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Background: Anthracycline therapy-related cardiac dysfunction (ATRCD) is the most notorious adverse side-effect of chemotherapy. It has become a significant cardiovascular health concern for long-term cancer survivors. With the emerging concept of subclinical ATRCD and newer diagnostictools (Speckle Tracking Echocardiography (STE) and biomarkers), detecting anthracycline cardiac toxicity at an early stage has become an important step to prevent severe cardiac dysfunction and improve the cardiovascular outcome in cancer survivors. Despite the increasing population at risk in sub-Saharan Africa (SSA), there is no contemporary data in Uganda to address the burden, pathogenesis and risk factors of subclinical ATRCD. This big gap in knowledge has led to a lack of local guidelines for monitoring and management of ATRCD. Methods: SATRACD (Detecting Subclinical Anthracycline Therapy Related Cardiac Dysfunction In Low Income Country) study is an observational prospective cohort study. Three hundred and fifty-three anthracycline naïve cancer patients will be recruited at baseline. Patients are followed up on completion of anthracycline-based chemotherapy and at 6 months after completion of anthracycline therapy. Data on demographics, cancer profile and clinical presentation will be collected at baseline. Comprehensive cardiac assessment will be performed at each visit, including electrocardiogram, conventional echo- cardiography, STE, cardiac and oxidative stress markers. We will be able to determine the incidence of subclinical and clinical ATRCD at 6 months after completion of anthracycline therapy, determine whether hypertension is a major risk factor for ATRCD, evaluate the role of conventional echocardiography parameters, and biomarkers for detecting subclinical ATRCD. Conclusion: This SATRACD study will provide contemporary data on Ugandan cancer patients who have subclinical and clinical ATRCD, help in the development of local strategies to prevent and manage ATRCD, and improve cardiovascular outcome for Ugandan cancer survivors. Keywords: SATRACD study; subclinical anthracycline therapy; cardiac dysfunction; low income country.

International audience; Aims Our objectives were to validate a murine model of chronic cardiotoxicity induced by Doxorubicin (Dox) and Trastuzumab (Trast) and to test the potential cardio-protective effect of metoprolol. Methods and results Male C57Bl6 mice were intraperitoneally injected during 2 weeks with Dox (24 mg/kg) or saline, and then with Trast (10 mg/kg) or saline for two more weeks. Half of the mice received metoprolol (100 mg/kg). Cardiotoxicity was defined by a decline in left ventricular ejection fraction (LVEF) ≥ 10 points. At Day 42, Dox + Trast-treated mice exhibited a 13-points decline in LVEF (74 ± 2.6% vs. 87 ± 0.8% for control mice, P < 0.001) and a severe cardiac atrophy (heart weight: 105 ± 2.7 mg vs. 119 ± 3.9 mg for control mice, P < 0.01). This cardiac atrophy resulted from an excess of cardiac necrosis (assessed by plasma cardiac troponin I level: 3.2 ± 0.4 ng/L vs. 1.3 ± 0.06 ng/L for control mice, P < 0.01), an increase in apoptosis (caspase 3 activity showing a six-fold increase for Dox + Trast-treated mice vs. controls, P < 0.001), and cardiomyocyte atrophy (myocyte size: 0.67 ± 0.08 μm 2 vs. 1.36 ± 0.10 μm 2 for control mice, P < 0.001). In addition, Dox + Trast-treated mice were shown to have an increased cardiac oxidative stress (164 ± 14 dihydroethidine-marked nuclei per area vs. 56 ± 9.5 for control mice, P < 0.01) and increased cardiac fibrosis (the semi-quantitative fibrosis score was threefold higher for Dox + Trast-treated mice as compared with controls, P < 0.01). Metoprolol was not able to prevent either the decrease in LVEF or the severe cardiac atrophy, the cardiac necrosis, and the cardiac remodelling induced by chemotherapies. Conclusion A murine model of chronic cardiotoxicity induced by Dox and Trast was characterized by a decrease in cardiac function, a cardiac apoptosis and necrosis leading to cardiomyocyte atrophy. Metoprolol did not prevent this cardiotoxicity.

