ABSTRACT
Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients' physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.
Subject(s)
Heart Failure , Heart Transplantation , Quality of Life , Humans , Consensus , Europe , Exercise , Heart Failure/rehabilitation , Heart Failure/surgery , Heart Transplantation/adverse effects , Societies, MedicalABSTRACT
OBJECTIVE: Concerns exist about the possible detrimental effects of exercise training on aortic size and valve function in individuals with bicuspid aortic valve (BAV). This multicentre international study aimed to determine the characteristics of aortic size and valve function in athletes versus non-athletes with BAV and athletes with tricuspid aortic valve (TAV). METHODS: We enrolled competitive athletes with BAV and age- and sex-matched athletes with TAV and non-athletes with BAV. We assessed valve function, aortic size and biventricular measures using echocardiography. Individuals with established moderate-severe AV stenosis, regurgitation or significant aortic dilation were excluded from the study. RESULTS: The study population comprised 504 participants: 186 competitive athletes with BAV (84% males; age 30±11 years), 193 competitive athletes with TAV and 125 non-athletes with BAV. The aortic annulus was greater in athletes with BAV than athletes with TAV and non-athletes with BAV (p<0.001). Both athletic and non-athletic individuals with BAV had greater sinuses of Valsalva, sino-tubular junction and ascending aorta diameters than athletes with TAV (p<0.001). However, no significant differences were found between athletes and non-athletes with BAV. Left ventricular index volumes and mass were greater in athletes with BAV than in the other two groups (p<0.001). Individuals with BAV (athletes and non-athletes) had greater mean gradients than TAV athletes. CONCLUSION: This multicentre international study demonstrates no differences between athletes with BAV and non-athletes with BAV regarding aortic valve function or aortic dimensions. However, athletes with BAV have larger aortic diameters and a relatively worse valvular function than athletes with TAV.
ABSTRACT
Aortic regurgitation (AR) following continuous flow left ventricular assist device implantation (cf-LVAD) may adversely impact outcomes. We aimed to assess the incidence and impact of progressive AR after cf-LVAD on prognosis, biomarkers, functional capacity and echocardiographic findings. In an analysis of the PCHF-VAD database encompassing 12 European heart failure centers, patients were dichotomized according to the progression of AR following LVAD implantation. Patients with de-novo AR or AR progression (AR_1) were compared to patients without worsening AR (AR_0). Among 396 patients (mean age 53 ± 12 years, 82% male), 153 (39%) experienced progression of AR over a median of 1.4 years on LVAD support. Before LVAD implantation, AR_1 patients were less frequently diabetic, had lower body mass indices and higher baseline NT-proBNP values. Progressive AR did not adversely impact mortality (26% in both groups, HR 0.91 [95% CI 0.61-1.36]; P = 0.65). No intergroup variability was observed in NT-proBNP values and 6-minute walk test results at index hospitalization discharge and at 6-month follow-up. However, AR_1 patients were more likely to remain in NYHA class III and had worse right ventricular function at 6-month follow-up. Lack of aortic valve opening was related to de-novo or worsening AR (P < 0.001), irrespective of systolic blood pressure (P = 0.67). Patients commonly experience de-novo or worsening AR when exposed to continuous flow of contemporary LVADs. While reducing effective forward flow, worsening AR did not influence survival. However, less complete functional recovery and worse RV performance among AR_1 patients were observed. Lack of aortic valve opening was associated with progressive AR.
