reduction strategy. Clinical trial information: NCT02717507 .

Effects of switching from sacubitril/valsartan to valsartan alone on plasma levels of natriuretic peptides and myocardial remodeling in heart failure with reduced ejection fraction

BackgroundWe examined the effect of switching from angiotensin receptor-neprilysin inhibitor (ARNI) to angiotensin-receptor blocker (ARB) on plasma levels of natriuretic peptides and myocardial remodeling.MethodsThis is a prospective study that included 11 patients with heart failure (HF) treated with ARNI. The patients were divided into two groups: 5 patients who continued treatment with sacubitril/valsartan 194/206 mg/day (ARNI-continue group) and 6 patients who were switched to valsartan 160 mg/day (ARB-switch group). The primary endpoint was percent change (%Change) in plasma A-, B-, and N-terminal pro-B-type natriuretic peptide (ANP, BNP, and NT-proBNP) levels from the baseline to week 24. The secondary endpoint was the change in echocardiographic parameters related to myocardial remodeling from the baseline to week 24.ResultsANP levels in the ARB-switch group significantly decreased (from 1155.7 ± 592.6 pg/mL to 231.6 ± 233.8 pg/mL, p = 0.035), whereas those in the ARNI-continue group were not significant (p = 0.180). The %Change of decrease in ANP levels was significantly greater in the ARB-switch group than the ARNI-continue group (− 76.9% vs. −9.1%, p = 0.009). BNP levels were not significantly different between the baseline and week 24 in both groups. NT-proBNP levels in the ARB-switch group increased from 1185.3 ± 835.6 pg/mL to 1515.2 ± 1213.5 pg/mL, although the changes were not statistically significant (p = 0.345). The %Change of increase in NT-proBNP levels was significantly greater in the ARB-switch group than the ARNI-continue group (57.9% vs. 17.3%, p = 0.016). In the ARB-switch group, there was a significant increase in left ventricular (LV) end-systolic volume (from 41.3 ± 24.1 mL/m2 to 71.4 ± 8.8 mL/m2, p = 0.043) and LV peak-systolic wall stress (from 187.0 ± 42.7 × 103 dynes/cm2 to 279.7 ± 34.1 × 103 dynes/cm2, p = 0.012) from the baseline to week 24 and a trend toward a decrease in LV ejection fraction (p = 0.080). In the ARNI-continue group, no differences in echocardiographic parameters were observed from the baseline to week 24.ConclusionSwitching from ARNI to ARB may worsen HF due to returning to myocardial remodeling induced by a sustained decline in ANP levels.

Abstract 11330: Association of Left Ventricular Wall Stress and Incident Heart Failure in Elderly Community Dwelling Individuals

Introduction: Greater left ventricular (LV) wall stress is associated with adverse outcomes among patients with prevalent heart failure (HF). Less is known about the association between LV wall stress and risk of incident HF in community dwelling individuals. Methods: Using data from the NHLBI Biologic Specimen and Data Repository Information Coordinating Center, we studied 4,601 participants of the Atherosclerosis Risk in Communities study without prevalent HF who underwent echocardiography at visit 5 (2011-2013). LV end systolic and diastolic wall stress (LVESWS, LVEDWS) were calculated from chamber and wall thickness measures, E/e’ as a surrogate for LV end diastolic pressure, and systemic blood pressure. Incident HF was assessed by cohort surveillance for hospitalized HF through December 31, 2016. The relationship between LVESWS and LVEDWS was examined by Spearman rank correlation. The association between wall stress and risk of incident HF was tested in Cox regression adjusted for demographics, traditional CV risk factors, prevalent CAD and atrial fibrillation, as well as creatinine, NT-proBNP, troponin, triglycerides, C-reactive protein, LV ejection fraction, and LV mass. Results: The cohort was elderly (median age 75 years), predominantly female (58%), with 18% of individuals identifying as black. Median LVESWS and LVEDWS were 48.8 (IQR: 39.3, 60.1) and 18.9 (IQR: 15.8, 22.5) kdynes/cm2, respectively. LVESWS and LVEDWS were modestly correlated (rho = 0.30, p <0.001). Over a median follow-up of 4.6 years, 156 individuals developed incident HF. In multivariable Cox regression mutually adjusted for LVEDWS and LVESWS, each 1-unit increase in LVEDWS significantly associated with an increased risk of incident HF (HR: 1.03; 95% CI 1.01 - 1.06) (Figure), while LVESWS did not (HR: 1.00; 95% CI 0.99-1.01). Conclusions: Among community dwelling elderly individuals, greater non-invasively measured LVEDWS is associated with an increased risk for incident HF.