Critical care 25(1), 61 (2021). doi:10.1186/s13054-021-03471-2, Published by BioMed Centra, London

Aims The relationship between N‐terminal pro‐brain natriuretic peptide (NT‐pro‐BNP) and galectin‐3 and outcomes has not been studied in African patients with acute heart failure (AHF). The current analysis sought to describe the association between plasma levels of NT‐pro‐BNP and galectin‐3 and cardiovascular (CV) death or heart failure (HF) hospitalization, as well as their associations with symptoms and echocardiography markers of left and right ventricular remodelling among AHF patientsv in sub‐Saharan Africa. Methods and results In a subset of 80 patients with complete data in a study assessing the effects of hydralazine and nitrates in patients with AHF (BAHEF trial; NCT01822808), NT‐pro‐BNP and galectin‐3 analyses were performed, and the association with various characteristics and outcome measures assessed. The mean age of the patients for whom the aforementioned biomarkers were measured was 52.6 years, with 52.5% women. Galectin‐3 at baseline predicted changes (Week 24 to baseline) in left ventricular ejection fraction, left ventricular end‐systolic diameter, left ventricular end‐diastolic diameter, and tricuspid annular plane systolic excursion. Biomarkers and their changes were not associated with changes in 6 min walk test at 24 weeks. Baseline galectin‐3 and change in NT‐pro‐BNP were associated with improvements in dyspnoea at 24 weeks. Nine patients had an HF readmission or died of CV causes through 24 weeks (11.6%). Both biomarkers at baseline predicted combined CV death or HF hospitalization through Week 24 (P‐values = 0.0328 and 0.0001, respectively). Conclusions In a cohort of patients with AHF from sub‐Saharan Africa, NT‐pro‐BNP and galectin‐3 at baseline and their changes were associated with some changes in dyspnoea, echocardiographic remodelling, and CV death or HF hospitalization through Week 24. These tests have potential of being used for risk stratification of AHF patients in sub‐Saharan Africa where resources are scarce.

Hormones have a vital duty in the conservation of physiological cardiovascular function during pregnancy. Alterations in oestrogen, progesterone and prolactin levels are associated with changes in the cardiovascular system to support the growing foetus and counteract pregnancy stresses. Pregnancy hormones are, however, also linked to numerous pathophysiological outcomes on the cardiovascular system. The expression and effects of the three main pregnancy hormones (oestrogen, prolactin and progesterone) vary depending on the gestation period. However, the reaction of a target cell also depends on the abundance of hormone receptors and impacts put forth by other hormones. Hormonal interaction may be synergistic, antagonistic or permissive. It is crucial to explore the cross talk of pregnancy hormones during gestation, as this may have a greater impact on the overall changes to the cardiovascular system.

Peripartum cardiomyopathy (PPCM) is a life-threatening cardiomyopathy characterized by left ventricular (LV) systolic dysfunction late in pregnancy, during delivery, or in the first postpartum months, in women with no previously known heart disease. Today it is assumed that multiple pathomechanisms may induce the disease, including genetic and environmental factors. There is evidence that these factors may merge on common pathomechanistic pathways such as unbalanced oxidative stress and the cleavage of the nursing hormone prolactin (PRL) into an angiostatic 16 kDa-PRL fragment with subsequent vascular impairment and heart failure. Recent research on specific and common pathomechanisms discovered disease-specific biomarkers and therapies. The current knowledge on etiology and pathomechanisms of PPCM is summarized in the present chapter.

Background The link between cancer and cardiovascular disease is firmly established. We sought to investigate the prevalence of cardiovascular disease (CVD) risk factors in Uganda cancer patients, their pre-chemotherapy left ventricular strain echocardiographic pattern and its associations with the CVD risk factors. Methods and results Baseline pre-chemotherapy data of patients who were enrolled in the SATRACD study (a cancer cohort, who were planned for anthracycline therapy), were analyzed. The prevalence of cardiovascular risk factors and baseline strain echocardiographic images were assessed. Among the 355 patients who were recruited over a period of 15 months, 283 (79.7%) were female, with a mean age of 43 years. The types of cancer of the study patients included breast cancer (70.6%), lymphomas, sarcomas, leukemias and hepatocellular carcinoma. Hypertension was the most common comorbidity (27.0%). The prevalence of obesity was 12.1% and that of HIV was 18.3%. All patients had a normal left ventricular ejection fraction (LVEF). The mean global longitudinal strain (GLS) was -20.92 ±2.43%, with females having a significantly higher GLS than males (-21.09±2.42 vs -20.25±2.39, p = 0.008). Fifty-three patients (14.9%) had suboptimal GLS (absolute GLS≤18.00%), which was associated with obesity (POR = 3.07; 95% CI, 1.31–6.98; p = 0.003), alcohol use (POR = 1.94; 95% CI, 1.01–3.74; p = 0.044), long QTc interval in electrocardiogram (POR = 2.54; 95% CI, 1.06–5.74; p = 0.015,) and impaired left ventricular relaxation (POR = 2.24; 95% CI, 1.17–4.25; p = 0.007). On multivariable logistic regression analysis, obesity (POR = 2.95; 95% CI, 1.24–7.03; p = 0.014) was the only independent factor associated with suboptimal GLS. Conclusion There is high prevalence and a unique pattern of cardiovascular risk factors in Uganda cancer patients. In cancer patients with cardiovascular risk conditions, there is reduction in GLS despite preserved LVEF. Longitudinal research is needed to study the predictive value of cardiovascular risk factors and baseline GLS for post chemotherapy cardiac dysfunction.

