NF-κB Transcriptional Activity Indispensably Mediates Hypoxia-Reoxygenation Stress-Induced microRNA-210 Expression.

Ischemia-reperfusion (I-R) injury is a cardinal pathophysiological hallmark of ischemic heart disease (IHD). Despite significant advances in the understanding of what causes I-R injury and hypoxia-reoxygenation (H-R) stress, viable molecular strategies that could be targeted for the treatment of the deleterious biochemical pathways activated during I-R remain elusive. The master hypoxamiR, microRNA-210 (miR-210), is a major determinant of protective cellular adaptation to hypoxia stress but exacerbates apoptotic cell death during cellular reoxygenation. While the hypoxia-induced transcriptional up-regulation of miR-210 is well delineated, the cellular mechanisms and molecular entities that regulate the transcriptional induction of miR-210 during the cellular reoxygenation phase have not been elucidated yet. Herein, in immortalized AC-16 cardiomyocytes, we delineated the indispensable role of the ubiquitously expressed transcription factor, NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in H-R-induced miR-210 expression during cellular reoxygenation. Using dominant negative and dominant active expression vectors encoding kinases to competitively inhibit NF-κB activation, we elucidated NF-κB activation as a significant mediator of H-R-induced miR-210 expression. Ensuing molecular assays revealed a direct NF-κB-mediated transcriptional up-regulation of miR-210 expression in response to the H-R challenge that is characterized by the NF-κB-mediated reorchestration of the entire repertoire of histone modification changes that are a signatory of a permissive actively transcribed miR-210 promoter. Our study confers a novel insight identifying NF-κB as a potential novel molecular target to combat H-R-elicited miR-210 expression that fosters augmented cardiomyocyte cell death.

GSK3ß Inhibition Is the Molecular Pivot That Underlies the Mir-210-Induced Attenuation of Intrinsic Apoptosis Cascade during Hypoxia.

Apoptotic cell death is a deleterious consequence of hypoxia-induced cellular stress. The master hypoxamiR, microRNA-210 (miR-210), is considered the primary driver of the cellular response to hypoxia stress. We have recently demonstrated that miR-210 attenuates hypoxia-induced apoptotic cell death. In this paper, we unveil that the miR-210-induced inhibition of the serine/threonine kinase Glycogen Synthase Kinase 3 beta (GSK3ß) in AC-16 cardiomyocytes subjected to hypoxia stress underlies the salutary protective response of miR-210 in mitigating the hypoxia-induced apoptotic cell death. Using transient overexpression vectors to augment miR-210 expression concomitant with the ectopic expression of the constitutive active GSK3ß S9A mutant (ca-GSK3ß S9A), we exhaustively performed biochemical and molecular assays to determine the status of the hypoxia-induced intrinsic apoptosis cascade. Caspase-3 activity analysis coupled with DNA fragmentation assays cogently demonstrate that the inhibition of GSK3ß kinase activity underlies the miR-210-induced attenuation in the hypoxia-driven apoptotic cell death. Further elucidation and delineation of the upstream cellular events unveiled an indispensable role of the inhibition of GSK3ß kinase activity in mediating the miR-210-induced mitigation of the hypoxia-driven BAX and BAK insertion into the outer mitochondria membrane (OMM) and the ensuing Cytochrome C release into the cytosol. Our study is the first to unveil that the inhibition of GSK3ß kinase activity is indispensable in mediating the miR-210-orchestrated protective cellular response to hypoxia-induced apoptotic cell death.

Acute effects of high intensity training on cardiac function: a pilot study comparing subjects with type 2 diabetes to healthy controls.

This study evaluated acute cardiac stress after a high-intensity interval training session in patients with type 2 diabetes (T2D) versus healthy controls. High intensity aerobic exercise was performed by 4 × 4-min intervals (90-95% of maximal heart rate), followed by a ramp protocol to peak oxygen uptake. Echocardiography was performed before and 30 min after exercise. Holter electrocardiography monitored heart rhythms 24 h before, during, and 24 h after the exercise. Left atrial end-systolic volume, peak early diastolic mitral annular velocity, and the ratio of peak early to late diastolic mitral inflow velocity were reduced by approximately 18%, 15%, and 31%, respectively, after exercise across groups. Left ventricular end-diastolic wall thickness was the only echo parameter that significantly differed between groups in response to exercise. The T2D group had a rate of supraventricular extrasystoles per hour that was 265% greater than that of the controls before exercise, which remained higher after exercise. A single exhaustive exercise session impaired left ventricular diastolic function in both groups. The findings also indicated impaired right ventricular function in patients with T2D after exercise.ClinicalTrials.gov Identifier: NCT02998008.