Diastolic dysfunction in late postmenopausal patients with undifferentiated connective tissue disease and hypertension

Aim. To assess myocardial diastolic function (DF) in late postmenopausal women with undifferentiated connective tissue disease (UCTD) and hypertension (HTN).Material and methods. This cross-sectional study included 135 postmenopausal women, the median age of which was 68 years (65÷70,5 years). The anamnesis was collected using a standardized questionnaire. Verification of UCTD was carried out according to clinical guidelines. All patients underwent standard transthoracic echocardiography. The assessment of left ventricular (LV) DF was carried out according to the transmitral flow. LV diastolic dysfunction (DD) was classified into three types: rigid, pseudonormal, and restrictive. Statistical processing was carried out in the STATISTICA 13.0 environment. The measure of data averaging is the median, the measure of dispersion is 25%÷75%. The significance of differences was assessed using the Mann-Whitney test. Differences were considered significant at p˂0,05.Results. Group 1 — 20 (14,8%) patients with verified UCTD and HTN, group 2 — 88 (65,2%) patients with HTN without UCTD, control group — 23 (30%) patients without HTN and UCTD. There were no differences in age, duration of postmenopause and body mass index between the groups. In the first group, a significant decrease in the ratio of peak early to late diastolic LV filling velocity was revealed (p˂0,01). A significant increase in left ventricular end-systolic wall stress revealed in group 1. In 108 (100%) patients, LVDD was detected; among the patients of the control group, DD was not detected. In 8 (40%) patients in group 1, a pseudo-normal type of DD was detected, while in 12 out of 20 patients (60%) — rigid type of DD. When assessing DF in patients of group 2, a significant decrease was found in the ratio of peak early to late diastolic LV filling velocity, a significant increase in LV end-diastolic wall stress and end-diastolic pressure. In 2 out of 3 (57,80%) patients of group 2, DD of the rigid type was detected, while pseudonormal type — in 32,2% of patients in this group. Group 2 patients had a significant decrease in the early diastolic mitral annular velocity (p˂0,01).Conclusion. The analysis of myocardial echocardiographic characteristics indicates a significant contribution of HTN-associated UCTD to the development of LVDD in postmenopausal women.

Dexrazoxane Treatments Limits Subclinical Cardiac Dysfunction in Childhood Acute Lymphoblastic Leukemia Survivors Exposed to Doxorubicin Treatments.

Doxorubicin leads to dose dependent cardiotoxicity in childhood acute lymphoblastic leukemia (ALL) survivors. We investigated survivors' heart health using echocardiography and evaluated doxorubicin and dexrazoxane treatments on cardiac function. A total of 196 childhood ALL survivors were stratified (standard risk [SR], high risk with and without dexrazoxane (HR+DEX and HR). We performed a complete transthoracic echocardiographic assessment with M-mode echocardiography, Doppler, and Tissue Doppler. We used 2-dimensional and 3-dimensional echocardiography to measure the left ventricular ejection fraction, whereas myocardial strain imaging was used to obtain global strain indices. Although most cardiac and arterial dimension parameters were not different between groups, a difference was observed in posterior intima of the right carotid ( P =0.017). Diastolic functions analyses reported that LV shortening fraction and left and right ventricular lateral S' wave amplitudes were lower in HR than in SR and HR+DEX groups ( P =0.028, P =0.048, and P =0.005, respectively). The LV lateral E' in diastolic function was lower in the HR than in SR and HR+DEX groups ( P =0.036). The LV end-systolic wall stress was higher in HR than in SR and HR+DEX groups ( P =0.009). A decrease contractility was observed, while the effect was not group specific. Strain rate was not different between groups, as opposed to tissue Doppler measurements. This study showed that dexrazoxane treatments could limit subclinical cardiac dysfunction in childhood ALL survivors, whereas survivors in HR group who did not receive dexrazoxane had potential subclinical cardiac damage observable in heart failure patients. Echocardiographic screening for survivors must be part of the follow-up routine in cardio-oncology.

Peri-operative myocardial performance in infants with Down syndrome undergoing CHD repair

We aimed to characterise the impact of Down syndrome on myocardial performance and loading conditions in infants with Down syndrome and CHD over the peri-operative period by comparing them with infants matched for cardiac lesion with a normal microarray. Left ventricular global longitudinal strain, right ventricular free wall longitudinal strain, left ventricular end-systolic wall stress, and right ventricular systolic pressure were measured in the two groups over the peri-operative period. Fifty-five infants had a diagnosis of Down syndrome and these were compared with 29 control infants. Left ventricular global longitudinal strain decreased in both groups post-operatively with the Down syndrome group demonstrating some recovery pre-discharge (18 ± 3 versus 16 ± 3 %, p = 0.01). Right ventricular longitudinal strain significantly decreased in both groups post-operatively with the control group demonstrating better recovery by hospital discharge (14 ± 4 versus 18 ± 6 %, p < 0.01). End-systolic wall stress was lower and right ventricular systolic pressure was higher in the Down syndrome group throughout the study period (all p < 0.05). Down syndrome was an independent predictor of the duration of ventilation, post-operative use of inotropes, and intensive care stay. Right ventricular longitudinal strain was an independent predictor of duration of intensive care stay. This study demonstrates the difference between the two groups in relation to left and right ventricular function, particularly prior to discharge, and outlines the additional impact a diagnosis of Down syndrome has on myocardial performance during the peri-operative period.