Background Peripartum cardiomyopathy (PPCM) is an important cause of pregnancy-associated heart failure and occurs in women towards the end of pregnancy or within the first five months post-partum. Though PPCM is mostly associated with left ventricular (LV) recovery, many affected women develop chronic heart failure with persistently reduced LV ejection fraction (LVEF). Despite recent advances in the treatment of PPCM, clinical predictors of myocardial recovery remain sparse. Purpose N-terminal pro-brain natriuretic peptide (NT-pro-BNP) is the only clinically established biomarker with diagnostic value in PPCM. However, its prognostic value for LV recovery in PPCM remains uncertain. We aimed to establish whether NT-pro-BNP could serve as a predictor of LV recovery in PPCM, and if so, which levels would help with such risk stratification. Methods Women with PPCM seen at the Cardiomyopathy Clinic at Groote Schuur Hospital were recruited between 2012 and 2018. Clinical details and echocardiographic features were recorded at baseline and follow-up, and NT-pro-BNP was measured at baseline. LV recovery was defined as an LVEF of ≥50% at 12-month follow-up. Results This cohort of 42 women with PPCM had a mean age of 29.3±5.8 years and median parity of 2 (IQR 1–4). Almost half (45.2%) presented with a NYHA functional class III/IV. The median systolic and diastolic blood pressures were 117mmHg (IQR 105–133) and 75mmHg (IQR 68–85) respectively. The median heart was 94bpm (IQR 74–103). At diagnosis, mean LVEF was 31.1±8.4% and LV end-diastolic dimension (EDD) of 59mm (IQR 53–64), which improved to LVEF 44.5%±14.5 (p=0.001) and LVEDD 53.6mm (p=0.007) at 1 year. Median NT-pro-BNP at presentation was 915.8pg/mL (IQR 613.6–2422.5). Patients presenting with sinus tachycardia (heart rate >100 bpm) had significantly higher NT-pro-BNP values (1815 vs. 728pg/mL, p=0.009) at the time of diagnosis. At presentation, NT-pro-BNP tended to correlate with LVEDD (R 0.33, p=0.04) and was inversely correlated with LVEF (R −0.39, p=0.01). Whereas initial LVEDD and LVEF did not predict LV recovery at 1 year, NT-pro-BNP at the time of diagnosis had prognostic significance. Patients without LV recovery had a significantly higher NT-pro-BNP at diagnosis (1694.1pg/mL vs. 613.1pg/mL, p=0.02). As shown in Figure 1, NT-pro-BNP of >900pg/mL was associated with lower probability of LV recovery (OR 0.19 [95% CI 0.05–0.73], p=0.018). Conclusion We show, for the first time, that NT-pro-BNP has a prognostic value for LV recovery in PPCM. NT-pro-BNP may be useful in the risk stratification in PPCM and may be used to recommend more intensive follow-up of patients who have a NT-pro-BNP >900pg/mL at diagnosis. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This study was supported by the South African Medical Research Council and National Research Foundation of South Africa.

