Coronary "Microvascular Dysfunction": Evolving Understanding of Pathophysiology, Clinical Implications, and Potential Therapeutics.

Until recently, it has been generally held that stable angina pectoris (SAP) primarily reflects the presence of epicardial coronary artery stenoses due to atheromatous plaque(s), while acute myocardial infarction (AMI) results from thrombus formation on ruptured plaques. This concept is now challenged, especially by results of the ORBITA and ISCHEMIA trials, which showed that angioplasty/stenting does not substantially relieve SAP symptoms or prevent AMI or death in such patients. These disappointing outcomes serve to redirect attention towards anomalies of small coronary physiology. Recent studies suggest that coronary microvasculature is often both structurally and physiologically abnormal irrespective of the presence or absence of large coronary artery stenoses. Structural remodelling of the coronary microvasculature appears to be induced primarily by inflammation initiated by mast cell, platelet, and neutrophil activation, leading to erosion of the endothelial glycocalyx. This leads to the disruption of laminar flow and the facilitation of endothelial platelet interaction. Glycocalyx shedding has been implicated in the pathophysiology of coronary artery spasm, cardiovascular ageing, AMI, and viral vasculitis. Physiological dysfunction is closely linked to structural remodelling and occurs in most patients with myocardial ischemia, irrespective of the presence or absence of large-vessel stenoses. Dysfunction includes the impairment of platelet and vascular responsiveness to autocidal coronary vasodilators, such as nitric oxide, prostacyclin, and hydrogen sulphide, and predisposes both to coronary vasoconstriction and to a propensity for microthrombus formation. These findings emphasise the need for new directions in medical therapeutics for patients with SAP, as well as a wide range of other cardiovascular disorders.

Association of Circulating Plasma Secreted Frizzled-Related Protein 5 (Sfrp5) Levels with Cardiac Function.

Secreted frizzled-related protein 5 (SFRP5) is a novel anti-inflammatory adipokine that may play a role in cardiovascular development and disease. However, there is yet to be a comprehensive investigation into whether circulating SFRP5 can be a biomarker for cardiac function. Plasma SFRP5 levels were measured via ELISA in 262 patients admitted to a cardiology unit. Plasma SFRP5 levels were significantly lower in patients with a history of heart failure (HF), coronary artery disease (CAD), and atrial fibrillation (AF; p = 0.001). In univariate analyses, SFRP5 levels were also significantly positively correlated with left ventricular ejection fraction (LVEF) (r = 0.52, p < 0.001) and negatively correlated with E/E' (r = -0.30, p < 0.001). Patients with HF, CAD, low LVEF, low triglycerides, high CRP, and high eGFR were associated with lower SFRP5 levels independent of age, BMI, or diabetes after multivariate analysis (overall model r = 0.729, SE = 0.638). Our results show that low plasma SFRP5 levels are independently associated with the presence of HF, CAD, and, importantly, impaired LV function. These results suggest a potential role of SFRP5 as a biomarker, as well as a mediator of cardiac dysfunction independent of obesity and metabolic regulation.

Effects of Soluble Guanylate Cyclase Stimulators and Activators on Anti-Aggregatory Signalling in Patients with Coronary Artery Spasm.

Impairment of the nitric oxide/soluble guanylate cyclase (NO)/sGC) signalling cascade is associated with many forms of cardiovascular disease, resulting not only in compromised vasodilatation but also loss of anti-aggregatory homeostasis. Myocardial ischaemia, heart failure, and atrial fibrillation are associated with moderate impairment of NO/sGC signalling, and we have recently demonstrated that coronary artery spasm (CAS) is engendered by severe impairment of platelet NO/sGC activity resulting in combined platelet and vascular endothelial damage. We therefore sought to determine whether sGC stimulators or activators might normalise NO/sGC homeostasis in platelets. ADP-induced platelet aggregation and its inhibition by the NO donor sodium nitroprusside (SNP), the sGC stimulator riociguat (RIO), and the sCG activator cinaciguat (CINA) alone or in addition to SNP were quantitated. Three groups of individuals were compared: normal subjects (n = 9), patients (Group 1) with myocardial ischaemia, heart failure and/or atrial fibrillation (n = 30), and patients (Group 2) in the chronic stage of CAS (n = 16). As expected, responses to SNP were impaired (p = 0.02) in patients versus normal subjects, with Group 2 patients most severely affected (p = 0.005). RIO alone exerted no anti-aggregatory effects but potentiated responses to SNP to a similar extent irrespective of baseline SNP response. CINA exerted only intrinsic anti-aggregatory effects, but the extent of these varied directly (r = 0.54; p = 0.0009) with individual responses to SNP. Thus, both RIO and CINA tend to normalise anti-aggregatory function in patients in whom NO/sGC signalling is impaired. The anti-aggregatory effects of RIO consist entirely of potentiation of NO, which is not selective of platelet NO resistance. However, the intrinsic anti-aggregatory effects of CINA are most marked in individuals with initially normal NO/sGC signalling, and thus their magnitude is at variance with extent of physiological impairment. These data suggest that RIO and other sGC stimulators should be evaluated for clinical utility in both prophylaxis and treatment of CAS.