Abstract 16319: Large Weight Loss Improves Left Ventricular Geometry but Not Myocardial Function 6 Months After Bariatric Surgery (the Fatwest Study)

Background: Bariatric surgery causes rapid and large weight loss and improves cardiovascular risk profile, yet the effect on left ventricular (LV) systolic function has been less explored. Methods: In the prospective FatWest (Bariatric Surgery on the West Coast of Norway) study 98 severely obese patients (44±10 years, 72% women, preoperative body mass index [BMI] 41.8±4.8 kg/m 2 , 36% with hypertension) underwent echocardiography before and 5.9 months after gastric bypass surgery. We assessed changes in LV geometry and systolic function by biplane ejection fraction (EF), midwall shortening (MWS) and mitral annular systolic velocity (s′). LV hypertrophy was defined based on LV mass/height 2.7 . Myocardial O 2 demand was derived from the LV mass-wall stress-heart rate product. Results: Patients experienced on average a 10 kg/m 2 reduction in BMI, and a significant drop in heart rate and blood pressure (all p&lt;0.001). LV mass (-12 g) and myocardial O 2 demand improved significantly (all p&lt;0.01). However, LV EF (60 vs. 61%), s’ (8.5 vs. 8.3cm/s) and MWS (16.1 vs. 15.7%) remained unchanged, and 45% of patients had low MWS 6 months after surgery (Figure). In multivariable regression analyses, LV mass reduction was predicted by weight loss and female sex, independent of changes in blood pressure and heart rate (R 2 0.24, p &lt;0.001) while lower myocardial O2 demand was explained by improvement in its three components, particularly lower LV end-systolic wall stress (R 2 0.9, p&lt;0.001). Conclusion: In severely obese patients with normal EF, bariatric surgery induces a significant reduction in BMI, LV mass and myocardial O 2 demand, but no improvement in LV myocardial systolic function 6 months after surgery.

Chronic cardiac structural damage, diastolic and systolic dysfunction following acute myocardial injury due to bromine exposure in rats.

Accidental bromine spills are common and its large industrial stores risk potential terrorist attacks. The mechanisms of bromine toxicity and effective therapeutic strategies are unknown. Our studies demonstrate that inhaled bromine causes deleterious cardiac manifestations. In this manuscript we describe mechanisms of delayed cardiac effects in the survivors of a single bromine exposure. Rats were exposed to bromine (600ppm for 45min) and the survivors were sacrificed at 14 or 28days. Echocardiography, hemodynamic analysis, histology, transmission electron microscopy (TEM) and biochemical analysis of cardiac tissue were performed to assess functional, structural and molecular effects. Increases in right ventricular (RV) and left ventricular (LV) end-diastolic pressure and LV end-diastolic wall stress with increased LV fibrosis were observed. TEM images demonstrated myofibrillar loss, cytoskeletal breakdown and mitochondrial damage at both time points. Increases in cardiac troponin I (cTnI) and N-terminal pro brain natriuretic peptide (NT-proBNP) reflected myofibrillar damage and increased LV wall stress. LV shortening decreased as a function of increasing LV end-systolic wall stress and was accompanied by increased sarcoendoplasmic reticulum calcium ATPase (SERCA) inactivation and a striking dephosphorylation of phospholamban. NADPH oxidase 2 and protein phosphatase 1 were also increased. Increased circulating eosinophils and myocardial 4-hydroxynonenal content suggested increased oxidative stress as a key contributing factor to these effects. Thus, a continuous oxidative stress-induced chronic myocardial damage along with phospholamban dephosphorylation are critical for bromine-induced chronic cardiac dysfunction. These findings in our preclinical model will educate clinicians and public health personnel and provide important endpoints to evaluate therapies.

P1356 Effects of sacubitril/valsartan on vascular resistance in patients with heart failure with reduced ejection fraction and arterial hypertension

