Safety of magnetic resonance imaging in patients with cardiac implantable electronic devices and abandoned or epicardial leads: a systematic review and meta-analysis.

AIMS: Persistent reluctance to perform magnetic resonance imaging (MRI) in patients with abandoned and/or epicardial leads of cardiac implantable electronic devices is related to in vitro studies reporting tip heating. While there is a plethora of data on the safety of MRI in conditional and non-conditional implantable devices, there is a clear lack of safety data in patients with abandoned and/or epicardial leads. METHODS AND RESULTS: Relevant literature was identified in Medline and CINAHL using the key terms 'magnetic resonance imaging' AND 'abandoned leads' OR 'epicardial leads'. Secondary literature and cross-references were supplemented. For reporting guidance, the Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 was used. International Prospective Register of Systematic Reviews (PROSPERO) registration number 465530. Twenty-one publications with a total of 656 patients with 854 abandoned and/or epicardial leads and 929 MRI scans of different anatomical regions were included. No scan-related major adverse cardiac event was documented, although the possibility of under-reporting of critical events in the literature should be considered. Furthermore, no severe device dysfunction or severe arrhythmia was reported. Mainly transient lead parameter changes were observed in 2.8% in the subgroup of patients with functional epicardial leads. As a possible correlate of myocardial affection, subjective sensations occurred mainly in the subgroup with abandoned epicardial leads (4.0%), but no change in myocardial biomarkers was observed. CONCLUSION: Existing publications did not report any relevant adverse events for MRI in patients with abandoned and/or epicardial leads if performed according to strict safety guidelines. However, a more rigorous risk-benefit calculation should be made for patients with epicardial leads.

Delayed coronary perforation four days after percutaneous coronary intervention with subsequent cardiac tamponade: A case report.

Coronary artery perforation (CAP) is a rare but lethal complication of percutaneous coronary interventions (PCIs), and its incidence has been increasing with advances in PCI techniques. Delayed CAP presents a highly challenging complication, as it occurs 30 min-9 days after intervention, making subsequent diagnosis and treatment difficult. We present the case of a 63-year-old male patient who underwent PCI for an obtuse marginalis II because of posterior wall myocardial infarction. Following 4 days of uneventful postoperative stay, the patient developed angina pectoris and hypotension 4 h after reinitiation of anticoagulant therapy with edoxaban. Angiography revealed distal vessel perforation from a side branch of the obtuse marginalis II. The vessel was occluded using autologous fat embolization via a microcatheter, resulting in complete sealing of the perforation. After discharge, 4 weeks after the infarction, the patient started rehabilitation therapy. Distal vessel perforations are typically caused by wire damage. In our case, we also suspected distal wire perforation, which was initially not recognized possibly due to distal occlusion through the thrombotic material. The temporal correlation between the re-initiation of anticoagulant therapy and the occurrence of cardiac tamponade suggests that the thrombotic material was resolved due to the former. The management of delayed CAP does not differ from that of CAP; thus, this rare complication should be considered even days after PCI as it could prove lethal if not recognized early.

Relationship between fermented dairy consumption, circulating short-chain acylcarnitines and angiographic severity of coronary artery disease.