Overexpression of Neuron-Derived Orphan Receptor 1 (NOR-1) Rescues Cardiomyocytes from Cell Death and Improves Viability after Doxorubicin Induced Stress.

Following myocardial infarction, reperfusion injury (RI) is commonly observed due to the excessive formation of, e.g., reactive oxygen species (ROS). Doxorubicin (DOX), a widely used anti-cancer drug, is also known to cause cardiotoxicity due to excessive ROS production. Exercise training has been shown to protect the heart against both RI- and DOX-induced cardiotoxicity, but the exact mechanism is still unknown. Neuron-derived orphan receptor 1 (NOR-1) is an important exercise-responsive protein in the skeletal muscle which has also been reported to facilitate cellular survival during hypoxia. Therefore, we hypothesized that NOR-1 could protect cardiomyocytes (CMs) against cellular stress induced by DOX. We also hypothesized that NOR-1 is involved in preparing the CMs against a stress situation during nonstimulated conditions by increasing cell viability. To determine the protective effect of NOR-1 in CMs stressed with DOX challenge, we overexpressed NOR-1 in AC16 human CMs treated with 5 µM DOX for 12 h or the respective vehicle control, followed by performing Lactate dehydrogenase (LDH) activity, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and caspase-3 activity assays to measure cell death, cell viability, and apoptosis, respectively. In addition, Western blotting analysis was performed to determine the expression of key proteins involved in cardioprotection. We demonstrated that NOR-1 overexpression decreased cell death (p < 0.105) and apoptosis (p < 0.01) while increasing cell viability (p < 0.05) in DOX-treated CMs. We also observed that NOR-1 overexpression increased phosphorylation of extracellular signal-regulated kinase (ERK) (p < 0.01) and protein expression levels of B cell lymphoma extra-large (Bcl-xL) (p < 0.01). We did not detect any significant changes in phosphorylation of protein kinase B (Akt), glycogen synthase kinase-3ß (GSK-3ß) and signal transducer and activator of transcription 3 (STAT3) or expression levels of superoxide dismutase 2 (SOD2) and cyclin D1. Furthermore, we demonstrated that NOR-1 overexpression increased the cell viability (p < 0.0001) of CMs during nonstimulated conditions without affecting cell death or apoptosis. Our findings indicate that NOR-1 could serve as a potential cardioprotective protein in response to Doxorubicin-induced cellular stress.

Cardiac Exosomes in Ischemic Heart Disease- A Narrative Review.

Ischemic heart disease (IHD) is the primary cause of death globally. IHD is associated with the disruption of blood supply to the heart muscles, which often results in myocardial infarction (MI) that further may progress to heart failure (HF). Exosomes are a subgroup of extracellular vesicles that can be secreted by virtually all types of cells, including cardiomyocytes, cardiac fibroblasts, endothelial cells, and stem and progenitor cells. Exosomes represent an important means of cell-cell communication through the transport of proteins, coding and non-coding RNA, and other bioactive molecules. Several studies show that exosomes play an important role in the progression of IHD, including endothelial dysfunction, the development of arterial atherosclerosis, ischemic reperfusion injury, and HF development. Recently, promising data have been shown that designates exosomes as carriers of cardioprotective molecules that enhance the survival of recipient cells undergoing ischemia. In this review, we summarize the functional involvement of exosomes regarding IHD. We also highlight the cardioprotective effects of native and bioengineered exosomes to IHD, as well as the possibility of using exosomes as natural biomarkers of cardiovascular diseases. Lastly, we discuss the opportunities and challenges that need to be addressed before exosomes can be used in clinical applications.

miR-210 Regulates Apoptotic Cell Death during Cellular Hypoxia and Reoxygenation in a Diametrically Opposite Manner.