Subject(s)
Aortic Valve Insufficiency , Heart Failure , Heart-Assist Devices , Humans , Male , Adult , Middle Aged , Aged , Female , Aortic Valve Insufficiency/diagnosis , Aortic Valve Insufficiency/epidemiology , Aortic Valve Insufficiency/etiology , Heart-Assist Devices/adverse effects , Heart Failure/diagnosis , Heart Failure/therapy , Heart Failure/complications , Echocardiography , Ventricular Function, Right , Retrospective Studies , Treatment OutcomeABSTRACT
BACKGROUND: Low cardiorespiratory fitness (VÌO2peak) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve VÌO2peak, there is considerable inter-individual variability in the VÌO2peak response to the same dose of exercise. Understanding how genetic factors contribute to VÌO2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of VÌO2peak response following exercise training. METHODS: Participant change in objectively measured VÌO2peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P < 1 × 10-5) with the magnitude of VÌO2peak response. Findings were tested in an independent validation study (n = 39) and compared to previous research. RESULTS: No variants at the genome-wide significance level were found after adjusting for key covariates (baseline VÌO2peak, individual study, principal components which were significantly associated with the trait). A Quantile-Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with VÌO2peak response that reached suggestive significance (P < 1 × 10-5). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene (rs6959961, P = 2.61 × 10-7). A PPS created from the 12 lead SNPs was unable to predict VÌO2peak response in a tenfold cross validation, or in an independent (n = 39) validation study (P > 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P < 1 × 10-4) and the validation study (P < × 10-6), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent. CONCLUSIONS: Ongoing research and validation of current and previous findings is needed to determine if genetics does play a large role in VÌO2peak response variance, and whether genomic predictors for VÌO2peak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601&isReview=true .
Subject(s)
Cardiorespiratory Fitness/physiology , Exercise/physiology , Genetic Variation , Genome-Wide Association Study , Adult , Aged , Cohort Studies , Female , Humans , Male , Middle AgedABSTRACT
BACKGROUND: Toll-like receptors (TLRs) are a family of transmembrane pattern recognition receptors that are mainly expressed on immune cells. Recognition of various exogenous and endogenous molecular patterns activates the TLR signalling cascade, which orchestrates an inflammatory immune response. Dysfunctional immune responses, including aberrant TLR signalling, are increasingly implicated in the associations between sedentarism, chronic low-grade systemic inflammation and various non-communicable diseases. Conversely, exercise exerts anti-inflammatory effects, which could be conferred through its immunomodulatory properties, potentially affecting TLRs. This study aims to systematically review the effects of exercise on human TLR expression. METHOD: A systematic literature search of Pubmed, Embase, The Cochrane Library and SPORTDiscus for articles addressing the impact of exercise (as isolated intervention) on TLRs in humans was conducted, ending in February 2020. RESULTS: A total of 66 articles were included. The publications were categorised according to exercise modality and duration: acute resistance exercise (4 studies), acute aerobic exercise (26 studies), resistance training program (9 studies), aerobic training program (16 studies), combined (i.e. resistance and aerobic) training program (8 studies) and chronic exercise not otherwise classifiable (9 studies). Five articles investigated more than one of the aforementioned exercise categories. Several trends could be discerned with regard to the TLR response in the different exercise categories. Acute resistance exercise seemed to elicit TLR upregulation, whereas acute aerobic exercise had less activating potential with the majority of responses being neutral or, especially in healthy participants, downregulatory. Chronic resistance and combined exercise programs predominantly resulted in unaltered or decreased TLR levels. In the chronic aerobic exercise category, mixed effects were observed, but the majority of measurements demonstrated unchanged TLR expression. CONCLUSION: Currently published research supports an interplay between exercise and TLR signalling, which seems to depend on the characteristics of the exercise. However, there was large heterogeneity in the study designs and methodologies. Therefore, additional research is required to further corroborate these findings, to define its pathophysiological implications and to elucidate the mechanism(s) linking exercise to TLR signalling.
