Multi-Modality Imaging of Atheromatous Plaques in Peripheral Arterial Disease: Integrating Molecular and Imaging Markers.

Peripheral artery disease (PAD) is a common and debilitating condition characterized by the narrowing of the limb arteries, primarily due to atherosclerosis. Non-invasive multi-modality imaging approaches using computed tomography (CT), magnetic resonance imaging (MRI), and nuclear imaging have emerged as valuable tools for assessing PAD atheromatous plaques and vessel walls. This review provides an overview of these different imaging techniques, their advantages, limitations, and recent advancements. In addition, this review highlights the importance of molecular markers, including those related to inflammation, endothelial dysfunction, and oxidative stress, in PAD pathophysiology. The potential of integrating molecular and imaging markers for an improved understanding of PAD is also discussed. Despite the promise of this integrative approach, there remain several challenges, including technical limitations in imaging modalities and the need for novel molecular marker discovery and validation. Addressing these challenges and embracing future directions in the field will be essential for maximizing the potential of molecular and imaging markers for improving PAD patient outcomes.

Diabetes and other vascular risk factors in association with the risk of lower extremity amputation in chronic limb-threatening ischemia: a prospective cohort study.

BACKGROUND: Patients with diabetes are at increased risk of developing chronic limb-threatening ischemia (CLTI) due to peripheral arterial disease, and this often results in lower extremity amputation (LEA). Little is known of the interaction between diabetes and other vascular risk factors in affecting the risk of CLTI. METHODS: We investigated the association of diabetes, and its interaction with hypertension, body mass index (BMI) and smoking, with the risk of LEA due to CLTI in the population-based Singapore Chinese Health Study. Participants were interviewed at recruitment (1993-1998) and 656 incident LEA cases were identified via linkage with nationwide hospital database through 2017. Multivariate-adjusted Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% CIs for the associations. RESULTS: The HR (95% CI) for LEA risk was 13.41 (11.38-15.79) in participants with diabetes compared to their counterparts without diabetes, and the risk increased in a stepwise manner with duration of diabetes (P for trend < 0.0001). Hypertension and increased BMI independently increased LEA risk in those without diabetes but did not increase the risk in those with diabetes (P for interaction with diabetes ≤ 0.0006). Conversely, current smoking conferred a risk increment of about 40% regardless of diabetes status. CONCLUSIONS: Although diabetes conferred more than tenfold increase in risk of LEA, hypertension and increased BMI did not further increase LEA risk among those with diabetes, suggesting a common mechanistic pathway for these risk factors. In contrast, smoking may act via an alternative pathway and thus confer additional risk regardless of diabetes status.

A Systematic Quality Scoring Analysis to Assess Automated Cardiovascular Magnetic Resonance Segmentation Algorithms.

BACKGROUND: The quantitative measures used to assess the performance of automated methods often do not reflect the clinical acceptability of contouring. A quality-based assessment of automated cardiac magnetic resonance (CMR) segmentation more relevant to clinical practice is therefore needed. OBJECTIVE: We propose a new method for assessing the quality of machine learning (ML) outputs. We evaluate the clinical utility of the proposed method as it is employed to systematically analyse the quality of an automated contouring algorithm. METHODS: A dataset of short-axis (SAX) cine CMR images from a clinically heterogeneous population (n = 217) were manually contoured by a team of experienced investigators. On the same images we derived automated contours using a ML algorithm. A contour quality scoring application randomly presented manual and automated contours to four blinded clinicians, who were asked to assign a quality score from a predefined rubric. Firstly, we analyzed the distribution of quality scores between the two contouring methods across all clinicians. Secondly, we analyzed the interobserver reliability between the raters. Finally, we examined whether there was a variation in scores based on the type of contour, SAX slice level, and underlying disease. RESULTS: The overall distribution of scores between the two methods was significantly different, with automated contours scoring better than the manual (OR (95% CI) = 1.17 (1.07-1.28), p = 0.001; n = 9401). There was substantial scoring agreement between raters for each contouring method independently, albeit it was significantly better for automated segmentation (automated: AC2 = 0.940, 95% CI, 0.937-0.943 vs manual: AC2 = 0.934, 95% CI, 0.931-0.937; p = 0.006). Next, the analysis of quality scores based on different factors was performed. Our approach helped identify trends patterns of lower segmentation quality as observed for left ventricle epicardial and basal contours with both methods. Similarly, significant differences in quality between the two methods were also found in dilated cardiomyopathy and hypertension. CONCLUSIONS: Our results confirm the ability of our systematic scoring analysis to determine the clinical acceptability of automated contours. This approach focused on the contours' clinical utility could ultimately improve clinicians' confidence in artificial intelligence and its acceptability in the clinical workflow.