BACKGROUND AND AIMS: Current epidemiologic data suggest beneficial cardiovascular effects of fermented dairy products (FDP). However, the relationship between FDP consumption and angiographic coronary status has not been previously studied. Furthermore, the role of novel metabolomic biomarkers of cardiovascular risk in this context is unclear. We hypothesize that short-chain acylcarnitines (SCA) reflect the link between FDP intake and angiographic extent of stable coronary artery disease (CAD). METHODS AND RESULTS: We recruited 1185 patients admitted for suspected CAD [median age 62 years (interquartile range: 54-69); 714 men (60.3%)]. Prior to coronary angiography, each patient completed a validated Food Frequency Questionnaire. In addition, venous blood was collected from each patient for whole blood metabolomic analysis, using targeted mass-spectrometry. CAD was defined by the presence of ≥1 coronary stenosis ≥50%. Patients with CAD (n = 441) reported lower median FDP intake [86.8 g/day (IQR: 53.4-127.6)] than patients without CAD [n = 744; 103.9 g/day (IQR: 62.9-152.7); p < 0.001]. Upon adjustment for relevant confounders, increased circulating SCA, particularly level of acetylcarnitine (C2) associated with both higher CAD probability [SCA:ß(SE) = 0.584 (0.235), p = 0.013; C2:ß(SE) = 0.575 (0.242), p = 0.017] and decreased FDP consumption [SCA:ß/100 g FDP-increment/day (SE) = -0.785 (0.242), p = 0.001; C2:ß(SE) = -0.560 (0.230), p = 0.015]. By mediation analysis, neither SCA nor C2 showed relevant mediator effect linking FDP consumption to the risk of CAD. CONCLUSION: Increased consumption of fermented milk was associated with lower prevalence of CAD and correlated inversely with circulating SCA, in particular with acetylcarnitine. No substantial mediator effect of SCA linking fermented milk intake with risk of CAD was found. CLINICAL TRIAL REGISTRY: NCT00497887.

High-Intensity Interval Training in Patients With Heart Failure With Reduced Ejection Fraction.

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.

Alu elements in ANRIL non-coding RNA at chromosome 9p21 modulate atherogenic cell functions through trans-regulation of gene networks.

The chromosome 9p21 (Chr9p21) locus of coronary artery disease has been identified in the first surge of genome-wide association and is the strongest genetic factor of atherosclerosis known today. Chr9p21 encodes the long non-coding RNA (ncRNA) antisense non-coding RNA in the INK4 locus (ANRIL). ANRIL expression is associated with the Chr9p21 genotype and correlated with atherosclerosis severity. Here, we report on the molecular mechanisms through which ANRIL regulates target-genes in trans, leading to increased cell proliferation, increased cell adhesion and decreased apoptosis, which are all essential mechanisms of atherogenesis. Importantly, trans-regulation was dependent on Alu motifs, which marked the promoters of ANRIL target genes and were mirrored in ANRIL RNA transcripts. ANRIL bound Polycomb group proteins that were highly enriched in the proximity of Alu motifs across the genome and were recruited to promoters of target genes upon ANRIL over-expression. The functional relevance of Alu motifs in ANRIL was confirmed by deletion and mutagenesis, reversing trans-regulation and atherogenic cell functions. ANRIL-regulated networks were confirmed in 2280 individuals with and without coronary artery disease and functionally validated in primary cells from patients carrying the Chr9p21 risk allele. Our study provides a molecular mechanism for pro-atherogenic effects of ANRIL at Chr9p21 and suggests a novel role for Alu elements in epigenetic gene regulation by long ncRNAs.

Healthy lifestyle interventions to combat noncommunicable disease-a novel nonhierarchical connectivity model for key stakeholders: a policy statement from the American Heart Association, European Society of Cardiology, European Association for Cardiovascular Prevention and Rehabilitation, and American College of Preventive Medicine.

Noncommunicable diseases (NCDs) have become the primary health concern for most countries around the world. Currently, more than 36 million people worldwide die from NCDs each year, accounting for 63% of annual global deaths; most are preventable. The global financial burden of NCDs is staggering, with an estimated 2010 global cost of $6.3 trillion (US dollars) that is projected to increase to $13 trillion by 2030. A number of NCDs share one or more common predisposing risk factors, all related to lifestyle to some degree: (1) cigarette smoking, (2) hypertension, (3) hyperglycemia, (4) dyslipidemia, (5) obesity, (6) physical inactivity, and (7) poor nutrition. In large part, prevention, control, or even reversal of the aforementioned modifiable risk factors are realized through leading a healthy lifestyle (HL). The challenge is how to initiate the global change, not toward increasing documentation of the scope of the problem but toward true action-creating, implementing, and sustaining HL initiatives that will result in positive, measurable changes in the previously defined poor health metrics. To achieve this task, a paradigm shift in how we approach NCD prevention and treatment is required. The goal of this American Heart Association/European Society of Cardiology/European Association for Cardiovascular Prevention and Rehabilitation/American College of Preventive Medicine policy statement is to define key stakeholders and highlight their connectivity with respect to HL initiatives. This policy encourages integrated action by all stakeholders to create the needed paradigm shift and achieve broad adoption of HL behaviors on a global scale.