Introduction Peripartum cardiomyopathy (PPCM) is an important cause of pregnancy-associated heart failure worldwide. Although a significant number of women recover their left ventricular (LV) function within 12 months, some remain with persistently reduced systolic function. Methods Knowledge gaps exist on predictors of myocardial recovery in PPCM. N-terminal pro-brain natriuretic peptide (NT-proBNP) is the only clinically established biomarker with diagnostic value in PPCM. We aimed to establish whether NT-proBNP could serve as a predictor of LV recovery in PPCM, as measured by LV end-diastolic volume (LVEDD) and LV ejection fraction (LVEF). Results This study of 35 women with PPCM (mean age 30.0 ± 5.9 years) had a median NT-proBNP of 834.7 pg/ml (IQR 571.2–1840.5) at baseline. Within the first year of follow-up, 51.4% of the cohort recovered their LV dimensions (LVEDD 50%). Women without LV recovery presented with higher NT-proBNP at baseline. Multivariable regression analyses demonstrated that NT-proBNP of ≥ 900 pg/ml at the time of diagnosis was predictive of failure to recover LVEDD (OR 0.22, 95% CI 0.05–0.95, P = 0.043) or LVEF (OR 0.20 [95% CI 0.04–0.89], p = 0.035) at follow-up. Conclusions We have demonstrated that NT-proBNP has a prognostic value in predicting LV recovery of patients with PPCM. Patients with NT-proBNP of ≥ 900 pg/ml were less likely to show any improvement in LVEF or LVEDD. Our findings have implications for clinical practice as patients with higher NT-proBNP might require more aggressive therapy and more intensive follow-up. Point-of-care NT-proBNP for diagnosis and risk stratification warrants further investigation.

Sepsis is a global economic and health burden. Dipeptidyl peptidase 3 (DPP3) is elevated in the plasma of septic patients. The highest levels of circulating DPP3 (cDPP3) are found in non-survivor septic shock patients. The aim of this study was to evaluate the benefits of inhibiting cDPP3 by a specific antibody, Procizumab (PCZ), on cardiac function in an experimental model of sepsis, the caecal ligature and puncture (CLP) model. Rats were monitored by invasive blood pressure and echocardiography. Results are presented as mean ± SD, with p

Importance Arrhythmias are an important cause of maternal morbidity and mortality but remain difficult to diagnose. Objective To compare implantable loop recorder (ILR) plus 24-hour Holter electrocardiographic (ECG) monitoring with standard 24-hour Holter ECG monitoring alone in terms of acceptability, ability to identify significant arrythmias, and effect on management and pregnancy outcome in women who were symptomatic or at high risk of arrythmia because of underlying structural heart disease. Design, Setting, and Participants This single-center, prospective randomized clinical trial recruited 40 consecutive patients from the Cardiac Disease and Maternity Clinic at Groote Schuur Hospital in Cape Town, South Africa. Pregnant patients with symptoms of arrhythmia and/or structural heart disease at risk of arrhythmia were included. Intervention Patients were randomized to standard care (SC; 24-hour Holter ECG monitoring [n = 20]) or standard care plus ILR (SC-ILR; 24-hour Holter ECG monitoring plus ILR [n = 20]). Only 17 consented to ILR insertion, and the 3 who declined ILR were allocated to the SC group. Main Outcomes and Measures Arrhythmias considered included atrial fibrillation, atrial flutter, premature ventricular complexes, supraventricular tachycardia, ventricular tachycardia, or ventricular fibrillation. Results Among the 40 women in this trial, the mean (SD) age was 28.4 (5.5) years. Holter monitoring detected arrhythmias in 3 of 23 patients (13%) in the SC group and 4 of 17 patients (24%) in the SC-ILR group compared with 9 of 17 patients (53%) patients who had arrhythmias detected by ILR. Seven patients (4 with supraventricular tachycardia, 1 with premature ventricular complexes, and 2 with paroxysmal atrial fibrillation recorded by ILR) did not have arrhythmias detected by 24-hour Holter monitoring. Three of these 7 patients (43%) had a change in management as a result of their ILR recordings. There were no maternal deaths. However, the SC group had a significantly lower mean (SD) gestational stage at delivery (35 [5] weeks vs 38 [2], P = .04). Conclusions and Relevance The ILR was better than 24-hour Holter monitoring in detecting arrhythmias, which led to a change in management for a significant proportion of patients. Our findings suggest that ILR may be beneficial for pregnant women at risk of arrhythmia. Trial Registration ClinicalTrials.gov Identifier: NCT02249195

