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Starting out from a brief description of the determinants of coronary blood flow (perfusion, pressure, extravascular compression, autoregulation, metabolic regulation, endothelium‐mediated regulation and neurohumoral regulation) the present review highlights the overwhelming importance of metabolic regulation such that coronary blood flow is increased at increased heart rate under physiological circumstances and the overwhelming importance of extravascular compression such that coronary blood flow is decreased at increased heart rate through reduction of diastolic duration in the presence of severe coronary stenoses. The review goes on to characterize the role of heart rate in the redistribution of regional myocardial blood flow between a normal coronary vascular tree with preserved autoregulation and a poststenotic vasculature with exhausted coronary reserve. When flow is normalized by heart rate, there is a consistent close relationship of regional myocardial blood flow and contractile function for each single cardiac cycle no matter whether or not there is a coronary stenosis and what the actual blood flow is. β‐Blockade improves both flow and function along this relationship. When the heart rate reduction associated with β‐blockade is prevented by pacing, α‐adrenergic coronary vasoconstriction is unmasked and both flow and function are deteriorated. Selective heart rate reduction, however, improves both flow and function without any residual negative effect such as unmasked α‐adrenergic coronary vasoconstriction or negative inotropic action. British Journal of Pharmacology (2008) 153, 1589–1601; doi:10.1038/sj.bjp.0707673; published online 28 January 2008

The bradycardic agent ivabradine has proved to be of benefit in experimental models with the end points of ischaemic myocardial blood flow and contractile function, infarct size, post‐infarct remodelling and atherosclerosis. The benefits to ischaemic myocardial blood flow and contractile function are strictly heart rate dependent; those on infarct size are partly heart rate independent. The heart rate dependency of ivabradine's benefit for atherosclerotic vascular function is contradictory, and that on post‐infarct remodelling is entirely unclear. British Journal of Pharmacology (2008) 155, 970–971; doi:10.1038/bjp.2008.347; published online 1 September 2008

The Hatter Cardiovascular Institute biennial workshop, originally scheduled for April 2020 but postponed for 2 years due to the Covid pandemic, was organised to debate and discuss the future of Remote Ischaemic Conditioning (RIC). This evolved from the large multicentre CONDI-2–ERIC–PPCI outcome study which demonstrated no additional benefit when using RIC in the setting of ST-elevation myocardial infarction (STEMI). The workshop discussed how conditioning has led to a significant and fundamental understanding of the mechanisms preventing cell death following ischaemia and reperfusion, and the key target cyto-protective pathways recruited by protective interventions, such as RIC. However, the obvious need to translate this protection to the clinical setting has not materialised largely due to the disconnect between preclinical and clinical studies. Discussion points included how to adapt preclinical animal studies to mirror the patient presenting with an acute myocardial infarction, as well as how to refine patient selection in clinical studies to account for co-morbidities and ongoing therapy. These latter scenarios can modify cytoprotective signalling and need to be taken into account to allow for a more robust outcome when powered appropriately. The workshop also discussed the potential for RIC in other disease settings including ischaemic stroke, cardio-oncology and COVID-19. The workshop, therefore, put forward specific classifications which could help identify so-called responders vs. non-responders in both the preclinical and clinical settings.

Pre-clinical studies have indicated that mitoprotective drugs may add cardioprotection beyond rapid revascularization, antiplatelet therapy and risk modification. We review the clinical efficacy of mitoprotective drugs that have progressed to clinical testing comprising cyclosporine A, KAI-9803, MTP131 and TRO 40303. Whereas cyclosporine may reduce infarct size in patients undergoing primary angioplasty as evaluated by release of myocardial ischaemic biomarkers and infarct size imaging, the other drugs were not capable of demonstrating this effect in the clinical setting. The absent effect leaves the role of the mitochondrial permeability transition pore for reperfusion injury in humans unanswered and indicates that targeting one single mechanism to provide mitoprotection may not be efficient. Moreover, the lack of effect may relate to favourable outcome with current optimal therapy, but conditions such as age, sex, diabetes, dyslipidaemia and concurrent medications may also alter mitochondrial function. However, as long as the molecular structure of the pore remains unknown and specific inhibitors of its opening are lacking, the mitochondrial permeability transition pore remains a target for alleviation of reperfusion injury. Nevertheless, taking conditions such as ageing, sex, comorbidities and co-medication into account may be of paramount importance during the design of pre-clinical and clinical studies testing mitoprotective drugs.