Abstract Introduction Vascular resistance as assessed by noninvasive measurement of the pulse-wave velocity (PWV) is a well-established separate risk factor for early cardiovascular morbidity and mortality. High vascular resistance leads to higher pulse wave velocities and augmented values of systolic blood pressure (SBP). That leads to elevation in myocardial oxygen consumption and elevated left ventricular (LV) wall stress, indirectly worsening the systolic function of an already failing LV. PWV can be taken as an integral index of the vascular structure and function. Sacubitril/valsartan is the first ARNI approved for the treatment of heart failure with reduced ejection fraction (HFrEF) – it simultaneously inhibits the renin-angiotensin-aldosterone system and employs the positive effects of the natriuretic peptides. The mechanisms of these remarkable effects – reduction of cardiovascular morbidity, of heart failure hospitalisations, of sudden cardiac death and of composite mortality, in patients with HFrEF are quite complex. The concomitant lowering of BP is an important element of the pathophysiologic process that improves the haemodynamic status of the patients. Purpose To evaluate the effect of sacubitril/valsartan on vascular level parameters. Materials and methods In 18 newly established patients with HFrEF and arterial hypertension we prescribed 6-month sacubitril/valsartan treatment protocol at a dose level 97/103 mg. We measured the baseline office pressure, LV ejection fraction, 2D LV strain and Е/E1 values, and we performed analysis of the arterial rigidity by measuring the following parameters: Arterial elastance Еа= systolic BP / LV stroke volume LV endsystolic elastance ЕV = systolic BP / LV telesystolic volume End-systolic stress of the LV wall: ЕSS = (0.33 х TSDLV х SBP) / PW х (1 + PW) / TSDLV) Ventricular-arterial impedance: Zva = (SBP + mean transaortic gradient) / indexed LV stroke volume. At the end of the six months" treatment protocol we measured the same parameters again. Results During the six months treating period the systolic arterial pressure fell significantly from 128 ± 9.8 mmHg to 113 ± 17 mmHg (р=0.002), and diastolic BP, also significantly, fell from 83.5 ± 9.5 mmHg to 70.1 ± 6.8 mmHg (р=0.001). There was a significant decrease in PWV, arterial elastance, end-systolic LV wall stress and in ventricular-arterial impedance, but not in the other measured parameters. Conclusion Treatment with sacubitril/valsartan at a high dose level of 97/103 mg for six months improves the indices of arterial rigidity, but does not lead to significant change in ventricular-arterial coupling, despite of significant lowering of the arterial elastance and pulse wave velocity.

Ranolazine may exert its beneficial effects by increasing myocardial adenosine levels.

We hypothesized that ranolazine-induced adenosine release is responsible for its beneficial effects in ischemic heart disease. Sixteen open-chest anesthetized dogs with noncritical coronary stenosis were studied at rest, during dobutamine stress, and during dobutamine stress with ranolazine. Six additional dogs without stenosis were studied only at rest. Regional myocardial function and perfusion were assessed. Coronary venous blood was drawn. Murine endothelial cells and cardiomyocytes were incubated with ranolazine and adenosine metabolic enzyme inhibitors, and adenosine levels were measured. Cardiomyocytes were also exposed to dobutamine and dobutamine with ranolazine. Modeling was employed to determine whether ranolazine can bind to an enzyme that alters adenosine stores. Ranolazine was associated with increased adenosine levels in the absence (21.7 ± 3.0 vs. 9.4 ± 2.1 ng/mL, P < 0.05) and presence of ischemia (43.1 ± 13.2 vs. 23.4 ± 5.3 ng/mL, P < 0.05). Left ventricular end-systolic wall stress decreased (49.85 ± 4.68 vs. 57.42 ± 3.73 dyn/cm2, P < 0.05) and endocardial-to-epicardial myocardial blood flow ratio tended to normalize (0.89 ± 0.08 vs. 0.76 ± 0.10, P = nonsignificant). Adenosine levels increased in cardiac endothelial cells and cardiomyocytes when incubated with ranolazine that was reversed when cytosolic-5'-nucleotidase (cN-II) was inhibited. Point mutation of cN-II aborted an increase in its specific activity by ranolazine. Similarly, adenosine levels did not increase when cardiomyocytes were incubated with dobutamine. Modeling demonstrated plausible binding of ranolazine to cN-II with a docking energy of -11.7 kcal/mol. We conclude that the anti-adrenergic and cardioprotective effects of ranolazine-induced increase in tissue adenosine levels, likely mediated by increasing cN-II activity, may contribute to its beneficial effects in ischemic heart disease.NEW & NOTEWORTHY Ranolazine is a drug used for treatment of angina pectoris in patients with ischemic heart disease. We discovered a novel mechanism by which this drug may exhibit its beneficial effects. It increases coronary venous levels of adenosine both at rest and during dobutamine-induced myocardial ischemia. Ranolazine also increases adenosine levels in endothelial cells and cardiomyocytes in vitro, by principally increasing activity of the enzyme cytosolic-5'-nucleotidase. Adenosine has well-known myocardial protective and anti-adrenergic properties that may explain, in part, ranolazine's beneficial effect in ischemic heart disease.