Background Cardiac arrhythmia is an important cause of maternal morbidity and mortality in pregnancy, but is difficult to diagnose. Purpose The aim of this single-centre, prospective, randomized pilot study was to compare the implantable loop recorder (ILR) with standard assessment of arrhythmia (12-lead ECG; 24-hour Holter ECG) in terms of acceptability, detection of arrhythmias and impact on outcome in pregnant women with symptomatic arrhythmias and/or structural heart disease (SHD). Methods The study recruited 40 consecutive patients from a weekly, dedicated cardiac obstetric clinic. Inclusion criteria: symptoms of arrhythmia and/or having SHD at risk of arrhythmia. Patients were randomized to either standard care (SC) or standard care plus ILR (SC-ILR). ILR recordings were read at the monthly visits and/or when presenting with symptoms. Results There were no demographic differences between the study groups. Seventeen patients consented to ILR insertion, all of whom found the procedure acceptable. No arrhythmias were recorded by the 12-lead ECGs. Holter monitoring detected arrhythmias in 10 of 23 patients (43%) from the SC group. In the SC-ILR group, 8 of 17 patients (47%) had arrhythmias detected by Holter, whereas 13 of 17 patients (76%) patients had arrhythmias detected by ILR (p=0.157). One of 4 patients with supraventricular tachycardia, 2 of 3 patients with premature ventricular complexes and 2 patients with paroxysmal atrial fibrillation (AF) recorded by ILR did not have the arrhythmias detected by Holter monitoring (Figure 1A shows a scatter plot of the variable R-R intervals seen in AF and 1B a rhythm strip of AF with irregular RR intervals and the absence of P waves, both downloaded from the ILR). Four of these 5 patients (80%) had a change in management as a direct result of their ILR recordings. There were no maternal deaths up to 42 days postpartum in either of the study groups. Nine babies were born with a low birthweight ( Figure 1 Conclusion(s) This study suggests that an ILR is an acceptable diagnostic modality in pregnant women with a suspected or at risk of arrhythmia. The ILR increased the diagnostic yield to detect arrhythmias that were not detected by routine ECG and Holter monitoring which led to a change in management in the SC-ILR group and was associated with better maternal and neonatal outcomes. The impact of ILR monitoring should be further assessed in larger studies with longer follow up.

Aims Acute heart failure is a high mortality disease and its pathophysiology is not completely understood. Dipeptidyl peptidase 3 (DPP3) is a cytosolic enzyme involved in angiotensin II and enkephalins cleavage. The aim of this study was to investigate the association of circulating DPP3 (cDPP3) levels and mortality in cardiogenic shock patients and to determine the effects of high cDPP3 on organ function in a heart failure (HF) model in mice. Methods and results cDPP3 was measured in 174 patients in cardiogenic shock and high cDPP3 levels were associated with an increased short-term mortality risk (standardized hazard ratio: 1.4 (1.1-1.8)) and severe organ dysfunction. Additionally, a rapid decrease in cDPP3 in cardiogenic shock patients within 24 h of admission was associated with a favourable outcome. This study showed that injection of DPP3 induced myocardial depression (-10 ± 2% of shortening fraction) and impaired kidney haemodynamics (+0.30 ± 0.02 of renal resistive index) in healthy mice. cDPP3 inhibition by Procizumab, a specific antibody directed against cDPP3, promptly normalized cardiac function and kidney haemodynamics in an acute heart failure mouse model, with a marked reduction in oxidative stress and inflammatory signalling. Conclusion Our study demonstrated cDPP3 is a newly discovered myocardial depressant factor, the levels of which at admission are associated with mortality in severe HF patients. Furthermore, inhibition of cDPP3 by Procizumab improved haemodynamics in a mouse model of HF. Our results suggest that DPP3 could be a new biomarker and biotarget for severe HF.

OBJECTIVE: To examine whether treatment with beta-blockers (BBs) in pregnant women with structural heart disease (SHD) resulted in a decrease in foetal birth weight (FBW) in a South African cohort. METHODS: This was a prospective cohort study conducted in a tertiary-level hospital in Cape Town from 2010 to 2016. Of the 178 pregnant women with SHD, 24.2% received BBs for a minimum of two weeks. Adverse foetal outcomes and mean FBW were compared between the BB groups and subgroups (congenital, valvular, cardiomyopathy and other). Adverse foetal outcome was defined as: low birth weight (LBW) < 2 500 g, Apgar score < 7, premature birth (< 37 weeks) and small for gestational age (SGA). RESULTS: BB exposure during pregnancy was found to be associated with a non-significant increased FBW (2 912 vs 2 807 g, p = 0.347). A significant decrease (p = 0.009) was noted in FBW for valvular SHD pregnancies using BBs, while a significant increase (p = 0.049) was observed for the same outcome in the cardiomyopathy subgroup using BBs. A significant increase was observed for SGA (p = 0.010) and LBW (p = 0.003) pregnancies within the valvular subgroup when exposed to BBs. CONCLUSION: BB use in pregnant women with SHD in a South African cohort showed no association with a decrease in FBW or an increase in adverse foetal outcomes when compared to non-BB usage.