Subject(s)
Exercise , Resistance Training , Toll-Like Receptors , Humans , Receptors, Pattern Recognition , Signal TransductionABSTRACT
AIMS: We identified the first Belgian SCN5A founder mutation, c.4813 + 3_4813 + 6dupGGGT. To describe the clinical spectrum and disease severity associated with this mutation, clinical data of 101 SCN5A founder mutation carriers and 46 non-mutation carrying family members from 25 Belgian families were collected. METHODS AND RESULTS: The SCN5A founder mutation was confirmed by haplotype analysis. The clinical history and electrocardiographic parameters of the mutation carriers and their family members were gathered and compared. A cardiac electrical abnormality was observed in the majority (82%) of the mutation carriers. Cardiac conduction defects, defined as PR or QRS prolongation on electrocardiogram (ECG), were most frequent, occurring in 65% of the mutation carriers. Brugada syndrome (BrS) was the second most prevalent phenotype identified in 52%, followed by atrial dysrythmia in 11%. Overall, 33% of tested mutation carriers had a normal sodium channel blocker test. Negative tests were more common in family members distantly related to the proband. Overall, 23% of the mutation carriers were symptomatic, with 8% displaying major adverse events. As many as 13% of the patients tested with a sodium blocker developed ventricular arrhythmia. One family member who did not carry the founder mutation was diagnosed with BrS. CONCLUSION: The high prevalence of symptoms and sensitivity to sodium channel blockers in our founder population highlights the adverse effect of the founder mutation on cardiac conduction. The large phenotypical heterogeneity, variable penetrance, and even non-segregation suggest that other genetic (and environmental) factors modify the disease expression, severity, and outcome in these families.
Subject(s)
Brugada Syndrome , NAV1.5 Voltage-Gated Sodium Channel , Belgium/epidemiology , Electrocardiography , Humans , Mutation , NAV1.5 Voltage-Gated Sodium Channel/genetics , PhenotypeABSTRACT
Importance: Endurance exercise is effective in improving peak oxygen consumption (peak VÌo2) in patients with heart failure with preserved ejection fraction (HFpEF). However, it remains unknown whether differing modes of exercise have different effects. Objective: To determine whether high-intensity interval training, moderate continuous training, and guideline-based advice on physical activity have different effects on change in peak VÌo2 in patients with HFpEF. Design, Setting, and Participants: Randomized clinical trial at 5 sites (Berlin, Leipzig, and Munich, Germany; Antwerp, Belgium; and Trondheim, Norway) from July 2014 to September 2018. From 532 screened patients, 180 sedentary patients with chronic, stable HFpEF were enrolled. Outcomes were analyzed by core laboratories blinded to treatment groups; however, the patients and staff conducting the evaluations were not blinded. Interventions: Patients were randomly assigned (1:1:1; n = 60 per group) to high-intensity interval training (3 × 38 minutes/week), moderate continuous training (5 × 40 minutes/week), or guideline control (1-time advice on physical activity according to guidelines) for 12 months (3 months in clinic followed by 9 months telemedically supervised home-based exercise). Main Outcomes and Measures: Primary end point was change in peak VÌo2 after 3 months, with the minimal clinically important difference set at 2.5 mL/kg/min. Secondary end points included changes in metrics of cardiorespiratory fitness, diastolic function, and natriuretic peptides after 3 and 12 months. Results: Among 180 patients who were randomized (mean age, 70 years; 120 women [67%]), 166 (92%) and 154 (86%) completed evaluation at 3 and 12 months, respectively. Change in peak VÌo2 over 3 months for high-intensity interval training vs guideline control was 1.1 vs -0.6 mL/kg/min (difference, 1.5 [95% CI, 0.4 to 2.7]); for moderate continuous training vs guideline control, 1.6 vs -0.6 mL/kg/min (difference, 2.0 [95% CI, 0.9 to 3.1]); and for high-intensity interval training vs moderate continuous training, 1.1 vs 1.6 mL/kg/min (difference, -0.4 [95% CI, -1.4 to 0.6]). No comparisons were statistically significant after 12 months. There were no significant changes in diastolic function or natriuretic peptides. Acute coronary syndrome was recorded in 4 high-intensity interval training patients (7%), 3 moderate continuous training patients (5%), and 5 guideline control patients (8%). Conclusions and Relevance: Among patients with HFpEF, there was no statistically significant difference in change in peak VÌo2 at 3 months between those assigned to high-intensity interval vs moderate continuous training, and neither group met the prespecified minimal clinically important difference compared with the guideline control. These findings do not support either high-intensity interval training or moderate continuous training compared with guideline-based physical activity for patients with HFpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT02078947.
