To test whether remote ischaemic conditioning (RIC) as adjuvant to standard of care (SOC) would prevent progression towards heart failure (HF) after ST-elevation myocardial infarction (STEMI). ...Single-centre parallel 1:1 randomized trial (computerized block-randomization, concealed allocation) to assess superiority of RIC (3 cycles of intermittent 5 min lower limb ischaemia) over SOC in consecutive STEMI patients (NCT02313961, clinical trials.gov). From 258 patients randomized to RIC or SOC, 9 and 4% were excluded because of unconfirmed diagnosis and previously unrecognized exclusion criteria, respectively. Combined primary outcome of cardiac mortality and hospitalization for HF was reduced in RIC compared with SOC (
n
= 231 and 217, respectively; HR = 0.35, 95% CI 0.15–0.78) as well as each outcome in isolation. No difference was found in serum troponin I levels between groups. Median and maximum follow-up time were 2.1 and 3.7 years, respectively. In-hospital HF (RR = 0.68, 95% CI 0.47–0.98), need for diuretics (RR = 0.68, 95% CI 0.48–0.97) and inotropes and/or intra-aortic balloon pump (RR = 0.17, 95% CI 0.04–0.76) were decreased in RIC. On planned 12 months follow-up echocardiography (
n
= 193 and 173 in RIC and SOC, respectively) ejection fraction (EF) recovery was enhanced in patients presenting with impaired left ventricular (LV) function (10% absolute difference in median EF compared with SOC;
P
< 0.001). In addition to previously reported improved myocardial salvage index and reduced infarct size RIC was shown beneficial in a combined hard clinical endpoint of cardiac mortality and hospitalization for HF. Improved EF recovery was also documented in patients with impaired LV function.
Formerly regarded purely as passive energy storage, adipose tissue is now recognized as a vital endocrine organ. Adipocytes secrete diverse peptide hormones named adipokines, which act in a ...autocrine, paracrine or endocrine way to influence several biological functions. Adipokines comprise diverse bioactive substances, including cytokines, growth, and complement factors, which perform essential regulatory functions related to energy balance, satiety and immunity. Presently adipokines have been widely implicated in obesity, diabetes, hypertension and cardiovascular diseases.
In this article we aim to present a brief description of the roles and potential therapeutic modulation of adipokines, such as leptin, resistin, adiponectin, apelin, visfatin, FABP-4, tumor necrosis factor-α (TNF-α), interleukin-6 and plasminogen activator inhibitor-1 (PAI-1).
Abstract
Echocardiography is a reliable and reproducible method to assess non-invasively cardiac function in clinical and experimental research. Significant progress in the development of ...echocardiographic equipment and transducers has led to the successful translation of this methodology from humans to rodents, allowing for the scoring of disease severity and progression, testing of new drugs, and monitoring cardiac function in genetically modified or pharmacologically treated animals. However, as yet, there is no standardization in the procedure to acquire echocardiographic measurements in small animals. This position paper focuses on the appropriate acquisition and analysis of echocardiographic parameters in adult mice and rats, and provides reference values, representative images, and videos for the accurate and reproducible quantification of left ventricular function in healthy and pathological conditions.
Graphical Abstract
Although biologically appealing, the concept of tissue regeneration underlying first- and second-generation cell therapies has failed to translate into consistent results in clinical trials. Several ...types of cells from different origins have been tested in pre-clinical models and in patients with acute myocardial infarction (AMI). Mesenchymal stromal cells (MSCs) have gained attention because of their potential for immune modulation and ability to promote endogenous tissue repair, mainly through their secretome. MSCs can be easily obtained from several human tissues, the umbilical cord being the most abundant source, and further expanded in culture, making them attractive as an allogeneic “of-the-shelf” cell product, suitable for the AMI setting. The available evidence concerning umbilical cord-derived MSCs in AMI is reviewed, focusing on large animal pre-clinical studies and early human trials. Molecular and cellular mechanisms as well as current limitations and possible translational solutions are also discussed.