Depressed systemic arterial compliance and impaired left ventricular midwall performance in aortic stenosis with concomitant type 2 diabetes: a retrospective cross-sectional study

BackgroundDegenerative aortic stenosis (AS), a disease of the elderly, frequently coexists with concomitant diseases, including type 2 diabetes (T2DM) which amplifies the cardiovascular (CV) risk. T2DM affects left ventricular (LV) structure and function via hemodynamic and metabolic factors. In concentric LV geometry, typical for AS, indices of LV midwall mechanics are better estimates of LV function than ejection fraction (EF). Effects of T2DM coexisting with AS on circumferential LV midwall systolic function and large artery properties have not been reported so far. Our aim was to compare characteristics of AS patients with and without T2DM, with a focus on LV midwall systolic function and arterial compliance.MethodsMedical records of 130 electively hospitalized patients with moderate or severe isolated degenerative AS were retrospectively analyzed. Exclusion criteria included clinical instability, atrial fibrillation, coronary artery disease and relevant non-cardiac diseases. From in-hospital echocardiography and blood pressure, we calculated LV midwall fractional shortening (mwFS), circumferential end-systolic LV wall stress (cESS) and valvulo-arterial impedance (Zva), estimates of LV afterload, as well as systemic arterial compliance.ResultsPatients with (n = 50) and without T2DM (n = 80) did not differ in age, AS severity, LV mass and LV diastolic diameter. T2DM patients exhibited elevated cESS (247 ± 105 vs. 209 ± 84 hPa, p = 0.025) and Zva (5.8 ± 2.2 vs. 5.1 ± 1.8 mmHg per mL/m2, p = 0.04), and lower stroke volume index (33 ± 10 vs. 38 ± 12 mL/m2, p = 0.01) and systemic arterial compliance (0.53 ± 0.16 vs. 0.62 ± 0.22 mL/m2 per mmHg, p = 0.01). mwFS (11.9 ± 3.9 vs. 14.1 ± 3.7%, p = 0.001), but not EF (51 ± 14 vs. 54 ± 13%, p = n.s.), was reduced in T2DM. mwFS and cESS were inversely interrelated in patients both with (r = − 0.59, p < 0.001) and without T2DM (r = − 0.53, p < 0.001) By multiple regression, higher cESS (p < 0.001) and T2DM (p = 0.02) were independent predictors of depressed mwFS.ConclusionsIn AS, coexistent T2DM appears associated with reduced systemic arterial compliance and LV dysfunction at the midwall level, corresponding to slightly depressed myocardial contractility.

Markers of Bone Mineral Metabolism and Cardiac Structure and Function in Perinatally HIV-Infected and HIV-Exposed but Uninfected Children and Adolescents.

Disordered bone mineral metabolism and low vitamin D concentrations are associated with cardiovascular abnormalities; few studies have evaluated this relationship in HIV-infected youth. The Adolescent Master Protocol is a Pediatric HIV/AIDS Cohort Study network study conducted across 14 US sites. Among perinatally HIV-infected (PHIV) and perinatally HIV-exposed but uninfected (PHEU) youth enrolled in the Adolescent Master Protocol, we evaluated associations of vitamin D [measured as 25-hydroxy-vitamin D (25-OHD)], parathyroid hormone (PTH), calcium, phosphate, and fibroblast growth factor-23 (FGF-23) concentrations with echocardiographic measures of left ventricular (LV) structure, function, and concentrations of NT-proBNP, a biomarker of cardiac damage. Among 485 participants (305 PHIV and 180 PHEU) with echocardiograms and bone mineralization measures, low 25-OHD (<20 ng/mL) was common among all participants (48% PHIV and 44% PHEU), but elevated PTH (>65 pg/mL) was identified more often among PHIV participants than PHEU participants (9% vs 3%, P = 0.02). After adjusting for HIV status and demographic covariates, both low 25-OHD and elevated PTH were associated with lower mean LV mass z-scores, whereas elevated PTH was associated with higher mean fractional shortening z-scores. Participants with low 25-OHD also had slightly higher mean LV end-systolic wall stress z-scores, but differences were more pronounced in PHEU participants than in PHIV participants. FGF-23 was inversely related to end-diastolic septal thickness, both overall and among PHIV participants. In this cohort of PHIV and PHEU youth, we observed associations of 25-OHD, PTH, and FGF-23 with both structural and functional cardiac parameters, supporting links between bone mineral metabolism and cardiac status.

Hemodynamic effects of incremental lung hyperinflation.