Subject(s)
Exercise Therapy/methods , Exercise , Heart Failure/metabolism , High-Intensity Interval Training , Oxygen Consumption , Aged , Evidence-Based Medicine , Exercise Tolerance , Female , Heart Failure/physiopathology , Heart Failure/therapy , Humans , Male , Practice Guidelines as Topic , Stroke VolumeABSTRACT
Clinical and animal studies have demonstrated that chemotherapeutic doxorubicin (DOX) increases arterial stiffness, a predictor of cardiovascular risk. Despite consensus about DOX-impaired endothelium-dependent vasodilation as a contributing mechanism, some studies have reported conflicting results on vascular smooth muscle cell (VSMC) function after DOX treatment. The present study aimed to investigate the effects of DOX on VSMC function. To this end, mice received a single injection of 4 mg DOX/kg, or mouse aortic segments were treated ex vivo with 1 µM DOX, followed by vascular reactivity evaluation 16 h later. Phenylephrine (PE)-induced VSMC contraction was decreased after DOX treatment. DOX did not affect the transient PE contraction dependent on Ca2+ release from the sarcoplasmic reticulum (0 mM Ca2+), but it reduced the subsequent tonic phase characterised by Ca2+ influx. These findings were supported by similar angiotensin II and attenuated endothelin-1 contractions. The involvement of voltage-gated Ca2+ channels in DOX-decreased contraction was excluded by using levcromakalim and diltiazem in PE-induced contraction and corroborated by similar K+ and serotonin contractions. Despite the evaluation of multiple blockers of transient receptor potential channels, the exact mechanism for DOX-decreased VSMC contraction remains elusive. Surprisingly, DOX reduced ex vivo but not in vivo arterial stiffness, highlighting the importance of appropriate timing for evaluating arterial stiffness in DOX-treated patients.
Subject(s)
Calcium/metabolism , Doxorubicin/toxicity , Endothelium, Vascular/pathology , Muscle Contraction , Muscle, Smooth, Vascular/pathology , Vascular Stiffness/drug effects , Vasoconstriction , Animals , Antibiotics, Antineoplastic/toxicity , Calcium Channels/metabolism , Endothelium, Vascular/drug effects , Male , Mice , Mice, Inbred C57BL , Muscle, Smooth, Vascular/drug effectsABSTRACT
The myocardium is a highly structured pluricellular tissue which is governed by an intricate network of intercellular communication. Endothelial cells are the most abundant cell type in the myocardium and exert crucial roles in both healthy myocardium and during myocardial disease. In the last decade, microRNAs have emerged as new actors in the regulation of cellular function in almost every cell type. Here, we review recent evidence on the regulatory function of different microRNAs expressed in endothelial cells, also called endothelial microRNAs, in healthy and diseased myocardium. Endothelial microRNA emerged as modulators of angiogenesis in the myocardium, they are implicated in the paracrine role of endothelial cells in regulating cardiac contractility and homeostasis, and interfere in the crosstalk between endothelial cells and cardiomyocytes.
Subject(s)
Cardiovascular Diseases/genetics , Endothelial Cells/metabolism , MicroRNAs/metabolism , Myocardium/metabolism , Animals , Humans , MicroRNAs/genetics , Myocardium/pathology , Neovascularization, Physiologic/genetics , Paracrine Communication/geneticsABSTRACT
Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high-throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC-associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype-phenotype correlations based on available evidence.