Heart failure (HF) triggered by cardiovascular and non-cardiovascular diseases is a leading cause of death worldwide and translational research is urgently needed to better understand the mechanisms ...of the failing heart. For this purpose, rodent models of heart disease combined with
in vivo
cardiac functional assessment have provided valuable insights into the physiological significance of a given genetic or pharmacological modification. In small animals, cardiac function and structure can be evaluated by methods such as echocardiography, telemetry or hemodynamics using conductance catheters. Indeed, hemodynamic analysis of pressure-volume loops (PV-loops) has become the gold standard methodology to study
in vivo
cardiac function in detail. This method provides simultaneous measurement of both pressure and volume signals from rodents intact beating hearts. On the one hand, PV-loop analysis has deeply expanded the knowledge on molecular cardiac physiology by allowing establishing important functional correlations. On the other hand, these measurements allow dissecting the cardiovascular functional impact of certain therapeutic interventions or specific signaling pathways using transgenic models of disease. However, a detailed assessment of cardiac function and structure
in vivo
still warrants proper standardization and optimization to boost the progress of HF research. With increasing concerns over data accuracy and reproducibility, guidelines and best practices for cardiac physiology measurements in experimental settings are needed. This article aims to review the best practices for carrying out cardiac hemodynamic assessment using PV-loops
in vivo
in rodents intact beating hearts, also providing an overview of its advantages, disadvantages and applications in cardiovascular research.
We conducted a meta-analysis of randomized controlled trials (RCTs) and propensity score (PS) studies comparing survival and major adverse cardiac and cerebrovascular events (MACCEs) of patients who ...underwent coronary artery bypass grafting (CABG) with multiple (MAG) versus single arterial grafting (SAG).
MEDLINE, Web of Science and Cochrane Library were used to find relevant literature (1960–2018). Survival at a follow-up ≥1 year, MACCEs and early outcomes were evaluated. Time-to-event outcomes were collected through hazard ratio (HR) along with their variance, and the other endpoints using frequencies from matched sample or adjusted odds ratios. Random effect models were used to compute combined statistical measures and 95% confidence intervals (CI) through generic inverse variance method (time-to-event) or Mantel-Haenszel method (binary events).
Twenty-nine PS cohorts and 8 RCTs comprising 122,832 patients (52,178 MAG and 70,654 SAG) were included in this meta-analysis. MAG was associated with lower early mortality (OR: 0.82, 95%CI: 0.71–0.95, p = .007), long-term mortality (HR: 0.76, 95%CI: 0.73–0.78, p < .001) and MACCEs (HR: 0.85, 95%CI: 0.79–0.91, p < .001). Increased risk of sternal wound complications (SWC) was only observed when the bilateral internal mammary artery configuration was used for MAG (OR MAG BIMA: 1.96, 95%CI: 1.37–2.81, p < .001).
Although the BIMA configuration increases the risk of SWC, MAG improves both early and long-term survival as well as MACCEs in CABG.
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•This meta-analysis suggests a benefit of MAG vs. SAG in long-term survival and MACCEs.•BIMA configuration in MAG associates with higher risk of sternal complications.•Powered RCTs are needed to settle MAG vs. SAG issue which ROMA trial aims to address.
Introduction:
Management of acute myocardial infarction (MI) mandates careful optimization of volemia, which can be challenging due to the inherent risk of congestion. Increased myocardial compliance ...in response to stretching, known as stretch-induced compliance (SIC), has been recently characterized and partly ascribed to cGMP/cGMP-dependent protein kinase (PKG)-related pathways. We hypothesized that SIC would be impaired in MI but restored by activation of PKG, thereby enabling a better response to volume loading in MI.
Methods:
We conducted experiments in
ex vivo
rabbit right ventricular papillary muscles under ischemic and non-ischemic conditions as well as pressure–volume hemodynamic evaluations in experimental
in vivo
MI induced by left anterior descending artery ligation in rats.
Results:
Acutely stretching muscles
ex vivo
yielded increased compliance over the next 15 min, but not under ischemic conditions. PKG agonists, but not PKC agonists, were able to partially restore SIC in ischemic muscles. A similar effect was observed with phosphodiesterase-5 inhibitor (PDE5
i
) sildenafil, which was amplified by joint B-type natriuretic peptide or nitric oxide donor administration.
In vivo
translation revealed that volume loading after MI only increased cardiac output in rats infused with PDE5
i
. Contrarily to vehicle, sildenafil-treated rats showed a clear increase in myocardial compliance upon volume loading.