Peripartum cardiomyopathy (PPCM) is an idiopathic disorder defined as heart failure occurring in women during the last month of pregnancy and up to 5 months postpartum. In this review, we outline recent reports about the disease pathogenesis and management and highlight the use of diagnosis and prognosis biomarkers. Novel data strengthen the implication of endothelial function in PPCM pathogenesis. The first international registry showed that patient presentations were similar globally, with heterogeneity in patient management and outcome. Despite large improvement in patient management and treatment, there is still a sub-group of women who die from PPCM or who will not recover their cardiac function. Remarkable advances in the comprehension of disease incidence, pathogenesis, and prognosis could be determined with multi-center and international registries. ClinicalTrials.gov Identifier: NCT02590601

Background: Late maternal mortality (up-to 1-year postpartum) is poorly reported globally and is commonly due to cardiovascular disease (CVD). We investigated targeted interventions aiming at reducing peripartum heart failure admission and late maternal death. Methods and results: Prospective single-centre study of 269 peripartum women presenting with CVD in pregnancy, orwithin 6-months postpartum. Both cardiac diseasematernity (CDM) Group-I andGroup-IIwere treated by a dedicated cardiac-obstetric team. CDM Group-II received additional interventions: 1. Early (2–6 weeks) postpartum follow-up at the CDM clinic and immediate referral to dedicated CVD specialist clinics. 2. Betablocker therapy was continued in women with LVEFb45% while pregnant, or immediately started postpartum. Of 269 consecutive women (mean age 28.6 ± 5.9), 213 presented prepartum, 22% in NYHA groups III–IV and 79% in modified WHO groups III–IV. Patients were diagnosed with congenital heart disease (30%), valvular heart disease (25%) and cardiomyopathy (31%). The groups were similar in age, diagnosis, NYHA, modified WHO, BP and HIV, but Group-II had a higher rate of previously known CVD (p b 0.001) and a lower rate of being nulliparous (p b 0.0005). Of Group-I patients 9 died within the 12-month follow-up period versus one death in Group-II (p = 0.047). Heart failure leading to admission was 32% in Group-I versus 14% in Group-II (p = 0.0008), with Group-II having a higher betablocker use peripartum(p=0.009). Perinatalmortality ratewas 22/1000 live birthswith no differences between groups. Conclusion: Early follow-up in a dedicated CDMclinicwith targeted pharmacological interventions led to a significant reduction in peripartum heart failure admission and mortality.

During pregnancy, heart rate ( HR ) is physiologically elevated but recovery occurs within 4 weeks of delivery. Peripartum cardiomyopathy ( PPCM ) is an acute condition which manifests with symptoms of heart failure late during pregnancy, or within 6 months of delivery. One of its main symptoms is elevated HR. Current standard therapy for PPCM makes use of diuretics, ACE inhibitors and beta-blockers. This approach does not satisfactorily improve HR in patients, even after 6 months of treatment. Strong evidence from both experimental and clinical studies suggests that modulation of the sino-atrial node with drugs such as ivabradine may benefi t patients suffering from PPCM . The activity of ivabradine is likely two-fold – direct with regards to heart rate and indirect with long-term structural changes affecting the heart itself, as well as the vascular and endogenous physiological systems. Large clinical trials are needed to validate this concept and further exploration of this hypothesis in an established rodent model of PPCM is required to investigate the outcome on both HR and its effects on other observable systems affected by PPCM .