Subject(s)
Cardiomyopathies/genetics , Filamins/genetics , Muscular Diseases/genetics , Animals , Arrhythmias, Cardiac/genetics , Cardiomyopathy, Dilated/genetics , Disease Models, Animal , Genetic Association Studies , Humans , Mutation , Myopathies, Structural, Congenital/geneticsABSTRACT
The myocardium is a highly structured tissue consisting of different cell types including cardiomyocytes, endothelial cells, fibroblasts, smooth muscle cells, inflammatory cells, and stem cells. Microvascular endothelial cells are the most abundant cell type in the myocardium and play crucial roles during cardiac development, in normal adult myocardium, and during myocardial diseases such as heart failure. In the last decade, epigenetic changes have been described regulating cellular function in almost every cell type in the organism. Here, we review recent evidence on different epigenetic changes that regulate intercellular communication in normal myocardium and during myocardial diseases, including cardiac remodeling. Epigenetic changes influence many intercellular communication signaling systems, including the nitric oxide, angiotensin, and endothelin signaling systems. In this review, we go beyond discussing classic endothelial function (for instance nitric oxide secretion) and will discuss epigenetic regulation of intercellular communication.
Subject(s)
Cell Communication/genetics , DNA Methylation , Epigenesis, Genetic , Heart Diseases/genetics , Myocardium/metabolism , Ventricular Remodeling/genetics , Acetylation , Angiotensins/genetics , Angiotensins/metabolism , Animals , Chromatin Assembly and Disassembly , Endothelins/genetics , Endothelins/metabolism , Fibrosis , Gene Expression Regulation , Heart Diseases/metabolism , Heart Diseases/pathology , Heart Diseases/physiopathology , Histones/genetics , Histones/metabolism , Humans , Myocardium/pathology , Nitric Oxide/metabolism , Signal TransductionABSTRACT
BACKGROUND: Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE). METHODS: Two hundred sixty-one patients with left ventricular ejection fraction ≤35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks. RESULTS: Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT (P=0.45); left ventricular end-diastolic diameter changes compared with RRE were -2.8 mm (-5.2 to -0.4 mm; P=0.02) in HIIT and -1.2 mm (-3.6 to 1.2 mm; P=0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake (P=0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P=0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT. CONCLUSIONS: HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046.
Subject(s)
Heart Failure/diagnosis , High-Intensity Interval Training , Stroke Volume/physiology , Aged , Echocardiography , Exercise Test , Exercise Tolerance , Female , Follow-Up Studies , Heart Failure/physiopathology , Heart Rate/physiology , Heart Ventricles/diagnostic imaging , Humans , Male , Middle Aged , Quality of Life , Ventricular RemodelingABSTRACT
Endothelial function and arterial stiffness are known to be altered in preeclamptic pregnancies. Previous studies have shown conflicting results regarding the best technique for assessing vascular function in pregnancy. In this study, we made a comprehensive evaluation of in vivo vascular function [including flow-mediated dilatation (FMD), peripheral arterial tonometry (PAT), and arterial stiffness] in preeclamptic patients and compared them with normal pregnancies. In addition, we assessed the relation between vascular function and systemic inflammation. Fourteen patients with preeclampsia (PE) and 14 healthy pregnant controls were included. Endothelial function was determined by FMD and PAT and arterial stiffness by carotid-femoral pulse-wave velocity and augmentation index. Systemic inflammation was assessed using mean platelet volume (MPV) and neutrophil-lymphocyte ratio (NLR). The reactive hyperemia index, assessed using PAT, is decreased at the third trimester compared with the first trimester in a normal, uncomplicated pregnancy (P = 0.001). Arterial stiffness is significantly higher in PE versus normal pregnancy (P < 0.001). Endothelial function, obtained by FMD, is deteriorated in PE versus normal pregnancy (P = 0.015), whereas endothelial function assessment by PAT is improved in PE versus normal pregnancy (P = 0.001). Systemic inflammation (MPV and NLR) increases during normal pregnancy. FMD and PAT are disturbed in PE. Endothelial function, assessed by FMD and PAT, shows distinct results. This may indicate that measurements with FMD and PAT reflect different aspects of endothelial function and that PAT should not be used as a substitute for FMD as a measure of endothelial function in pregnancy.