Apoptotic cell death of cardiomyocytes is a characteristic hallmark of ischemia-reperfusion (I/R) injury. The master hypoxamiR, microRNA-210 (miR-210), is considered the primary driver of the cellular response to hypoxic stress. However, to date, no consensus has emerged with regards to the polarity of the miR-210-elicited cellular response, as miR-210 has been shown to exacerbate as well as attenuate hypoxia-driven apoptotic cell death. Herein, in AC-16 cardiomyocytes subjected to hypoxia-reoxygenation (H-R) stress, we unravel novel facets of miR-210 biology and resolve the biological response mediated by miR-210 into the hypoxia and reoxygenation temporal components. Using transient overexpression and decoy/inhibition vectors to modulate miR-210 expression, we elucidated a Janus role miR-210 in the cellular response to H-R stress, wherein miR-210 mitigated the hypoxia-induced apoptotic cell death but exacerbated apoptotic cell death during cellular reoxygenation. We further delineated the underlying cellular mechanisms that confer this diametrically opposite effect of miR-210 on apoptotic cell death. Our exhaustive biochemical assays cogently demonstrate that miR-210 attenuates the hypoxia-driven intrinsic apoptosis pathway, while significantly augmenting the reoxygenation-induced caspase-8-mediated extrinsic apoptosis pathway. Our study is the first to unveil this Janus role of miR-210 and to substantiate the cellular mechanisms that underlie this functional duality.

microRNA-451a prevents activation of matrix metalloproteinases 2 and 9 in human cardiomyocytes during pathological stress stimulation.

Matrix metalloproteinases (MMP) are important for cardiac remodeling. Recently, microRNA (miR)-451a has been found to inhibit the expression of both MMP-2 and MMP-9 in human malignancies, but its role in cardiomyocytes has not been explored. We hypothesized that miR-451a modulates MMP-2 and MMP-9 levels in human cardiomyocytes. The role of miR-451a on regulation of MMP-2 and MMP-9 was evaluated in two separate pathological models using Cor.4U human inducible pluripotent stem cell-derived cardiomyocytes (hiPS-CMs): 1) endothelin-1 (ET-1), and 2) 48-h hypoxia (1% O2). Both models were transfected with synthetic miR-451a mimics or scramble control. Expression of both mRNA and miR was determined by quantitative real-time polymerase chain reaction and protein activity by (MMP-2/9) activity assay. Bioinformatic analyses were performed using Targetscan 7.1 and STRING 10.5. hiPS-CMs stimulated by hypoxia increased both MMP-2 and MMP-9 expression levels compared with normoxia (P < 0.05), whereas ET-1 stimulation only increased the MMP-9 level compared with vehicle controls (P < 0.05). miR-451a mimics prevented the increase of MMP-2 and MMP-9 expression in both models. Protein activity of MMP-2 and MMP-9 was confirmed to be lower following treatment with miR-451a mimic compared with scramble-controls. Six of 28 predicted gene transcripts of miR-451a were linked to MMP-2 and MMP-9; Macrophage migration inhibitory factor (MIF) was the only predicted target of miR-451a that was increased by ET-1 and hypoxia and reduced following miR-451a mimic transfection. miR-451a prevent the increase of MMP-2 and MMP-9 in human cardiomyocytes during pathological stress. The modulation by miR-451a on MMP-2 and MMP-9 is caused by MIF.

Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129.

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).

Human cardiomyocyte calcium handling and transverse tubules in mid-stage of post-myocardial-infarction heart failure.

AIMS: Cellular processes in the heart rely mainly on studies from experimental animal models or explanted hearts from patients with terminal end-stage heart failure (HF). To address this limitation, we provide data on excitation contraction coupling, cardiomyocyte contraction and relaxation, and Ca2+ handling in post-myocardial-infarction (MI) patients at mid-stage of HF. METHODS AND RESULTS: Nine MI patients and eight control patients without MI (non-MI) were included. Biopsies were taken from the left ventricular myocardium and processed for further measurements with epifluorescence and confocal microscopy. Cardiomyocyte function was progressively impaired in MI cardiomyocytes compared with non-MI cardiomyocytes when increasing electrical stimulation towards frequencies that simulate heart rates during physical activity (2 Hz); at 3 Hz, we observed almost total breakdown of function in MI. Concurrently, we observed impaired Ca2+ handling with more spontaneous Ca2+ release events, increased diastolic Ca2+ , lower Ca2+ amplitude, and prolonged time to diastolic Ca2+ removal in MI (P < 0.01). Significantly reduced transverse-tubule density (-35%, P < 0.01) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase 2a (SERCA2a) function (-26%, P < 0.01) in MI cardiomyocytes may explain the findings. Reduced protein phosphorylation of phospholamban (PLB) serine-16 and threonine-17 in MI provides further mechanisms to the reduced function. CONCLUSIONS: Depressed cardiomyocyte contraction and relaxation were associated with impaired intracellular Ca2+ handling due to impaired SERCA2a activity caused by a combination of alteration in the PLB/SERCA2a ratio and chronic dephosphorylation of PLB as well as loss of transverse tubules, which disrupts normal intracellular Ca2+ homeostasis and handling. This is the first study that presents these mechanisms from viable and intact cardiomyocytes isolated from the left ventricle of human hearts at mid-stage of post-MI HF.