ST-segment elevation myocardial infarction with non-chest pain presentation at the Emergency Department: Insights from the Singapore Myocardial Infarction Registry.

ST-segment elevation myocardial infarction (STEMI) often presents acutely at the Emergency Department (ED). Although chest pain is a classical symptom, a significant proportion of patients do not present with chest pain. The impact of a non-chest pain (NCP) presentation on ED processes-of-care and outcomes is not fully understood. We utilised a national registry to characterise predictors, processes-of-care, and outcomes of NCP STEMI presentations. Retrospective data for all STEMI cases occurring between 2010 and 2012 were analysed from the Singapore Myocardial Infarction Registry. Cases of inpatient onset, inter-facility transfers, and out-of-hospital cardiac arrests were excluded. Univariable analysis of demographic, clinical, processes-of-care, and outcome variables was conducted. Multivariable logistic regression ascertained independent predictors of a NCP presentation and 28-day mortality. Of 4667 STEMI cases, 12.9% presented without chest pain. Patients with NCP presentation were older (median, years = 74 vs. 58; p < 0.001), more likely to be female (39.1% vs. 15.7%; p < 0.001), of the Chinese race (72.5% vs. 62.7%; p < 0.001), and with diabetes (48.6% vs. 36.7%; p < 0.001). These patients were more likely to present with syncope (6.0% vs. 1.9%; p < 0.001) or epigastric pain (10.6% vs. 4.9%; p < 0.001). Patients with NCP presentation were less likely to receive percutaneous coronary intervention (27.0% vs. 75.6%; p < 0.001), had longer door-to-balloon time (median, minutes = 83 vs. 63; p < 0.001), and experienced greater mortality at 28 days (31.2% vs. 4.5%; p < 0.001). On multivariable logistic regression, independent predictors of a NCP presentation included age (adjusted odds ratio [aOR] = 1.05, 95% confidence interval [CI] 1.04-1.07), diabetes (aOR = 1.76, 95% CI 1.40-2.19), BMI (aOR = 0.93, 95% CI 0.91-0.96), and dyslipidemia (aOR = 0.73, 95% CI 0.58-0.91). Absence of chest pain was an independent predictor for 28-day mortality (aOR = 3.46, 95% CI 2.64-4.52). Patients who presented with a NCP STEMI had a distinct clinical profile and experienced poorer outcomes. Routine triage ECG could be considered for patients with high-risk factors and non-classical symptoms.

Epigenomic and transcriptomic approaches in the post-genomic era: path to novel targets for diagnosis and therapy of the ischaemic heart? Position Paper of the European Society of Cardiology Working Group on Cellular Biology of the Heart.

Despite advances in myocardial reperfusion therapies, acute myocardial ischaemia/reperfusion injury and consequent ischaemic heart failure represent the number one cause of morbidity and mortality in industrialized societies. Although different therapeutic interventions have been shown beneficial in preclinical settings, an effective cardioprotective or regenerative therapy has yet to be successfully introduced in the clinical arena. Given the complex pathophysiology of the ischaemic heart, large scale, unbiased, global approaches capable of identifying multiple branches of the signalling networks activated in the ischaemic/reperfused heart might be more successful in the search for novel diagnostic or therapeutic targets. High-throughput techniques allow high-resolution, genome-wide investigation of genetic variants, epigenetic modifications, and associated gene expression profiles. Platforms such as proteomics and metabolomics (not described here in detail) also offer simultaneous readouts of hundreds of proteins and metabolites. Isolated omics analyses usually provide Big Data requiring large data storage, advanced computational resources and complex bioinformatics tools. The possibility of integrating different omics approaches gives new hope to better understand the molecular circuitry activated by myocardial ischaemia, putting it in the context of the human 'diseasome'. Since modifications of cardiac gene expression have been consistently linked to pathophysiology of the ischaemic heart, the integration of epigenomic and transcriptomic data seems a promising approach to identify crucial disease networks. Thus, the scope of this Position Paper will be to highlight potentials and limitations of these approaches, and to provide recommendations to optimize the search for novel diagnostic or therapeutic targets for acute ischaemia/reperfusion injury and ischaemic heart failure in the post-genomic era.