Subject(s)
Arteries/physiopathology , Endothelium, Vascular/physiopathology , Pre-Eclampsia/physiopathology , Vasodilation/physiology , Adult , Dilatation/methods , Female , Humans , Hyperemia/physiopathology , Infant , Manometry/methods , Pregnancy , Vascular StiffnessABSTRACT
BACKGROUND: MicroRNA are noncoding RNA that have a significant role in both inflammatory and cardiovascular diseases. AIMS: We aimed to assess whether the inflammation-related microRNA-155 is associated with the development of adverse left ventricular (LV) remodeling following ST elevation myocardial infarction (STEMI). METHODS: Peripheral blood samples were collected in the inflammatory (day 2), proliferative (day 5), and maturation phases (6 months) after STEMI (n = 20). Granulocytes, monocytes, and lymphocytes were enumerated with flow cytometry. The changes in LV volumes were assessed with 3-D echocardiography on day 1 and after 6 months. Adverse remodeling was defined as a >20% increase in end-diastolic volume. Healthy subjects were recruited as controls. RESULTS: MicroRNA-155 measured on day 5 correlated positively with the relative change in end-diastolic volume (ρ = 0.490, p = 0.028). MicroRNA-155 (day 5) was significantly higher in patients with compared to patients without adverse LV remodeling. The expression level was similar in healthy subjects (n = 8) and in patients with LV remodeling. There was a positive correlation between microRNA-155 and the amount of monocytes (day 5, ρ = 0.463, p = 0.046). CONCLUSION: Impaired downregulation of microRNA-155 during the second phase of the post- STEMI inflammatory response is a determinant of the development of adverse LV remodeling.
Subject(s)
MicroRNAs/blood , ST Elevation Myocardial Infarction/blood , ST Elevation Myocardial Infarction/physiopathology , Ventricular Remodeling , Aged , Case-Control Studies , Echocardiography, Three-Dimensional , Female , Gene Expression Regulation , Humans , Logistic Models , Male , MicroRNAs/genetics , Middle Aged , Percutaneous Coronary Intervention , ST Elevation Myocardial Infarction/surgery , Treatment Outcome , Ventricular Function, LeftABSTRACT
Objective We aimed to investigate (1) the effects of aerobic interval training (AIT) and aerobic continuous training (ACT) on (sub)maximal exercise measures and its determinants including endothelial function, muscle strength and cardiac autonomic function, and (2) the relationship between exercise capacity and these determinants. Methods Two-hundred coronary artery disease (CAD) patients (58.4 ± 9.1 years) were randomized to AIT or ACT for 12 weeks. All patients performed a cardiopulmonary exercise test and endothelial function measurements before and after the intervention; a subpopulation underwent muscle strength and heart rate variability (HRV) assessments. Results The VO2, heart rate and workload at peak and at first and second ventilatory threshold increased (P-time <0.001); the oxygen uptake efficiency slope (P-time <0.001) and half time of peak VO2 (P-time <0.001) improved. Endothelial function and heart rate recovery (HRR) at 1 and 2 min improved (P-time <0.001), while measures of muscle strength and HRV did not change. Both interventions were equally effective. Significant correlations were found between baseline peak VO2 and (1) quadriceps strength (r = 0.44; P < 0.001); (2) HRR at 2 min (r = 0.46; P < 0.001). Changes in peak VO2 correlated significantly with changes in (1) FMD (ρ = 0.17; P < 0.05); (2) quadriceps strength (r = 0.23; P < 0.05); (3) HRR at 2 min (ρ = 0.18; P < 0.05) and Total power of HRV (ρ = 0.41; P < 0.05). Conclusions This multicentre trial shows equal improvements in maximal and submaximal exercise capacity, endothelial function and HRR after AIT and ACT, while these training methods seem to be insufficient to improve muscle strength and HRV. Changes in peak VO2 were linked to changes in all underlying parameters.