Mechanical circulatory support in cardiogenic shock.

Despite advances in coronary revascularization and widespread use of primary percutaneous interventions, cardiogenic shock complicating an acute ST-elevation myocardial infarction (CSMI) remains a clinical challenge with high mortality rates. Conservative management with catecholamines is associated with serious limitations, including arrhythmias, increased myocardial oxygen consumption, and inadequate circulatory support. Clinicians have therefore turned to mechanical means of circulatory support. Circulatory assist systems for CSMI can be distinguished by the method of placement (i.e. percutaneous vs. surgical), the type of circulatory support (i.e. left ventricular, right ventricular, or biventricular pressure and/or volume unloading), and whether they are combined with extracorporal membrane oxygenation (ECMO). The percutaneous assist systems most commonly used in CSMI are the intra-aortic balloon pump (IABP), venoarterial ECMO, the Impella pump, and the TandemHeart. Decades of clinical studies and experience demonstrated haemodynamic improvement, including elevation of diastolic perfusion pressure and cardiac output. Recently, the large randomized IABP-Shock II Trial did not show a significant reduction in 30-day mortality in CSMI with IABP insertion. There are no randomized study data available for ECMO use in CSMI. Both the Impella pump and the TandemHeart did not reduce 30-day mortality when compared with IABP in small randomized controlled trials (RCTs). In conclusion, despite the need for effective mechanical circulatory support in CSMI, current devices, as tested, have not been demonstrated to improve short- or long-term survival rates. RCTs testing the optimal timing of device therapy and optimal device design are needed to improve outcomes in CSMI.

Myocardial Late Gadolinium Enhancement (LGE) in Cardiac Magnetic Resonance Imaging (CMR)-An Important Risk Marker for Cardiac Disease.

Cardiovascular magnetic resonance (CMR) has significantly revolutionized the comprehension and diagnosis of cardiac diseases, particularly through the utilization of late gadolinium enhancement (LGE) imaging for tissue characterization. LGE enables the visualization of expanded extracellular spaces in conditions such as fibrosis, fibrofatty tissue, or edema. The growing recognition of LGE's prognostic capacity underscores its importance, evident in the increasing explicit recommendations within guidelines. Notably, the contemporary characterization of cardiomyopathies relies on LGE-based scar assessment by CMR to a large extent. This review describes the pattern and prognostic value of LGE in detail for various cardiac diseases. Despite its merits, establishing LGE as a reliable risk marker encounters challenges. Limitations arise from the fact that not all diseases show LGE, and it should always be analyzed in the context of all CMR sequences and the patient's medical history. In summary, LGE stands as a robust indicator of adverse outcomes in diverse cardiovascular diseases. Its further integration into routine practice is desirable, necessitating widespread availability and application to accumulate both individual and scientific experience.

Exercise training attenuates MuRF-1 expression in the skeletal muscle of patients with chronic heart failure independent of age: the randomized Leipzig Exercise Intervention in Chronic Heart Failure and Aging catabolism study.