Acute exhaustive aerobic exercise training impair cardiomyocyte function and calcium handling in Sprague-Dawley rats.

INTRODUCTION: Recent data from long-distance endurance participants suggest that cardiac function is impaired after completion. Existing data further indicate that right ventricular function is more affected than left ventricular function. The cellular mechanisms underpinning cardiac deterioration are limited and therefore the aim of this study was to examine cardiomyocyte and molecular responses of the right and left ventricle to an acute bout of exhaustive endurance exercise. MATERIALS AND METHODS: Male Sprague-Dawley rats were assigned to sedentary controls or acute exhaustive endurance exercise consisting of a 120 minutes long forced treadmill run. The contractile function and Ca2+ handling properties in isolated cardiomyocytes, protein expression levels of sarcoplasmic reticulum Ca2+-ATPase and phospholamban including two of its phosphorylated states (serine 16 and threonine 17), and the mitochondrial respiration in permeabilized cardiac muscle fibers were analyzed. RESULTS: The exercise group showed a significant reduction in cardiomyocyte fractional shortening (right ventricle 1 Hz and 3 Hz p<0.001; left ventricle 1 Hz p<0.05), intracellular Ca2+ amplitude (right ventricle 1 and 3 Hz p<0.001; left ventricle 1 Hz p<0.01 and 3 Hz p<0.05) and rate of diastolic Ca2+ decay (right ventricle 1 Hz p<0.001 and 3 Hz p<0.01; left ventricle 1 and 3 Hz p<0.01). Cardiomyocyte relaxation during diastole was only significantly prolonged at 3 Hz in the right ventricle (p<0.05) compared to sedentary controls. We found an increase in phosphorylation of phospholamban at serine 16 and threonine 17 in the left (p<0.05), but not the right, ventricle from exhaustively exercised animals. The protein expression levels of sarcoplasmic reticulum Ca2+-ATPase and phospholamban was not changed. Furthermore, we found a reduction in maximal oxidative phosphorylation and electron transport system capacities of mitochondrial respiration in the right (p<0.01 and p<0.05, respectively), but not the left ventricle from rats subjected to acute exhaustive treadmill exercise. CONCLUSION: Acute exhaustive treadmill exercise is associated with impairment of cardiomyocyte Ca2+ handling and mitochondrial respiration that causes depression in both contraction and diastolic relaxation of cardiomyocytes.

Role of KATP Channels in Beneficial Effects of Exercise in Ischemic Heart Failure.

PURPOSE: Exercise training reduces pathological remodeling and improves cardiac function in ischemic heart failure; however, causal mechanisms underlying the cardiac benefits of exercise are poorly understood. Because opening of adenosine triphosphate (ATP)-sensitive K ⁺(KATP) channels protects the heart during myocardial stress, we hypothesized that such a mechanism is responsible for some of the cardiac benefits induced by exercise in postinfarction chronic heart failure (CHF). METHODS: Left ventricular myocytes were isolated from three groups of rats: Sham, CHF Tr (4 wk after myocardial infarction, rats underwent 8 wk of aerobic interval training 5 d·wk⁻¹) and CHF Sed (rats sedentary for 12 wk after infarction). Cardiomyocyte survival after oxidative stress exposure (200 µM H2O2) and calcium handling (cells loaded with Fura-2 AM and electrically paced at 1 Hz) were assessed in the presence of KATP channel inhibitor glibenclamide. Expression of KATP subunits (SUR2A and Kir6.2) was evaluated using immunoblotting. RESULTS: Exercise improved cardiac function in CHF Tr animals. Cardiomyocytes from CHF Sed rats were more susceptible to oxidative stress-induced cell death than CHF Tr and Sham cardiomyocytes, with glibenclamide completely abolishing the protective effect of exercise. Glibenclamide did not affect cardiomyocyte survival in Sham or CHF Sed rats. In addition, exercise increased the systolic Ca²âº transient amplitude and improved diastolic Ca²âº removal in CHF Tr cardiomyocytes (compared with CHF Sed); both were significantly attenuated by glibenclamide. Exercise resulted in increased expression of KATP channel subunits in CHF Tr hearts, with more pronounced and significant effect on SUR2A. CONCLUSIONS: Our data suggest that KATP channel upregulation induced by chronic exercise likely mediates some of exercise-induced beneficial effects on cardiac function in postischemic heart failure.