Subject(s)
Coronary Artery Disease/rehabilitation , Exercise Therapy/methods , Exercise Tolerance/physiology , Heart Rate/physiology , Muscle Strength/physiology , Oxygen Consumption/physiology , Coronary Artery Disease/physiopathology , Exercise Test , Female , Humans , Male , Middle Aged , PrognosisABSTRACT
The initial promising prospect of autologous bone marrow-derived stem cell therapy in the setting of cardiovascular diseases has been overshadowed by functional shortcomings of the stem cell product. As powerful epigenetic regulators of (stem) cell function, microRNAs are valuable targets for novel therapeutic strategies. Indeed, modulation of specific miRNA expression could contribute to improved therapeutic efficacy of stem cell therapy. First, this review elaborates on the functional relevance of miRNA dysregulation in bone marrow-derived progenitor cells in different cardiovascular diseases. Next, we provide a comprehensive overview of the current evidence on the effect of specific miRNA modulation in several types of progenitor cells on cardiac and/or vascular regeneration. By elaborating on the cardioprotective regulation of progenitor cells on cardiac miRNAs, more insight in the underlying mechanisms of stem cell therapy is provided. Finally, some considerations are made regarding the potential of circulating miRNAs as regulators of the miRNA signature of progenitor cells in cardiovascular diseases.
Subject(s)
Cardiovascular Diseases/surgery , Genetic Therapy/methods , MicroRNAs/genetics , Myocardium , Myocytes, Cardiac/transplantation , Regeneration , Stem Cell Transplantation/methods , Animals , Cardiovascular Diseases/genetics , Cardiovascular Diseases/pathology , Cardiovascular Diseases/physiopathology , Epigenesis, Genetic , Gene Expression Regulation , Humans , MicroRNAs/metabolism , Myocardium/metabolism , Myocardium/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathologyABSTRACT
BACKGROUND: Exercise intolerance is an important feature in patients with chronic kidney disease (CKD) and is prognostic for both increased morbidity and mortality. Little is known about the underlying mechanisms in predialysis CKD. This study aimed to gain more insight into the role of vascular dysfunction in the exercise intolerance of predialysis CKD. In addition, vascular-related microRNAs (miRNAs)-as epigenetic regulators of exercise capacity-were analysed. METHODS: Sixty-three patients with CKD stages 1-5 and 18 healthy controls were included. Peak oxygen consumption (VO2peak) was determined by cardiopulmonary exercise testing, endothelial function by flow-mediated dilation (FMD) and arterial stiffness by carotid-femoral pulse wave velocity (PWV). Plasma miRNA levels (miR-21, miR-126, miR-146a, miR-150 and miR-210) were quantified by quantitative RT-PCR. RESULTS: VO2peak was already impaired in mild CKD (stages 1-3A) and significantly correlated with estimated glomerular filtration rate (eGFR; r = 0.525, P < 0.001). Likewise, both FMD and PWV were significantly correlated with eGFR (r = 0.319, P = 0.007 and r = -0.365, P = 0.001, respectively). In multiple regression analysis, PWV remained one of the strongest independent determinants of VO2peak (ß = -0.301, P = 0.01). Of the studied miRNA, circulating levels of miR-146a and miR-150 correlated with eGFR, PWV and VO2peak, but the association with the latter was lost when correcting for PWV. CONCLUSIONS: Arterial stiffness contributes to the observed reduced aerobic capacity in predialysis CKD, independent of age, haemoglobin levels and endothelial function and represents a promising therapeutic target for improving exercise capacity in this population. Future work is required to elucidate why higher circulating levels of miR-146a and miR-150 are associated with impaired renal function and increased arterial stiffness.