BACKGROUND: Muscle wasting occurs in both chronic heart failure (CHF) and normal aging and contributes to exercise intolerance and increased morbidity/mortality. However, the molecular mechanisms of muscle atrophy in CHF and their interaction with aging are still largely unknown. We therefore measured the activation of the ubiquitin-proteasome system and the lysosomal pathway of intracellular proteolysis in muscle biopsies of CHF patients and healthy controls in two age strata and assessed the age-dependent effects of a 4-week endurance training program on the catabolic-anabolic balance. METHODS AND RESULTS: Sixty CHF patients (30 patients aged ≤55 years, mean age 46±5 years; 30 patients aged ≥65 years, mean age 72±5 years) and 60 healthy controls (30 subjects aged ≤55 years, mean age 50±5 years; 30 subjects aged ≥65 years, mean age 72±4 years) were randomized to 4 weeks of supervised endurance training or to a control group. Before and after the intervention, vastus lateralis muscle biopsies were obtained. The expressions of cathepsin-L and the muscle-specific E3 ligases MuRF-1 and MAFbx were measured by real-time polymerase chain reaction and confirmed by Western blot. At baseline, MuRF-1 expression was significantly higher in CHF patients versus healthy controls (mRNA: 624±59 versus 401±25 relative units; P=0.007). After 4 weeks of exercise training, MuRF-1 mRNA expression was reduced by -32.8% (P=0.02) in CHF patients aged ≤55 years and by -37.0% (P<0.05) in CHF patients aged ≥65 years. CONCLUSIONS: MuRF-1, a component of the ubiquitin-proteasome system involved in muscle proteolysis, is increased in the skeletal muscle of patients with heart failure. Exercise training results in reduced MuRF-1 levels, suggesting that it blocks ubiquitin-proteasome system activation and does so in both younger and older CHF patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00176319.

Age-related effects of exercise training on diastolic function in heart failure with reduced ejection fraction: the Leipzig Exercise Intervention in Chronic Heart Failure and Aging (LEICA) Diastolic Dysfunction Study.

AIMS: Diastolic dysfunction (DD) was identified as a predictor of adverse prognosis in heart failure with reduced ejection fraction (HFREF). It is, however, unknown if DD is improved by exercise training, which is known to induce reverse remodelling, and if the training effect is attenuated in elderly HFREF patients. We therefore assessed DD in a cohort of referent controls (RCs) and HFREF patients and studied the response of DD to endurance exercise in two age groups (≤55 years and ≥65 years). METHODS AND RESULTS: Sixty RC (30 ≤ 55 years, mean age 50 ± 5 years; 30 ≥ 65 years, 72 ± 4 years) and 60 HFREF patients (30 ≤ 55 years, 46 ± 5 years; 30 ≥ 65 years, 72 ± 5 years, EF 28 ± 5%) were randomized to 4 weeks of supervised endurance training or to a control group. Exercise training was effective in reducing LV isovolumetric relaxation time by 29% in young and by 26% in old HFREF patients (P< 0.05 for both). As assessed by tissue Doppler, septal E' increased by 37% in young and by 39% among old HFREF patients (P< 0.005 for both) resulting in a significant decrease in the E/E' ratio from 13 ± 1 to 10 ± 1 in young and 14 ± 1 to 11 ± 1 in old HFREF patients (P< 0.05 for both). Serum levels of N-terminal pro brain natriuretic peptide were significantly reduced after endurance training in HFREF patients of all ages. CONCLUSION: In HFREF, diastolic function is significantly impaired in all age groups. Endurance training is highly effective in improving left ventricular diastolic function in HFREF patients regardless of age. This study is registered at ClinicalTrials.gov (number: NCT00176319).

[General Estimation of Cardiovascular Risk]. / Allgemeine Abschätzung des kardiovaskulären Risikos.

The assessment of individual cardiovascular disease risk (CVD) is essential for a cost-effective prevention of cardiovascular morbidity and mortality. While almost half of the population have a very low CVD risk approximately 1/5th of the population have a CVD risk >20% over the next 10 years.Modern risk scores like the ESC-SCORE2 help to identify those in need of intensified preventive efforts based on basic risk factors like smoking, systolic blood pressure, total cholesterol, age, and sex. According to current ESC-guidelines all men >45 years and all women >55 years should be assessed with SCORE2, which is the best calibrated and validated scoring system for Europe.The calculation of total cardiovascular risk also permits to calculate an individual heart-age, which makes it easier for the individual patient to understand his own risk profile. Most current risk estimation systems can be accessed online under u-prevent.com/calculators.

[The ECG in cardiac rehabilitation]. / Das EKG in der Rehabilitation.

The concept and the benefits of cardiac rehabilitation are well established and scientifically proven. In the context of shortened in-hospital stays and older patients receiving more complex interventions, complications of those procedures might occur during cardiac rehabilitation. This article discusses guideline-directed diagnosis and treatment of complications after transcatheter aortic valve replacement, especially delayed-onset heart block, post-operative atrial fibrillation, and acute coronary ischemia in the setting of pre-existent bundle branch block.