Mitochondrial respiration and microRNA expression in right and left atrium of patients with atrial fibrillation.

Atrial fibrillation (AF) is the most common cardiac arrhythmia with a potential to cause serious complications. Mitochondria play central roles in cardiomyocyte function and have been implicated in AF pathophysiology. MicroRNA (miR) are suggested to influence both mitochondrial function and the development of AF. Yet mitochondrial function and miR expression remain largely unexplored in human atrial tissue. This study aims to investigate mitochondrial function and miR expression in the right (RA) and left atria (LA) of patients with AF and sinus rhythm (SR). Myocardial tissue from the RA and LA appendages was investigated in 37 patients with AF (n = 21) or SR (n = 16) undergoing coronary artery bypass surgery and/or heart valve surgery. Mitochondrial respiration was measured in situ after tissue permeabilization by saponin. MiR expression was assessed by miR array and real-time quantitative reverse-transcription polymerase chain reaction. Maximal mitochondrial respiratory rate was increased in both RA and LA tissue of patients with AF vs. SR. Biatrial downregulation of miR-208a and upregulation of miR-106b, -144, and -451 were observed in AF vs. SR. In addition, miR-15b was upregulated in AF within RA only, and miR-106a, -18a, -18b, -19a, -19b, -23a, -25, -30a, -363, -486-5p, -590-5p, and -93 were upregulated in AF within LA only. These findings suggest that mitochondrial function and miR are involved in AF pathophysiology and should be areas of focus in the exploration for potential novel therapeutic targets.

Exercise training and losartan improve endothelial function in heart failure rats by different mechanisms.

OBJECTIVES: To investigate the mechanisms of losartan- and exercise training-induced improvements on endothelial dysfunction in heart failure. DESIGN: Sprague-Dawley rats subjected to left coronary artery ligation inducing myocardial infarction and heart failure were randomized to losartan treatment, high-intensity exercise training, or both. RESULTS: Losartan, but not exercise training, reduced the heart failure-associated elevation in left ventricular end-diastolic pressure (26 ± 2 mmHg vs. 19 ± 1 mmHg after losartan). In contrast, both exercise training and losartan improved exercise capacity, by 40% and 20%, respectively; no additional effects were observed when exercise training and losartan were combined. Aortic segments were mounted on a force transducer to determine vasorelaxation. Heart failure impaired endothelium-dependent vasorelaxation, observed as a 1.9-fold reduced response to acetylcholine (EC50). Exercise and losartan improved acetylcholine-mediated vasorelaxation to the same extent, but by different mechanisms. Exercise training upregulated the nitric oxide pathway, whereas losartan upregulated a non-nitric oxide or -prostacyclin pathway; possibly involving the endothelium-dependent hyperpolarizing factor. CONCLUSIONS: Both losartan and exercise training reversed endothelial dysfunction in heart failure; exercise training via nitric oxide-dependent vasorelaxation, and losartan via an unknown mechanism that may involve endothelium-dependent hyperpolarizing factor. Thus, the combined treatment activated an additional nitric oxide- independent mechanism that contributed to reduce endothelial dysfunction.

Interval training normalizes cardiomyocyte function, diastolic Ca2+ control, and SR Ca2+ release synchronicity in a mouse model of diabetic cardiomyopathy.