Discussion:
Our results suggest that ischemia impairs the adaptive myocardial response to acute stretching and that this may be partly prevented by pharmacological manipulation of the cGMP/PKG pathway, namely, with PDE5
i
. Further studies are warranted to further elucidate the potential of this intervention in the clinical setting of acute myocardial ischemia.
The metabolic syndrome and associated comorbidities, like diabetes, hypertension and obesity, have been implicated in the development of heart failure with preserved ejection fraction (HFpEF). The ...molecular mechanisms underlying the development of HFpEF remain to be elucidated. We developed a cardiome-directed network analysis and applied this to high throughput cardiac RNA-sequencing data from a well-established rat model of HFpEF, the obese and hypertensive ZSF1 rat. With this novel system biology approach, we explored the mechanisms underlying HFpEF.
Unlike ZSF1-Lean, ZSF1-Obese and ZSF1-Obese rats fed with a high-fat diet (HFD) developed diastolic dysfunction and reduced exercise capacity. The number of differentially expressed genes amounted to 1591 and 1961 for the ZSF1-Obese vs. Lean and ZSF1-Obese+HFD vs. Lean comparison, respectively. For the cardiome-directed network analysis (CDNA) eleven biological processes related to cardiac disease were selected and used as input for the STRING protein-protein interaction database. The resulting STRING network comprised 3.460 genes and 186.653 edges. Subsequently differentially expressed genes were projected onto this network. The connectivity between the core processes within the network was assessed and important bottleneck and hub genes were identified based on their network topology.
Classical gene enrichment analysis highlighted many processes related to mitochondrial oxidative metabolism. The CDNA indicated high interconnectivity between five core processes: endothelial function, inflammation, apoptosis/autophagy, sarcomere/cytoskeleton and extracellular matrix. The transcription factors Myc and Peroxisome Proliferator-Activated Receptor-α (Ppara) were identified as important bottlenecks in the overall network topology, with Ppara acting as important link between cardiac metabolism, inflammation and endothelial function.
This study presents a novel systems biology approach, directly applicable to other cardiac disease-related transcriptome data sets. The CDNA approach enabled the identification of critical processes and genes, including Myc and Ppara, that are putatively involved in the development of HFpEF.
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Pressure overload-induced hypertrophy compromises cardiac stretch-induced compliance (SIC) after acute volume overload (AVO). We hypothesized that SIC could be enhanced by physiological hypertrophy ...induced by pregnancy's chronic volume overload. This study evaluated SIC-cardiac adaptation in pregnant women with or without cardiovascular risk (CVR) factors. Thirty-seven women (1st trimester, 1
T) and a separate group of 31 (3rd trimester, 3
T) women healthy or with CVR factors (obesity and/or hypertension and/or with gestational diabetes) underwent echocardiography determination of left ventricular end-diastolic volume (LVEDV) and
before (T0), immediately after (T1), and 15 min after (T2; SIC) AVO induced by passive leg elevation. Blood samples for NT-proBNP quantification were collected before and after the AVO. Acute leg elevation significantly increased inferior vena cava diameter and stroke volume from T0 to T1 in both 1
T and 3
T, confirming AVO. LVEDV and
also increased immediately after AVO (T1) in both 1
T and 3
T. SIC adaptation (T2, 15 min after AVO) significantly decreased
in both trimesters, with additional expansion of LVEDV only in the 1
T. NT-pro-BNP increased slightly after AVO but only in the 1
T. CVR factors, but not parity or age, significantly impacted SIC cardiac adaptation. A distinct functional response to SIC was observed between 1
T and 3
T, which was influenced by CVR factors. The LV of 3
T pregnant women was hypertrophied, showing a structural limitation to dilate with AVO, whereas the lower LV filling pressure values suggest increased diastolic compliance.
The sudden increase of volume overload triggers an acute myocardial stretch characterized by an immediate rise in contractility by the Frank-Starling mechanism, followed by a progressive increase known as the slow force response. The present study is the first to characterize echocardiographically the stretch-induced compliance (SIC) mechanism in the context of physiological hypertrophy induced by pregnancy. A distinct functional adaptation to SIC was observed between first and third trimesters, which was influenced by cardiovascular risk factors.
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