Impact of educational attainment on preventive efforts after myocardial infarction: results of the IPP and NET-IPP trials.

AIMS: Educational attainment might impact secondary prevention after myocardial infarction (MI). The purpose of the present study was to compare the rate of risk factors and the efficacy of an intensive prevention program (IPP), performed by prevention assistants and supervised by physicians, in patients with MI and different levels of education. METHODS: In this post hoc analysis of the multicenter IPP and NET-IPP trials, patients with MI were stratified into two groups according to educational attainment: no "Abitur" (no A) vs. "Abitur" or university degree (AUD). The groups were compared at the time of index MI and after 12-month IPP vs. usual care. RESULTS: Out of n = 462 patients with MI, 76.0% had no A and 24.0% had AUD. At the time of index, MI rates of obesity (OR 2.4; 95%CI 1.4-4.0), smoking (OR 2.2, 95%CI 1.4-3.6), and physical inactivity (OR 1.6; 95%CI 1.0-2.5) were significantly elevated in patients with no A. At 12 months after index MI, larger improvements of the risk factors smoking and physical inactivity were observed in patients with IPP and no A than in patients with IPP and AUD or with usual care. LDL cholesterol levels were reduced by IPP compared to usual care, with no difference between no A vs. AUD. A matched-pair analysis revealed that high baseline risk was an important reason for the large risk factor reductions in patients with IPP and no A. CONCLUSION: The study demonstrates that patients with MI and lower educational level have an increased rate of lifestyle-related risk factors and a 12-month IPP, which is primarily performed by non-physician prevention assistants, is effective to improve prevention in this high-risk cohort.

Muscle function and running activity in mouse models of hereditary muscle dystrophy: impact of double knockout for dystrophin and the transcription factor MyoD.

INTRODUCTION: Mice that lack both the transcription factor MyoD and dystrophin display a more pronounced myopathic phenotype when compared with mdx mice. No data on skeletal muscle function and the impact of exercise training are available. METHODS: Six-month-old wild-type, mdx, myoD(-/-), mdx:myoD(+/-), and mdx:myoD(-/-) mice were randomly assigned to either 4 weeks of voluntary running or sedentary behavior. The mdx:myoD(-/-) mice were not able to exercise at all and were kept sedentary. RESULTS: The soleus muscle of sedentary 7-month-old mdx:myoD(-/-) mice showed a significantly lower force development compared with all other mice. Voluntary running beginning at the age of 6 months led to lower force development of soleus muscle in the mdx animals. CONCLUSIONS: mdx:myoD(-/-) is not a suitable model to study exercise-induced effects on dystrophic muscles. Voluntary exercise in adult mdx mice seems to have detrimental effects on the function of soleus muscle.

From inoperable to back to life: a case report of successfully treated obstructive right ventricular primary cardiac lymphoma.

BACKGROUND: Cardiac masses include various tumourous and non-tumourous lesions. Primary cardiac tumours are very rare and most commonly benign. Primary cardiac lymphomas (PCL) account for 1-2% of malignant primary cardiac tumours. Only 197 cases of PCL have been reported between 1949 and 2009. CASE SUMMARY: We report a case of a 73-year-old patient who presented with atrial flutter. The diagnosis was a tumourous cardiac mass in the right atrium with signs of the infiltration of the tricuspid valve insertion and pericardium. There were no signs of extracardiac disease at the initial presentation. The patient was deemed to be inoperable by cardiac surgeons. Rapid tumour progression caused atrioventricular-block type Mobitz 2 with concomitant obstruction of the tricuspid valve and axillary lymph node metastasizing. Excision of the axillary lymph node revealed a diffuse large B-cell non-Hodgkin lymphoma. An epicardial right ventricle single lead pacemaker was sited, and chemotherapy was administered, resulting in complete remission. DISCUSSION: Cardiac masses are rare and challenging cases. Although current imaging procedures deliver extensive information, histological examination is still required in many cases. We encountered a tumourous mass with deep infiltration. After the patient was deemed inoperable, later lymph node invasion allowed histological examination, revealing PCL. Primary cardiac lymphomas are life-threatening tumours with rapid and aggressive growth. Treatment is based on chemotherapy consisting of anthracycline-containing regimens. This case report highlights the curative potential of chemotherapy, as we report a rapid regression of the tumour as well as the disappearance of arrhythmias and conduction disorders after treatment.