Subject(s)
Peripheral Vascular Diseases/physiopathology , Renal Insufficiency, Chronic/physiopathology , Adult , Aged , Case-Control Studies , Female , Humans , Male , MicroRNAs/blood , Middle Aged , Oxygen Consumption , Peripheral Vascular Diseases/blood , Peripheral Vascular Diseases/etiology , Physical Endurance , Physical Exertion , Pulse Wave Analysis , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/complications , Vascular Stiffness , VasodilationABSTRACT
Exercise training is an effective way to improve exercise capacity in chronic kidney disease (CKD), but the underlying mechanisms are only partly understood. In healthy subjects (HS), microRNA (miRNA or miR) are dynamically regulated following exercise and have, therefore, been suggested as regulators of cardiovascular adaptation to exercise. However, these effects were not studied in CKD before. The effect of acute exercise (i.e., an acute exercise bout) was assessed in 32 patients with CKD and 12 age- and sex-matched HS (study 1). miRNA expression in response to chronic exercise (i.e., a 3-mo exercise training program) was evaluated in 40 CKD patients (study 2). In a subgroup of study 2, the acute-exercise induced effect was evaluated at baseline and at follow-up. Plasma levels of a preselected panel miRNA, involved in exercise adaptation processes such as angiogenesis (miR-126, miR-210), inflammation (miR-21, miR-146a), hypoxia/ischemia (miR-21, miR-210), and progenitor cells (miR-150), were quantified by RT-PCR. Additionally, seven miRNA involved in similar biological processes were quantified in the subgroup of study 2. Baseline, studied miRNA were comparable in CKD and HS. Following acute exercise, miR-150 levels increased in both CKD (fold change 2.12 ± 0.39, P = 0.002; and HS: fold change 2.41 ± 0.48 P = 0.018, P for interaction > 0.05). miR-146a acutely decreased in CKD (fold change 0.92 ± 0.13, P = 0.024), whereas it remained unchanged in HS. Levels of miR-21, miR-126, and miR-210 remained unaltered. Chronic exercise did not elicit a significant change in the studied miRNA levels. However, an acute exercise-induced decrease in miR-210 was observed in CKD patients, only after training (fold change 0.76 ± 0.15). The differential expression in circulating miRNA in response to acute and chronic exercise may point toward a physiological role in cardiovascular adaptation to exercise, also in CKD.
Subject(s)
Exercise Therapy/methods , MicroRNAs/blood , Renal Insufficiency, Chronic/blood , Renal Insufficiency, Chronic/therapy , Adult , Aged , Anaerobic Threshold , Cell Proliferation , Disease Progression , Exercise Test , Female , Glomerular Filtration Rate , Humans , Hypoxia/genetics , Hypoxia/pathology , Inflammation/genetics , Inflammation/pathology , Kidney Function Tests , Male , Middle Aged , Neovascularization, Physiologic/genetics , Stem Cells/metabolismABSTRACT
In this large multicenter trial, we aimed to assess the effect of aerobic exercise training in stable coronary artery disease (CAD) patients on cellular markers of endothelial integrity and to examine their relation with improvement of endothelial function. Two-hundred CAD patients (left ventricular ejection fraction > 40%, 90% male, mean age 58.4 ± 9.1 yr) were randomized on a 1:1 base to a supervised 12-wk rehabilitation program of either aerobic interval training or aerobic continuous training on a bicycle. At baseline and after 12 wk, numbers of circulating CD34(+)/KDR(+)/CD45dim endothelial progenitor cells (EPCs), CD31(+)/CD3(+)/CXCR4(+) angiogenic T cells, and CD31(+)/CD42b(-) endothelial microparticles (EMPs) were analyzed by flow cytometry. Endothelial function was assessed by flow-mediated dilation (FMD) of the brachial artery. After 12 wk of aerobic interval training or aerobic continuous training, numbers of circulating EPCs, angiogenic T cells, and EMPs were comparable with baseline levels. Whereas improvement in peak oxygen consumption was correlated to improvement in FMD (Pearson r = 0.17, P = 0.035), a direct correlation of baseline or posttraining EPCs, angiogenic T cells, and EMP levels with FMD was absent. Baseline EMPs related inversely to the magnitude of the increases in peak oxygen consumption (Spearman rho = -0.245, P = 0.027) and FMD (Spearman rho = -0.374, P = 0.001) following exercise training. In conclusion, endothelial function improvement in response to exercise training in patients with CAD did not relate to altered levels of EPCs and angiogenic T cells and/or a diminished shedding of EMPs into the circulation. EMP flow cytometry may be predictive of the increase in aerobic capacity and endothelial function.