Comparison of short and long forms of the Flinders program of chronic disease SELF-management for participants starting SGLT-2 inhibitors for congestive heart failure (SELFMAN-HF): protocol for a prospective, observational study.

Introduction: Congestive heart failure (CHF) causes significant morbidity and mortality. It is an epidemic, and costs are escalating. CHF is a chronic disease whose trajectory includes stable phases, periods of decompensation, and finally palliation. Health services and medical therapies must match the various patient needs. Chronic disease self-management (CDSM) programmes that are patient-focused, identify problems and set actionable goals that appear as a logical, cost-friendly method to navigate patient journeys. There have been challenges in standardising and implementing CHF programmes. Methods and analysis: SELFMAN-HF is a prospective, observational study to evaluate the feasibility and validity of the SCRinHF tool, a one-page self-management and readmission risk prediction tool for CHF, with an established, comprehensive CDSM tool. Eligible patients will have CHF with left ventricular ejection fraction <40% and commenced sodium glucose co-transporter-2 inhibitors (SGLT2-i) within 6 months of recruitment. The primary endpoint is the 80% concordance in readmission risk predicted by the SCRinHF tool. The study will recruit >40 patients and is expected to last 18 months. Ethics and dissemination: This study has been approved by the St Vincent's ethics committee (approval no. LRR 177/21). All participants will complete a written informed consent prior to enrolment in the study. The study results will be disseminated widely via local and international health conferences and peer-reviewed publications.

The Wider Considerations in Closing Chronic Disease Gaps - Focus on Heart Failure and Implementation.

BACKGROUND: Heart failure (HF) is predominately a chronic disease. There are overlaps in HF and chronic disease research and care. Chronic disease and HF research are conducted with multiple goals. The overarching goal is "optimized patient outcomes at maximum costeffectiveness". However, observations on patients can come with many variables; thus, we see differences in clinical translation. This document discusses an argument for three important gaps common to HF and chronic disease, i.e., screening, self-management, and patient-reported outcomes (PRO), and provides a glance of how it could fit into the evidence tree. Pertinent arguments for a framework for health services and models of care are provided as a prelude to future consensus. METHODOLOGY: 1) A preliminary literature review to identify a taxonomy for cardiovascular research, and 2) a review of the published literature describing the translation of research studies into clinical practice for cardiovascular disorders. A spectrum from observational to large randomized controlled trials to post-marketing studies were identified. DISCUSSION: A brief discussion on traditional research and differences focusing on screening, mixed methods research concepts, and chronic diseases models of care. Six steps to facilitate this: 1) Research design; 2) Research application (translation) i. routine ii. challenges; 3. Transforming research to translational level; 4. Funding and infrastructure; 5. Clinical Centres of Research Excellence (CCRE) and collaboration; 6. Governance and cost-effectiveness. CONCLUSION: Implementation research that aims to link research findings to improved patient outcomes in an efficient and effective way is a neglected area. Skills required to perform implementation research are complex. Ways to maximize translational impacts for chronic disease research to clinical practice are described in a HF context.

'Bushfire Season' in Australia: Determinants of Increases in Risk of Acute Coronary Syndromes and Takotsubo Syndrome.