A metabolomic approach to identify the link between sports activity and atheroprotection.

AIMS: Physical activity (PA) is a mainstay of cardiovascular prevention. This study aimed to identify metabolic mediators of PA that protect against the development of atherosclerosis. METHODS AND RESULTS: A total of 2160 participants in the LIFE heart study were analysed with data on PA and vascular phenotyping. In a targeted metabolomic approach, 61 metabolites (amino acids and acylcarnitines) were measured using liquid chromatography-tandem mass spectrometry. We investigated the interactions between PA, metabolites and markers of atherosclerosis in order to uncover possible mediation effects. Intended sports activity, but no daily PA, was associated with a lower degree of atherosclerosis, odds ratio (OR) for total atherosclerotic burden of 0.76 (95% confidence interval 0.62-0.94), carotid artery plaque OR 0.79 (0.66-0.96), and peripheral artery disease OR 0.74 (0.56-0.98). Twelve amino acids, free carnitine, five acylcarnitines were associated with sports activity. Of these, eight metabolites were also associated with the degree of atherosclerosis. In the mediation analyses, a cluster of amino acids (arginine, glutamine, pipecolic acid, taurine) were considered as possible mediators of atheroprotection. In contrast, a group of members of the carnitine metabolism (free carnitine, acetyl carnitine, octadecenoyl carnitine) were associated with inactivity and higher atherosclerotic burden. CONCLUSION: Our metabolomic approach, which is integrated into a mediation model, provides transformative insights into the complex metabolic processes involved in atheroprotection. Metabolites with antioxidant and endothelial active properties are believed to be possible mediators of atheroprotection. The metabolomic mediation approach can support the understanding of complex diseases in order to identify targets for prevention and therapy.

Functional and structural adaptations of the coronary macro- and microvasculature to regular aerobic exercise by activation of physiological, cellular, and molecular mechanisms: ESC Working Group on Coronary Pathophysiology and Microcirculation position paper.

Regular aerobic exercise (RAEX) elicits several positive adaptations in all organs and tissues of the body, culminating in improved health and well-being. Indeed, in over half a century, many studies have shown the benefit of RAEX on cardiovascular outcome in terms of morbidity and mortality. RAEX elicits a wide range of functional and structural adaptations in the heart and its coronary circulation, all of which are to maintain optimal myocardial oxygen and nutritional supply during increased demand. Although there is no evidence suggesting that oxidative metabolism is limited by coronary blood flow (CBF) rate in the normal heart even during maximal exercise, increased CBF and capillary exchange capacities have been reported. Adaptations of coronary macro- and microvessels include outward remodelling of epicardial coronary arteries, increased coronary arteriolar size and density, and increased capillary surface area. In addition, there are adjustments in the neural and endothelial regulation of coronary macrovascular tone. Similarly, there are several adaptations at the level of microcirculation, including enhanced (such as nitric oxide mediated) smooth muscle-dependent pressure-induced myogenic constriction and upregulated endothelium-dependent/shear-stress-induced dilation, increasing the range of diameter change. Alterations in the signalling interaction between coronary vessels and cardiac metabolism have also been described. At the molecular and cellular level, ion channels are key players in the local coronary vascular adaptations to RAEX, with enhanced activation of influx of Ca2+ contributing to the increased myogenic tone (via voltage-gated Ca2+ channels) as well as the enhanced endothelium-dependent dilation (via TRPV4 channels). Finally, RAEX elicits a number of beneficial effects on several haemorheological variables that may further improve CBF and myocardial oxygen delivery and nutrient exchange in the microcirculation by stabilizing and extending the range and further optimizing the regulation of myocardial blood flow during exercise. These adaptations also act to prevent and/or delay the development of coronary and cardiac diseases.