Dynamic hyperinflation (DH) is common in chronic obstructive pulmonary disease and is associated with dyspnea and exercise intolerance. DH also has adverse cardiac effects, although the magnitude of DH and the mechanisms responsible for the hemodynamic impairment remain unclear. We hypothesized that incrementally increasing DH would systematically reduce left ventricular (LV) end-diastolic volume (LVEDV) and LV stroke volume (LVSV) because of direct ventricular interaction. Twenty-three healthy subjects (22 ± 2 yr) were exposed to varying degrees of expiratory loading to induce DH such that inspiratory capacity was decreased by 25%, 50%, 75%, and 100% (100% DH = inspiratory capacity of resting tidal volume plus inspiratory reserve volume ≈ 0.5 l). LV volumes, LV geometry, inferior vena cava collapsibility, and LV end-systolic wall stress were assessed by triplane echocardiography. 25% DH reduced LVEDV (-6 ± 5%) and LVSV (-9 ± 8%). 50% DH elicited a similar response in LVEDV (-6 ± 7%) and LVSV (-11 ± 10%) and was associated with significant septal flattening [31 ± 32% increase in the radius of septal curvature at end diastole (RSC-ED)]. 75% DH caused a larger reduction in LVEDV and LVSV (-9 ± 7% and -16 ± 10%, respectively) and RSC-ED (49 ± 70%). 100% DH caused the largest reduction in LVEDV and LVSV (-13 ± 9% and -18 ± 9%) and an increase in RSC-ED (56 ± 63%). Inferior vena cava collapsibility and LV afterload (LV end-systolic wall stress) were unchanged at all levels of DH. Modest DH (-0.6 ± 0.2 l inspiratory reserve volume) reduced LVSV because of reduced LVEDV, likely because of increased pulmonary vascular resistance. At higher levels of DH, direct ventricular interaction may be the primary cause of attenuated LVSV, as indicated by septal flattening because of a greater relative increase in right ventricular pressure and/or mediastinal constraint. NEW & NOTEWORTHY By systematically reducing inspiratory capacity during spontaneous breathing, we demonstrate that dynamic hyperinflation (DH) progressively reduces left ventricular (LV) end diastolic volume and LV stroke volume. Evidence of significant septal flattening suggests that direct ventricular interaction may be primarily responsible for the reduced LV stroke volume during DH. Hemodynamic impairment appears to occur at relatively lower levels of DH and may have important clinical implications for patients with chronic obstructive pulmonary disease.

Growth Hormone Deficiency Is Associated with Worse Cardiac Function, Physical Performance, and Outcome in Chronic Heart Failure: Insights from the T.O.S.CA. GHD Study.

BackgroundAlthough mounting evidence supports the concept that growth hormone (GH) deficiency (GHD) affects cardiovascular function, no study has systematically investigated its prevalence and role in a large cohort of chronic heart failure (CHF) patients. Aim of this study is to assess the prevalence of GHD in mild-to-moderate CHF and to explore clinical and functional correlates of GHD.MethodsOne-hundred thirty CHF patients underwent GH provocative test with GHRH+arginine and accordingly categorized into GH-deficiency (GHD, n = 88, age = 61.6±1.1 years, 68% men) and GH-sufficiency (GHS, n = 42, age = 63.6±1.5 years, 81% men) cohorts. Both groups received comprehensive cardiovascular examination and underwent Doppler echocardiography, cardiopulmonary exercise testing, and biochemical and hormonal assay.ResultsGHD was detected in roughly 30% of CHF patients. Compared to GHD, GHS patients showed smaller end-diastolic and end-systolic LV volumes (-28%, p = .008 and -24%, p = .015, respectively), lower LV end-systolic wall stress (-21%, p = .03), higher RV performance (+18% in RV area change, p = .03), lower estimated systolic pulmonary artery pressure (-11%, p = .04), higher peak VO2 (+20%, p = .001) and increased ventilatory efficiency (-12% in VE/VCO2 slope, p = .002). After adjusting for clinical covariates (age, gender, and tertiles of LV ejection fraction, IGF-1, peak VO2, VE/VCO2 slope, and NT-proBNP), logistic multivariate analysis showed that peak VO2 (β = -1.92, SE = 1.67, p = .03), VE/VCO2 slope (β = 2.23, SE = 1.20, p = .02) and NT-proBNP (β = 2.48, SE = 1.02, p = .016), were significantly associated with GHD status. Finally, compared to GHS, GHD cohort showed higher all-cause mortality at median follow-up of 3.5 years (40% vs. 25%, p < .001, respectively), independent of age, sex, NT-proBNP, peak VO2 and LVEF.ConclusionsGH deficiency identifies a subgroup of CHF patients characterized by impaired functional capacity, LV remodeling and elevated NT-proBNP levels. GHD is also associated with increased all-cause mortality.

Extensive use of vasodilator agents and functional echocardiography to monitor extremely-low-birth-weight infants in Japan.

National surveys were conducted in Japan to assess the current practices for circulatory management of extremely-low-birth-weight infants (ELBWIs) in acute phases. Approximately 80 and 100 institutions were surveyed in 2006 and 2011, respectively. Echocardiography was identified as an important diagnostic tool at 95% of the surveyed institutions. Furthermore, 74% of the institutions survey in 2011 used vasodilator agents. In 2011, the mean velocity of circumferential fiber shortening (mVcfc) and left ventricular end-systolic wall stress (ESWS) were used by 60% of the surveyed institutions to evaluate the relationship between afterload of the left ventricle and left ventricular contractility. Overall, the data collected from these national surveys clarified the current practices for circulatory management of ELBWIs in Japan, particularly the use of echocardiography and cardiovascular agents, including catecholamines and vasodilators.