BACKGROUND: Climate change has resulted in an increase in ambient temperatures during the summer months as well as an increase in risk of associated air pollution and of potentially disastrous bushfires throughout much of the world. The increasingly frequent combination of elevated summer temperatures and bushfires may be associated with acute increases in risks of cardiovascular events, but this relationship remains unstudied. We evaluated the individual and cumulative impacts of daily fluctuations in temperature, fine particulate matter of less than 2.5 µm (PM2.5) pollution and presence of bushfires on incidence of acute coronary syndromes and Takotsubo syndrome. METHODS: From November 1, 2019, to February 28, 2020, all admissions with acute coronary syndromes or Takotsubo syndrome to South Australian tertiary public hospitals were evaluated. Univariate and combined associations were sought among each of 1) maximal daily temperature, 2) PM2.5 concentrations, and 3) presence of active bushfires within 200 km of the hospitals concerned. RESULTS: A total of 504 patients with acute coronary syndromes and 35 with Takotsubo syndrome were studied. In isolation, increasing temperature was associated (rs = 0.26, P = .005) with increased incidence of acute coronary syndromes, while there were similar, but nonsignificant correlations for PM2.5 and presence of bushfires. Combinations of all these risk factors were also associated with a doubling of risk of acute coronary syndromes. No significant associations were found for Takotsubo syndrome. CONCLUSION: The combination of high temperatures, presence of bushfires and associated elevation of atmospheric PM2.5 concentrations represents a substantially increased risk for precipitation of acute coronary syndromes; this risk should be factored into health care planning including public education and acute hospital preparedness.

Perhexiline Therapy in Patients with Type 2 Diabetes: Incremental Insulin Resistance despite Potentiation of Nitric Oxide Signaling.

Perhexiline (Px) inhibits carnitine palmitoyltransferase 1 (CPT1), which controls uptake of long chain fatty acids into mitochondria. However, occasional cases of hypoglycaemia have been reported in Px-treated patients, raising the possibility that Px may also increase sensitivity to insulin. Furthermore, Px increases anti-aggregatory responses to nitric oxide (NO), an effect which may theoretically parallel insulin sensitization. We therefore sought to examine these relationships in patients with stable Type 2 diabetes (T2D) and cardiovascular disease (n = 30). Px was initiated, and dosage was titrated, to reach the therapeutic range and thus prevent toxicity. Investigations were performed before and after 2 weeks, to examine changes in insulin sensitivity and, utilizing aggregometry in whole blood, platelet responsiveness to the anti-aggregatory effects of the NO donor sodium nitroprusside (SNP). Other parameters that affect may affect NO signalling were also evaluated. Px substantially potentiated inhibition of platelet aggregation by SNP (from 16.7 ± 3.0 to 27.3 ± 3.7%; p = 0.005). Px did not change fasting blood glucose concentrations but reduced insulin sensitivity (HOMA-IR score increased from median of 4.47 to 6.08; p = 0.028), and increased fasting plasma insulin concentrations (median 16.5 to 19.0 mU/L; p = 0.014). Increases in SNP responses tended (r = -0.30; p = 0.11) to be reciprocally related to increases in HOMA-IR, and increases in HOMA-IR were greater (p = 0.002) in patients without NO-sensitizing effects. No patient developed symptomatic hypoglycaemia, nor was there any other short-term toxicity of Px. Thus, in patients with stable T2D and cardiovascular disease, Px increases anti-aggregatory responsiveness to NO, but is not an insulin sensitizer, and does not induce hypoglycaemia. Absence of NO-sensitizing effect occurs in approximately 30% of Px-treated patients with T2D, and is associated with induction of insulin resistance in these patients.

Risk factors for a broken heart: understanding drug-induced causes for Takotsubo syndrome and pharmacological treatment options.