Inflammatory cell infiltration is central to healing after acute myocardial infarction (AMI). The relation of regional inflammation to edema, infarct size (IS), microvascular obstruction (MVO), intramyocardial hemorrhage (IMH), and regional and global LV function is not clear. Here we noninvasively characterized regional inflammation and contractile function in reperfused AMI in pigs using fluorine (19F) cardiovascular magnetic resonance (CMR). Adult anesthetized pigs underwent left anterior descending coronary artery instrumentation with either 90 min occlusion (n = 17) or without occlusion (sham, n = 5). After 3 days, in surviving animals a perfluorooctyl bromide nanoemulsion was infused intravenously to label monocytes/macrophages. At day 6, in vivo 1H-CMR was performed with cine, T2 and T2* weighted imaging, T2 and T1 mapping, perfusion and late gadolinium enhancement followed by 19F-CMR. Pigs were sacrificed for subsequent ex vivo scans and histology. Edema extent was 35 ± 8% and IS was 22 ± 6% of LV mass. Six of ten surviving AMI animals displayed both MVO and IMH (3.3 ± 1.6% and 1.9 ± 0.8% of LV mass). The 19F signal, reflecting the presence and density of monocytes/macrophages, was consistently smaller than edema volume or IS and not apparent in remote areas. The 19F signal-to-noise ratio (SNR) > 8 in the infarct border zone was associated with impaired remote systolic wall thickening. A whole heart value of 19F integral (19F SNR × milliliter) > 200 was related to initial LV remodeling independently of edema, IS, MVO, and IMH. Thus, 19F-CMR quantitatively characterizes regional inflammation after AMI and its relation to edema, IS, MVO, IMH and regional and global LV function and remodeling.

A long-standing aim in the setting of various pathologies including acute myocardial infarction, chronic kidney disease (CKD), and ischaemic stroke, has been to identify successful approaches to augment cellular and organ protection. Although the continual evolution and refinement of ideas over the past few decades has allowed the field to progress, we are yet to realise successful clinical translation of this concept. The 12th Hatter Cardiovascular Workshop identified a number of important points and key questions for future research relating to cardio- and neuro-protection and interorgan communication. Specific topics that were discussed include the ‘cardio-metabolic-renal’ axis of organ protection, the parasympathetic signalling hypothesis, the role of the coronary microvasculature in myocardial infarction, the RISK pathway of cardioprotection, extracellular vesicles and the way forward, the future for clinical studies of remote ischaemic conditioning, and new experimental models for cardio-oncology investigations.

The detrimental actions of leptin on cardiovascular function are well established. Smith et al. report the novel finding of a reduction of infarct size by exogenous leptin when given at reperfusion. The involvement of the reperfusion injury salvage kinase (RISK) pathway in such reduction of infarct size and its relation to ischemic pre‐ and postconditioning are discussed and some methodological issues in its assessment are raised. Obesity has possibly opposite effects on the incidence and outcome of myocardial infarction. British Journal of Pharmacology (2006) 149, 1–3. doi:10.1038/sj.bjp.0706833

It is now about 8 years since the first whole-body integrated PET/MRI has been installed. First, reports on technical characteristics and system performance were published. Early after, reports on the first use of PET/MRI in oncological patients were released. Interestingly, the first article on the application in cardiology was a review article, which was published before the first original article was put out. Since then, researchers have gained a lot experience with the PET/MRI in various cardiovascular diseases and an increasing number on auspicious indications is appearing. In this review article, we give an overview on technical updates within these last years with potential impact on cardiac imaging and summarize those scenarios where PET/MRI plays a pivotal role in cardiovascular medicine.

Connexin (Cx) 43 is the predominant protein forming gap junctions and non-junctional hemichannels in ventricular myocardium. The Cx43 proteins are central to the cardioprotection afforded by ischaemic preconditioning (IP). The specific role of mitochondrial C×43 in protection by IP is reviewed.

Histone H3 serine 28 (H3S28) phosphorylation and de-repression of polycomb repressive complex (PRC)-mediated gene regulation is linked to stress conditions in mitotic and post-mitotic cells. To better understand the role of H3S28 phosphorylation in vivo , we studied a Drosophila strain with ectopic expression of constitutively-activated H3S28A, which prevents PRC2 binding at H3S28, thus mimicking H3S28 phosphorylation. H3S28A mutants showed prolonged life span and improved resistance against starvation and paraquat-induced oxidative stress. Morphological and functional analysis of heart tubes revealed smaller luminal areas and thicker walls accompanied by moderately improved cardiac function after acute stress induction. Whole-exome deep gene-sequencing from isolated heart tubes revealed phenotype-corresponding changes in longevity-promoting and myotropic genes. We also found changes in genes controlling mitochondrial biogenesis and respiration. Analysis of mitochondrial respiration from whole flies revealed improved efficacy of ATP production with reduced electron transport-chain activity. Finally, we analyzed posttranslational modification of H3S28 in an experimental heart failure model and observed increased H3S28 phosphorylation levels in HF hearts. Our data establish a critical role of H3S28 phosphorylation in vivo for life span, stress resistance, cardiac and mitochondrial function in Drosophila . These findings may pave the way for H3S28 phosphorylation as a putative target to treat stress-related disorders such as heart failure.