Medical interventions for treating anthracycline-induced symptomatic and asymptomatic cardiotoxicity during and after treatment for childhood cancer.

Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline-induced cardiotoxicity. This review is an update of a previously published Cochrane review. To compare the effect of medical interventions on anthracycline-induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions, or no treatment. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 8), MEDLINE/PubMed (1949 to September 2015), and EMBASE/Ovid (1980 to September 2015) for potentially relevant articles. In addition, we searched reference lists of relevant articles, conference proceedings of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), the International Conference on Long-Term Complications of Treatment of Children & Adolescents for Cancer, and the European Symposium on Late Complications from Childhood Cancer (from 2005 to 2015), and ongoing trial databases (the ISRCTN Register, the National Institutes of Health (NIH) Register, and the trials register of the World Health Organization (WHO); all searched in September 2015). Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline-induced cardiotoxicity with either placebo, other medical interventions, or no treatment. Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments, which another review author checked. We performed analyses according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions. In the original version of the review we identified two RCTs; in this update we identified no additional studies. One trial (135 participants) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline-induced cardiac dysfunction. The other trial (68 participants) compared a two-week treatment of phosphocreatine with a control treatment (vitamin C, adenosine triphosphate, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline-induced cardiotoxicity. Both studies had methodological limitations.The RCT on enalapril showed no statistically significant differences in overall survival, mortality due to heart failure, development of clinical heart failure, and quality of life between treatment and control groups. A post-hoc analysis showed a decrease (that is improvement) in one measure of cardiac function (left ventricular end-systolic wall stress (LVESWS): -8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Participants treated with enalapril had a higher risk of dizziness or hypotension (risk ratio 7.17, 95% confidence interval 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013).The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function, and adverse events between treatment and control groups. Only one trial evaluated the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side effects of enalapril in childhood cancer survivors with asymptomatic anthracycline-induced cardiotoxicity.Only one trial evaluated the effect of phosphocreatine in childhood cancer patients with anthracycline-induced cardiotoxicity. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatments on echocardiographic function and clinical outcomes.We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors.High-quality studies should be performed.

Abstract 19201: Clinical Impact of Cardiac Regenerative Therapy With Autologous Skeletal Stem Cell Sheet Implantation on Treating Severe Heart Failure

Background: Transplantation of autologous somatic tissue-derived cells into the heart has been shown to yield functional recovery of the failing heart via “paracrine effects” that enhance the native regenerative process. We have introduced skeletal stem cell (SSC) sheet methods for treating severe heart failure (HF), in which scaffold-free cell-sheets are attached on the epicardial surface to maximize the paracrine effects. We herein report feasibility, safety and efficacy of SSC sheet transplantation for treating advanced HF. Methods: This study enrolled 27 patients (mean age, 51±15 years, DCM in 15 patients and ICM in 12 patients) with chronic advanced HF despite optimum treatments. Scaffold-free cell-sheets containing SSC (average: 3.5±1.9х108 cells) was transplanted over the left ventricular (LV) free wall via the left thoracotomy. Average follow-up was 2.5 (0.6-5.1) years. Results: All patients discharged from the hospital without procedure-related complications. Re-In-hospital treatment for congestive HF was required in 8 patients, who we defined as non-responder (Group N: n=8), while the other patients who were free from in-hospital cardiac treatments were defined as responder (Group R: n=19). The Group R exhibited decreased NYHA functional class (2.8±0.6 to 1.6±1.1 p&lt;0.05) and increased 6-minute walk test (444±110 to 499±114m p&lt;0.05) at 6 months, while these values maintained until the latest follow-up. Echocardiographically, LV systolic and diastolic diameters significantly decreased and ejection fraction significantly increased. In addition, both LV end-systolic and diastolic wall stress, assessed by cardiac CT scanning, significantly decreased (systolic: 377±76 to 317±88, diastolic: 116±98 to 51±32 kdynes/cm2, p&lt;0.05 respectively) in the Group R. Multivariate analysis showed that preoperative duration of HF was a single independent risk factor for Group N with its hazard ratio 1.8 (p&lt;0.05). Three-year freedom from cardiac death was 92%, while that from recurrence of HF was 70%. Conclusions: SSC sheet transplantation was feasible and safe in advanced HF patients. Functional recovery, including reduced LV wall stress, was gained in the selected patients, who received this treatment in early stage of advanced HF.