INTRODUCTION: Takotsubo syndrome (TTS) is an acute inflammatory disorder involving first the vasculature and then the myocardium. It occurs relatively frequently, especially in aging women after acute physical and emotional stress. There is also increasing recognition that TTS attacks are sometimes precipitated by pharmacotherapy. AREAS COVERED: The pathogenesis of TTS is described, including components of a complex biochemical 'cascade' centering on aberrant post-receptor signaling following ß2-adrenoceptors stimulation and resultant nitric oxide (NO) release and development of nitrosative stress. Examples and significance of drug-induced TTS are also described. Currently available therapeutic information regarding TTS is presented, both for management of patients acutely and in the long-term. Furthermore, development of specific therapies to block components of the pathogenetic TTS 'cascade' is discussed. EXPERT OPINION: The biochemical 'cascade' in TTS revolves around an aberrant post-receptor response to ß2-adrenoceptor stimulation, increased responsiveness to NO and triggering of activation of poly(ADP-ribose) polymerase (PARP). In theory, interruption of this 'cascade' represents a logical approach to improving both symptomatic status and survival post TTS. Currently, there is some evidence supporting routine long-term treatment post TTS with either ACE inhibitors or angiotensin receptor antagonists, both to reduce risk of recurrence and to improve survival. Results of ongoing controlled clinical trials are awaited.

Biomarkers and heart failure events in patients with atrial fibrillation in the ARISTOTLE trial evaluated by a multi-state model.

BACKGROUND: Atrial fibrillation (AF) and heart failure (HF) often coexist. We investigated the prognostic impact of biomarkers on the development of HF and death in patients with AF and different left ventricular systolic function considering the influence of competing events. METHODS: The study included 11,818 patients with AF from the ARISTOTLE trial who at entry had information on history of HF, an estimate of left ventricular function and plasma samples for determination of biomarkers representing cardiorenal dysfunction (NT-proBNP, troponin T, cystatin C) and inflammation (GDF-15, IL-6, CRP). Patients were categorized into: (I) HF with reduced ejection fraction (HFrEF, n = 2,048), (II) HF with preserved ejection fraction (HFpEF, n = 2,520), and (III) No HF (n = 7,250). Biomarker associations with HF hospitalization and death were analyzed using a multi-state model accounting also for repeated events. RESULTS: Baseline levels of NT-proBNP, troponin T, cystatin C, GDF-15, IL-6, and CRP were highest in HFrEF and lowest in No HF. During median 1.9 years follow-up, 546 patients were hospitalized at least once for HF and 819 died. Higher levels of all investigated biomarkers were associated with both outcomes (all P< .0001), with highest event rates in HFrEF and lowest in No HF. The associations remained after adjustments and were more pronounced for first than for recurrent events. CONCLUSIONS: In anticoagulated patients with AF, biomarkers indicating cardiorenal dysfunction and inflammation improve the identification of patients at risk of developing HF or worsening of already existing HF. These biomarkers might be useful for targeting novel HF therapies in patients with AF.

Transdiagnostic Cognitive-Behavioral Therapy for Depression and Anxiety Disorders in Cardiovascular Disease Patients: Results From the CHAMPS Pilot-Feasibility Trial.

Objective: The aim of the Cardiovascular Health in Anxiety and Mood Problems Study (CHAMPS) is to pilot the Unified Protocol (UP) for the transdiagnostic treatment of depression and anxiety disorders in patients recently hospitalized for cardiovascular diseases (CVDs) and evaluate the feasibility. Methods: The present study is a controlled, block randomized pragmatic pilot-feasibility trial incorporating qualitative interview data, comparing UP (n = 9) with enhanced usual care (EUC, n = 10). Eligible trial participants had a recent CVD-cause admission and were above the severity threshold for depression or anxiety denoted by Patient Health Questionnaire (PHQ-9) total scores ≥10 and/or Generalized Anxiety Disorder (GAD-7) total scores ≥7 respectively on two occasions, and met criteria for one or more depression or anxiety disorders determined by structured clinical interview. Study outcomes were analyzed as intention-to-treat using linear mixed models and qualitative interview data were analyzed with content analysis. Results: Quantitative and qualitative measured indicated acceptability of the transdiagnostic CBT intervention for CVD patients with depression or anxiety disorders. Satisfaction with UP was comparable to antidepressant therapy and higher than general physician counseling. However, there were difficulties recruiting participants with current disorders and distress on two occasions. The UP was associated with a reduction in total number of disorders determined by blinded raters. Linear mixed models indicated that a significantly greater reduction in anxiety symptoms was evident in the UP group by comparison to the EUC group (GAD-7, p between groups = 0.011; Overall Anxiety Severity and Impairment Scale, p between groups = 0.013). Results favored the UP group by comparison to EUC for change over 6 months on measures of physical quality of life and harmful alcohol use. There was no difference between the two groups on changes in depression symptoms (PHQ-9), stress, metacognitive worry beliefs, physical activity, or adherence. Discussion: In conclusion, this feasibility trial indicates acceptability of transdiagnostic CBT intervention for CVD patients with depression or anxiety disorders that is tempered by difficulties with recruitment. Larger trials are required to clarify the efficacy of transdiagnostic depression and anxiety disorder CBT in populations with CVDs and depressive or anxiety disorders. Clinical Trial Registration: https://www.australianclinicaltrials.gov.au/anzctr/trial/ACTRN12615000555550, identifier: ACTRN12615000555550.