Inflammation plays a key role in ischemic stroke pathophysiology: microglial/macrophage cells and type-1 helper cells (Th1) seem deleterious, while type-2 helper cells (Th2) and regulatory T cells (Treg) seem protective. CD4 Th0 differentiation is modulated by microglial cytokine secretion. Glatiramer Acetate (GA) is an immunomodulatory drug that has been approved for the treatment of human multiple sclerosis by means of a number of mechanisms: reduced microglial activation and pro-inflammatory cytokine production, Th0 differentiation shifting from Th2 to Th2 and Treg with anti-inflammatory cytokine production and increased neurogenesis. We induced permanent (pMCAo) or transient middle cerebral artery occlusion (tMCAo) and GA (2 mg) or vehicle was injected subcutaneously immediately after cerebral ischemia. Mice were sacrificed at D3 to measure neurological deficit, infarct volume, microglial cell density and qPCR of TNFα and IL-1β (pro-inflammatory microglial cytokines), IFNγ (Th2 cytokine), IL-4 (Th2 cytokine), TGFβ and IL-10 (Treg cytokines), and at D7 to evaluate neurological deficit, infarct volume and neurogenesis assessment. We showed that in GA-treated pMCAo mice, infarct volume, microglial cell density and cytokine secretion were not significantly modified at D3, while neurogenesis was enhanced at D7 without significant infarct volume reduction. In GA-treated tMCAo mice, microglial pro-inflammatory cytokines IL-1β and TNFα were significantly decreased without modification of microglial/macrophage cell density, cytokine secretion, neurological deficit or infarct volume at D3, or modification of neurological deficit, neurogenesis or infarct volume at D7. In conclusion, Glatiramer Acetate administered after cerebral ischemia does not reduce infarct volume or improve neurological deficit in mice despite a significant increase in neurogenesis in pMCAo and a microglial pro-inflammatory cytokine reduction in tMCAo.

Cardiac remodeling is a deleterious consequence of arterial hypertension. This remodeling results in cardiac transcriptomic changes induced by mechanical and hormonal factors (angiotensin II and aldosterone are the most important). The major features of cardiac remodeling are the hypertrophy of cardiomyocytes, interstitial and perivascular fibrosis, and microvascular rarefaction. Inappropriate stimulation of the renin-angiotensin-aldosterone system (RAAS) participates to the development of heart failure. The respective roles of angiotensin II and aldosterone in cardiac remodeling are poorly understood. The development of fibrosis in the heart depends of a balance between profibrotic (TGFβ, CTGF, inflammation) and antifibrotic (BNP, ANP, BMP4 and BMP7) factors. The profibrotic and proinflammatory effects of angiotensin II and aldosterone are very well demonstrated; however, their actions on antifibrotic factors expression are unknown. In order to explore this, we used RenTgKC mice overexpressing renin into the liver, leading to an increased plasma angiotensin II and thus induction of severe hypertension, and AS mice overexpressing aldosterone synthase (AS) in cardiomyocytes which have a doubled intracardiac aldosterone concentration. Male AS mice have a dysfunction of the coronary arteries relaxation without structural and functional changes of the myocardium. Mice derived from a crossing between the RenTgKC and AS strains were used in this work. It is shown that angiotensin II induces the expression of BNP and BMPs which ultimately slows the progression of myocardial fibrosis, and that aldosterone inhibits the expression of these factors and thus worsens the fibrosis.

Introduction Trastuzumab (anti ErbB2 targeted therapy) and anthracyclin can lead to a synergistic cardiotoxicity with a severe decrease of cardiac function. To date, a cardioprotective treatment is not recommended in all patients. Objective Our objective was to define whether metoprolol (β1blocker) used as a cardioprotective treatment was efficient to prevent signs of chronic cardiotoxicity induced by doxorubicin and trastuzumab. Method Males C57Bl/6 mice (n = 60) were injected during 2 weeks with intraperitoneal (IP) doxorubicin (total dose: 24 mg/kg) or saline, and then with IP trastuzumab (total dose of 10 mg/kg) or saline for 2 more weeks. Half of mice received metoprolol (100 mg/kg) in drinking water 10 days before starting protocol and during all the study (42 days). A functional exploration was carried out by transthoracic echocardiography. Biological analysis included quantification of plasma troponin I, cardiac transcript using RT-qPCR, signaling pathways using Western Blotting and immunohistology. Results We observed an excess of mortality in the metroprolol group (22% vs. 7% P Conclusion Albeit previous work suggested a cross-regulation between ErbB2 and β adrenergic signaling pathway, our data indicated that metoprolol used as cardioprotective treatment, did not protect heart from toxicity induced by doxorubicin and trastuzumab.

Angiotensin II and aldosterone have both beneficial and deleterious effects that affect the function of cardiovascular system (blood vessels and heart), the kidneys and other organs. The history of the discoveries of Angiotensin II and aldosterone, and of the molecules that inhibit their synthesis or antagonize their receptors, is an excellent example of translational research. Indeed, a series of experiments have been determinant to initiate clinical studies, and conversely, some unexpected secondary effects observed in treated patients have been understood by experimental research. This chapter will describe the functions of the renin-angiotensin-aldosterone system and the progression of ideas which have allowed to introduce some of the most successful drugs used in hypertension and heart failure.