Mitochondrial-Shaping Proteins in Cardiac Health and Disease - the Long and the Short of It!

Mitochondrial health is critically dependent on the ability of mitochondria to undergo changes in mitochondrial morphology, a process which is regulated by mitochondrial shaping proteins. Mitochondria undergo fission to generate fragmented discrete organelles, a process which is mediated by the mitochondrial fission proteins (Drp1, hFIS1, Mff and MiD49/51), and is required for cell division, and to remove damaged mitochondria by mitophagy. Mitochondria undergo fusion to form elongated interconnected networks, a process which is orchestrated by the mitochondrial fusion proteins (Mfn1, Mfn2 and OPA1), and which enables the replenishment of damaged mitochondrial DNA. In the adult heart, mitochondria are relatively static, are constrained in their movement, and are characteristically arranged into 3 distinct subpopulations based on their locality and function (subsarcolemmal, myofibrillar, and perinuclear). Although the mitochondria are arranged differently, emerging data supports a role for the mitochondrial shaping proteins in cardiac health and disease. Interestingly, in the adult heart, it appears that the pleiotropic effects of the mitochondrial fusion proteins, Mfn2 (endoplasmic reticulum-tethering, mitophagy) and OPA1 (cristae remodeling, regulation of apoptosis, and energy production) may play more important roles than their pro-fusion effects. In this review article, we provide an overview of the mitochondrial fusion and fission proteins in the adult heart, and highlight their roles as novel therapeutic targets for treating cardiac disease.

Remote ischemic conditioning: from bench to bedside.

Remote ischemic conditioning (RIC) is a therapeutic strategy for protecting organs or tissue against the detrimental effects of acute ischemia-reperfusion injury (IRI). It describes an endogenous phenomenon in which the application of one or more brief cycles of non-lethal ischemia and reperfusion to an organ or tissue protects a remote organ or tissue from a sustained episode of lethal IRI. Although RIC protection was first demonstrated to protect the heart against acute myocardial infarction, its beneficial effects are also seen in other organs (lung, liver, kidney, intestine, brain) and tissues (skeletal muscle) subjected to acute IRI. The recent discovery that RIC can be induced non-invasively by simply inflating and deflating a standard blood pressure cuff placed on the upper arm or leg, has facilitated its translation into the clinical setting, where it has been reported to be beneficial in a variety of cardiac scenarios. In this review article we provide an overview of RIC, the potential underlying mechanisms, and its potential as a novel therapeutic strategy for protecting the heart and other organs from acute IRI.

Blood pressure oscillations during tilt testing as a predictive marker of vasovagal syncope.

AIMS: During head-up tilt (HUT) testing, a period of haemodynamic instability, marked by oscillations in blood pressure, often precedes vasovagal syncope. We hypothesized that the presence of oscillations in blood pressure during HUT testing predicts a positive diagnosis for vasovagal syncope. METHODS AND RESULTS: The haemodynamic profiles of 42 consecutive patients non-responsive to passive HUT and glyceryl trinitrate (GTN) provocation ('non-responders') and, contemporaneously, 41 consecutive patients responsive to passive HUT and GTN provocation ('responders') were assigned oscillation-positive or oscillation-negative depending on the presence or absence of a characteristic oscillation in systolic blood pressure which varied by > or =30 mmHg (peak-to-trough). All the non-responders proceeded to an isoprenaline (Iso) challenge test. Of the 42 non-responders, 27 patients were Iso tilt-positive; all of these patients were assigned oscillation-positive. The other 15 non-responders were Iso tilt-negative; of these 9 were assigned oscillation-positive and 6 were assigned oscillation-negative. Of the 41 responder patients, 33 were assigned oscillation-positive, whereas 8 were assigned oscillation-negative. Overall, the presence of oscillations as a diagnostic predictor for vasovagal syncope had a sensitivity of 88% (positive predictive value of 87%) and a specificity of 40% (negative predictive value of 43%). CONCLUSION: In patients non-responsive to passive HUT and GTN provocation, the presence of an oscillating systolic blood pressure varying > or =30 mmHg may still indicate a diagnosis of vasovagal syncope, possibly obviating the need for Iso testing.