Abstract 15490: Immunogenic Verification of MHC-homo iPS Cell-derived Cardiomyocytes Transplantation to an MHC-matched Non-human Primate Ischemic Cardiomyopathy Model: Pre-clinical Study for Allogenic Therapy Using iPS Cells

Introduction: Derivatives of allogeneic induced pluripotent stem cell (iPSC) are promising in clinical application of iPSC-based cardiac regeneration therapy. Although major histocompatibility complex (MHC)-matched allogeneic implantation (MMAI) is theoretically useful in minimizing immune rejection against the graft, graft survival or therapeutic efficacy of MMAI is poorly understood. Hypothesis: We herein hypothesized that MMAI of iPSC-derived cardiomyocytes (CM)-sheet may be therapeutically effective in a non-human primate ischemic cardiomyopathy model. Methods: iPSCs constitutively expressing GFP were established from Macaca fascicularis with homozygous MHC haplotypes, named “HT1”. Cardiomyogenic differentiation was induced in vitro. Heterozygous HT1 Macaca fascicularis ischemic model was made by ligation of left anterior descending artery (LAD) for 2 weeks, followed by transplantation of the derivatives containing 1.0х107 cells to the cardiac surface as MMAI with tacrolimus, mycophenolate mofetil and prednisolone given. Results: LAD ligation for 2 weeks successfully resulted in decrease of left ventricular ejection fraction (LVEF, 50.4±0.5% to 24.9±1.6%), increase of LV end-systolic volume (ESV, 3.2±0.4 mL to 8.2±0.4 mL) and LV global wall stress (GWS, 106±8 kdyne/cm2 to 203±22 kdyne/cm2). At 4 weeks after transplantation, GFP intensity of the graft was 3.6-fold greater in the MMAI group than the sham, although GFP intensity was not different between the two at 2 months, as assessed by stereomicroscope. LVEF, LVESV and GWS were recovered in the MMAI group at 1 month after the transplantation and then preserved until 5 months (LVEF; 32.4% and 33.8%, LVESV; 7.1 and 7.8 mL, GWS; 156.4 and 165.9 kdyne/cm2, respectively), whereas the sham group showed progressive functional deterioration at 1 and 5 months (LVEF; 20.9% and 21.5%, LVESV; 9.2 and 11.6 mL, GWS; 218.6 and 265.3 kdyne/cm2, respectively). Conclusions: Ischemic cardiomyopathy model was established in a non-human primate, for which MHC-homo-iPSCs-CM sheets were successfully transplanted as MMAI, inducing functional recovery with persistent presence of the graft. It was suggested that MHC-homo-iPSCs may be useful to realize iPSC-based cardiac regenerative therapy.

Screening and intervention for treatment-related cardiac dysfunction in childhood cancer survivors.

10.2217/FON.15.108 © 2015 Future Medicine Ltd During the past four decades, marked advances have been made in the treatment of childhood cancers, such that long-term survival is an expected outcome for many children diagnosed with cancer today [1]. However, improvements in outcome have come at a cost. It is estimated that nearly a third of all childhood cancer survivors will develop a severe or life-threatening health condition years after completion of cancerdirected therapy [2]; these include second cancers, endocrinopathies, neurosensory impairment and cardiovascular disease [2]. Outcomes following onset of cardiovascular disease are especially poor; 5-year overall survival is less than 50% [3], emphasizing the need to develop early screening and prevention strategies in survivors at highest risk of developing cardiovascular disease. Research on survivorship issues has revealed a clear association between certain therapeutic exposures such as anthracycline chemotherapy and/or mediastinal radiation and risk of cardiovascular complications such as heart failure [4]. In these survivors, there is often a long latency between initial exposure to cardiotoxic therapies and onset of clinically overt heart disease [4]. This period is characterized by the development of asymptomatic systolic and/or diastolic cardiomyopathy that can be detected using a variety of imaging modalities [4,5]. Radionuclide angiography (multigated acquisition scan and radionuclide ventriculography) was historically considered the gold standard for assessment of cardiac function [4,5]. However, exposure to ionizing radiation, along with a limited ability to detect structural abnormalities and early cardiac dysfunction, has limited its use in childhood cancer survivors [4,5]. 2D echocardiography offers a readily available assessment of both structure and function without exposure to radiation, and has therefore been widely used to follow childhood cancer survivors. [4,5] Frequently measured echocardiographic parameters of cardiac function include ejection fraction, shortening fraction, velocity of fiber shortening corrected for heart rate, stress–velocity index, left ventricular end-systolic wall stress and more subtle measures of diastolic function [4–6]. More recently, cardiac MRI has emerged as a sensitive and reproducible alternative to echocardiography in nononcology populations and cancer survivors [7,8]. However, despite its diagnostic advantages, higher cost and limited availability impede its use for routine screening. Consequently, current guidelines continue to recommend 2D echocardiography as the screening modality of choice for childhood cancer survivors [6]. COMMENTARY Special Focus Issue: Cardio-oncology