Cardiac remodeling is a deleterious consequence of arterial hypertension. This remodeling results from cardiac transcriptomic changes induced by mechanical and hormonal factors. Angiotensin II and aldosterone often collaborate in pathological situations to induce hypertrophy of cardiomyocytes, vascular inflammation, perivascular and interstitial fibrosis, and microvascular rarefaction. Experimental models of transgenic mice overexpressing renin in liver, leading to increased plasma angiotensin II and severe hypertension, and mice overexpressing aldosterone-synthase in cardiomyocytes, leading to a doubling of intracardiac aldosterone concentration have shown that cardiac fibrosis in the heart depends on a balance between pro-fibrotic (TGF-s, galectin-3) and anti-fibrotic (BNP, ANP) factors. Recent studies using cell-specific deletion of the mineralocorticoid receptor indicate that its activation in macrophages is a key step in the development of cardiac fibrosis in the setting of hemodynamic or hormonal challenges. This review focuses on the impact of inappropriate stimulation of aldosterone in the development of cardiac fibrosis.

The cardiovascular diseases are the leading cause of death in men and women in industrialized countries. The profound impact of biological sex on cardiovascular physiology or pathology has long been known, but the biological mechanisms responsible for sex-related differences have emerged more recently. Hormone therapy replacement is classically used to prevent cardiovascular pathologies in postmenopausal women but more recently, the beneficial effect of exercise begins to be taken into account. This review aimed to focus on the respective impact of sexual hormones, and/or exercise on the adaptive response of the heart to pathological situations such as severe pressure overload.

Purpose Studies have shown that aldosterone would have angiogenic effects, and therefore would be beneficial in the context of cardiovascular diseases. We thus investigated the potential involvement of aldosterone in triggering a cardiac angiogenic response in the context of type-2 diabetes, and the molecular pathways involved. Procedure 3 week-old male mice, overexpressing aldosterone-synthase (AS), and their controls littermates (WT) were fed with a standard or high fat, high sucrose (HFHS) diet. After 6 months of diet, mice were sacrificed and cardiac samples were assayed by RT-PCR, immuno-blotting and -histology. Findings HFHS-diet induced type-2 diabetes (D) in WT and AS mice. VEGFa mRNAs were decreased in WT-D (−43%, P Conclusions To our knowledge, this is the first study providing new insights into the mechanisms whereby aldosterone prevents diabetes-induced cardiac disorders.

Introduction The pathogenesis of diabetic cardiomyopathy is not fully elucidated. Numerous factors may contribute to the development of heart failure in a diabetic context, including the scarcity of microvasculature and neurohumoral dysregulation, particularly the renin-angiotensin-aldosterone-system. We have previously shown that a modest increase of intracardiac aldosterone prevents the development of cardiomyopathy in mice with type 1 diabetes, possibly through a prevention of cardiac capillary dropout (Messaoudi et al, Faseb J 2009). This study aimed to determine the pathophysiological effects and to study transduction pathways of insulin in the case of a cardiac hyperaldosteronism with or without type 2 diabetes (T2D). Materiels et methodes 3 week-old mice overexpressing aldosterone synthase (AS), n = 9, and their wild-type (WT) littermates n = 5 were fed a high fat, high sucrose diet (HFHSD : 41 % fat, 43 % carbohydrate) or a standard diet ad libitum . After 4 months of diet, glucose and insulin tolerance tests were performed. Echocardiography was done, mice were sacrificed and tissue samples were used for RT-PCR, for immunoblotting and histological analyses. In addition, to analyze the signaling pathways dependent of the insulin receptor and insulin growth factor receptor, some of these mice (n = 5 for each group) received a dose of insulin (1 UI/kg body weight) 30 minutes before the sacrifice (Shimizu et al, JCI 2010). Resultats After 4 months of HFHSD, both WT-D and AS-D mice had hyperglycemia (+55 %, 56 %, P Conclusion The results indicate that in mice developing T2D the AKT signaling pathway in heart could be stimulated by insulin only when cardiac hyperaldosteronism was present. This aldosterone-dependent activation of the AKT pathway might play a role in the induction of VEGFa in heart.