Cardioprotective actions of nitroxyl donor Angeli's salt are preserved in the diabetic heart and vasculature in the face of nitric oxide resistance.

BACKGROUND AND PURPOSE: The risk of fatal cardiovascular events is increased in patients with type 2 diabetes mellitus (T2DM). A major contributor to poor prognosis is impaired nitric oxide (NO•) signalling at the level of tissue responsiveness, termed NO• resistance. This study aimed to determine if T2DM promotes NO• resistance in the heart and vasculature and whether tissue responsiveness to nitroxyl (HNO) is affected. EXPERIMENTAL APPROACH: At 8 weeks of age, male Sprague-Dawley rats commenced a high-fat diet. After 2 weeks, the rats received low-dose streptozotocin (two intraperitoneal injections, 35 mg·kg-1 , over two consecutive days) and continued on the same diet. Twelve weeks later, isolated hearts were Langendorff-perfused to assess responses to the NO• donor diethylamine NONOate (DEA/NO) and the HNO donor Angeli's salt. Isolated mesenteric arteries were utilised to measure vascular responsiveness to the NO• donors sodium nitroprusside (SNP) and DEA/NO, and the HNO donor Angeli's salt. KEY RESULTS: Inotropic, lusitropic and coronary vasodilator responses to DEA/NO were impaired in T2DM hearts, whereas responses to Angeli's salt were preserved or enhanced. Vasorelaxation to Angeli's salt was augmented in T2DM mesenteric arteries, which were hyporesponsive to the relaxant effects of SNP and DEA/NO. CONCLUSION AND IMPLICATIONS: This is the first evidence that inotropic and lusitropic responses are preserved, and NO• resistance in the coronary and mesenteric vasculature is circumvented, by the HNO donor Angeli's salt in T2DM. These findings highlight the cardiovascular therapeutic potential of HNO donors, especially in emergencies such as acute ischaemia or heart failure.

Assessment of Artificial Intelligence in Echocardiography Diagnostics in Differentiating Takotsubo Syndrome From Myocardial Infarction.

Importance: Machine learning algorithms enable the automatic classification of cardiovascular diseases based on raw cardiac ultrasound imaging data. However, the utility of machine learning in distinguishing between takotsubo syndrome (TTS) and acute myocardial infarction (AMI) has not been studied. Objectives: To assess the utility of machine learning systems for automatic discrimination of TTS and AMI. Design, Settings, and Participants: This cohort study included clinical data and transthoracic echocardiogram results of patients with AMI from the Zurich Acute Coronary Syndrome Registry and patients with TTS obtained from 7 cardiovascular centers in the International Takotsubo Registry. Data from the validation cohort were obtained from April 2011 to February 2017. Data from the training cohort were obtained from March 2017 to May 2019. Data were analyzed from September 2019 to June 2021. Exposure: Transthoracic echocardiograms of 224 patients with TTS and 224 patients with AMI were analyzed. Main Outcomes and Measures: Area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity of the machine learning system evaluated on an independent data set and 4 practicing cardiologists for comparison. Echocardiography videos of 228 patients were used in the development and training of a deep learning model. The performance of the automated echocardiogram video analysis method was evaluated on an independent data set consisting of 220 patients. Data were matched according to age, sex, and ST-segment elevation/non-ST-segment elevation (1 patient with AMI for each patient with TTS). Predictions were compared with echocardiographic-based interpretations from 4 practicing cardiologists in terms of sensitivity, specificity, and AUC calculated from confidence scores concerning their binary diagnosis. Results: In this cohort study, apical 2-chamber and 4-chamber echocardiographic views of 110 patients with TTS (mean [SD] age, 68.4 [12.1] years; 103 [90.4%] were female) and 110 patients with AMI (mean [SD] age, 69.1 [12.2] years; 103 [90.4%] were female) from an independent data set were evaluated. This approach achieved a mean (SD) AUC of 0.79 (0.01) with an overall accuracy of 74.8 (0.7%). In comparison, cardiologists achieved a mean (SD) AUC of 0.71 (0.03) and accuracy of 64.4 (3.5%) on the same data set. In a subanalysis based on 61 patients with apical TTS and 56 patients with AMI due to occlusion of the left anterior descending coronary artery, the model achieved a mean (SD) AUC score of 0.84 (0.01) and an accuracy of 78.6 (1.6%), outperforming the 4 practicing cardiologists (mean [SD] AUC, 0.72 [0.02]) and accuracy of 66.9 (2.8%). Conclusions and Relevance: In this cohort study, a real-time system for fully automated interpretation of echocardiogram videos was established and trained to differentiate TTS from AMI. While this system was more accurate than cardiologists in echocardiography-based disease classification, further studies are warranted for clinical application.