RATIONALE: In the present study we explored the mechanisms behind excitation-contraction (EC) coupling defects in cardiomyocytes from mice with type-2 diabetes (db/db). OBJECTIVE: We determined whether 13 weeks of aerobic interval training could restore cardiomyocyte Ca(2+) cycling and EC coupling. METHODS AND RESULTS: Reduced contractility in cardiomyocytes isolated from sedentary db/db was associated with increased diastolic sarcoplasmic reticulum (SR)-Ca(2+) leak, reduced synchrony of Ca(2+) release, reduced transverse (T)-tubule density, and lower peak systolic and diastolic Ca(2+) and caffeine-induced Ca(2+) release. Additionally, the rate of SR Ca(2+) ATPase-mediated Ca(2+) uptake during diastole was reduced, whereas a faster recovery from caffeine-induced Ca(2+) release indicated increased Na(+)/Ca(2+)-exchanger activity. The increased SR-Ca(2+) leak was attributed to increased Ca(2+)-calmodulin-dependent protein kinase (CaMKIIdelta) phosphorylation, supported by the normalization of SR-Ca(2+) leak on inhibition of CaMKIIdelta (AIP). Exercise training restored contractile function associated with restored SR Ca(2+) release synchronicity, T-tubule density, twitch Ca(2+) amplitude, SR Ca(2+) ATPase and Na(+)/Ca(2+)-exchanger activities, and SR-Ca(2+) leak. The latter was associated with reduced phosphorylation of cytosolic CaMKIIdelta. Despite normal contractile function and Ca(2+) handling after the training period, phospholamban was hyperphosphorylated at Serine-16. Protein kinase A inhibition (H-89) in cardiomyocytes from the exercised db/db group abolished the differences in SR-Ca(2+) load when compared with the sedentary db/db mice. EC coupling changes were observed without changes in serum insulin or glucose levels, suggesting that the exercise training-induced effects are not via normalization of the diabetic condition. CONCLUSIONS: These data demonstrate that aerobic interval training almost completely restored the contractile function of the diabetic cardiomyocyte to levels close to sedentary wild type.

Effects of preterm birth and fetal growth retardation on cardiovascular risk factors in young adulthood.

BACKGROUND: The association between low birth weight (LBW) and increased risk of obesity, hypertension and cardiovascular disease later in life is well documented in epidemiological studies. However, clinical follow-up studies of LBW populations have only partly supported this. AIMS: Evaluate associations between LBW and body fat, blood pressure (BP), lung and endothelial function, and maximal oxygen uptake (VO(2max)) in 18 year old young adults. SUBJECTS: Thirty-seven subjects born prematurely with birth weight <1501 g (VLBW group), 47 born at term with low weight (<10th centile) for gestational age (SGA group) and 63 controls with normal birth weight participated in the study. OUTCOME MEASURES: Anthropometric measurements, BP, endothelial function, lung function and VO(2max) were recorded. RESULTS: Both LBW groups were shorter, lighter, had smaller head circumference and higher subscapular-to-triceps skinfold-ratio than controls. Systolic and mean arterial BP was higher in the VLBW compared with the control group, whereas there were no differences between the groups in endothelial function. The VLBW group had reduced dynamic lung volumes lower carbon monoxide transfer factor and lower VO(2max) compared with controls. In particular young adults born VLBW who were also growth retarded in utero had higher indices of central body fat, higher BP and lower VO(2max). CONCLUSION: We found that very preterm birth, but not growth retardation at term, was associated with higher BP and a less favourable fat distribution. In particular, the young adults born VLBW who were also growth retarded in utero had less favourable outcomes.

Exercise training restores aerobic capacity and energy transfer systems in heart failure treated with losartan.

OBJECTIVE: Clinical and experimental studies demonstrate that exercise training improves aerobic capacity and cardiac function in heart failure, even in patients on optimal treatment with angiotensin inhibitors and beta-blockers, but the cellular mechanisms are incompletely understood. Since myocardial dysfunction is frequently associated with impaired energy status, the aim of this study was to assess the effects of exercise training and losartan on myocardial systems for energy production and transfer in heart failure. METHODS: Maximal oxygen uptake, cardiac function and energy metabolism were assessed in heart failure after a myocardial infarction induced by coronary artery ligation in female Sprague-Dawley rats. Losartan was initiated one week after infarction and exercise training after four weeks, either as single interventions or combined. Animals were sacrificed 12 weeks after surgery. RESULTS: Heart failure, confirmed by left ventricular diastolic pressure >15 mmHg and by >20 mmHg drop in peak systolic pressure, was associated with 40% lower aerobic capacity and significant reductions in enzymes involved in energy metabolism. Combined treatment yielded best improvement of aerobic capacity and ventricular pressure characteristics. Exercise training completely restored aerobic capacity and partly or fully restored creatine and adenylate kinases, whereas losartan alone further reduced these enzymes. In contrast, losartan reduced left ventricle diastolic pressure, whereas exercise training had a neutral effect. CONCLUSION: Exercise training markedly improves aerobic capacity and cardiac function after myocardial infarction, either alone or in combination with angiotensin inhibition. The two interventions appear to act by complementary mechanisms; whereas exercise training restores cardiac energy metabolism, mainly at the level of energy transfer, losartan unloads the heart by lowering filling pressure and afterload.