The Antianginal Drug Perhexiline Displays Cytotoxicity against Colorectal Cancer Cells In Vitro: A Potential for Drug Repurposing.

Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide. Perhexiline, a prophylactic anti-anginal drug, has been reported to have anti-tumour effects both in vitro and in vivo. Perhexiline as used clinically is a 50:50 racemic mixture ((R)-P) of (-) and (+) enantiomers. It is not known if the enantiomers differ in terms of their effects on cancer. In this study, we examined the cytotoxic capacity of perhexiline and its enantiomers ((-)-P and (+)-P) on CRC cell lines, grown as monolayers or spheroids, and patient-derived organoids. Treatment of CRC cell lines with (R)-P, (-)-P or (+)-P reduced cell viability, with IC50 values of ~4 µM. Treatment was associated with an increase in annexin V staining and caspase 3/7 activation, indicating apoptosis induction. Caspase 3/7 activation and loss of structural integrity were also observed in CRC cell lines grown as spheroids. Drug treatment at clinically relevant concentrations significantly reduced the viability of patient-derived CRC organoids. Given these in vitro findings, perhexiline, as a racemic mixture or its enantiomers, warrants further investigation as a repurposed drug for use in the management of CRC.

Impairment of Anti-Aggregatory Responses to Nitric Oxide and Prostacyclin: Mechanisms and Clinical Implications in Cardiovascular Disease.

The propensity towards platelet-rich thrombus formation increases substantially during normal ageing, and this trend is mediated by decreases in platelet responsiveness to the anti-aggregatory nitric oxide (NO) and prostacyclin (PGI2) pathways. The impairment of soluble guanylate cyclase and adenylate cyclase-based signalling that is associated with oxidative stress represents the major mechanism of this loss of anti-aggregatory reactivity. Platelet desensitization to these autacoids represents an adverse prognostic marker in patients with ischemic heart disease and may contribute to increased thrombo-embolic risk in patients with heart failure. Patients with platelet resistance to PGI2 also are unresponsive to ADP receptor antagonist therapy. Apart from ischemia, diabetes and aortic valve disease are also associated with impaired anti-aggregatory homeostasis. This review examines the association of impaired platelet cyclic nucleotide (i.e., cGMP and cAMP) signalling with the emerging evidence of thromboembolic risk in cardiovascular diseases, and discusses the potential therapeutic strategies targeting this abnormality.

Contextualising evidence based medicine in determining the key root for translational effectiveness for chronic disease self-management and heart failure.

BACKGROUND: Congestive heart failure (CHF) management has proven devastating on morbidity, mortality, quality of life and also costly to health systems. Therapeutics for CHF have advanced and benefited greatly due to large multicentre randomised controlled trials and the evidence obtained from them. Management for chronic diseases and nonpharmaceutical therapies such as chronic disease self-management has lagged, and for CHF the evidence base has even been questioned. METHODS: Perspective and non systematic mini review. CONCLUSIONS: Advancing translational research standards is important to achieve optimal cost effectiveness. Importantly is understanding evidence generation in medicine, identifying the primary roots for management and its translation.