Advancing the access to cardiovascular diagnosis and treatment among women with cardiovascular disease: a joint British Cardiovascular Societies' consensus document.

Despite significant progress in cardiovascular pharmacotherapy and interventional strategies, cardiovascular disease (CVD), in particular ischaemic heart disease, remains the leading cause of morbidity and mortality among women in the UK and worldwide. Women are underdiagnosed, undertreated and under-represented in clinical trials directed at management strategies for CVD, making their results less applicable to this subset. Women have additional sex-specific risk factors that put them at higher risk of future cardiovascular events. Psychosocial risk factors, socioeconomic deprivation and environmental factors have an augmented impact on women's cardiovascular health, highlighting the need for a holistic approach to care that considers risk factors specifically related to female biology alongside the traditional risk factors. Importantly, in the UK, even in the context of a National Health Service, there exist significant regional variations in age-standardised mortality rates among patients with CVD. Given most CVDs are preventable, concerted efforts are necessary to address the unmet needs and ensure parity of care for women with CVD. The present consensus document, put together by the British Cardiovascular Society (BCS)'s affiliated societies, specifically portrays the current status on the sex-related differences in the diagnosis and treatment of each of the major CVD areas and proposes strategies to overcome the barriers in accessing diagnoses and treatments among women. This document aims at raising awareness of the scale of the current problem and hopes to stimulate a multifaceted approach to address sex disparities and enable future comprehensive sex- and gender-based research through collaboration across different affiliated societies within the BCS.

Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.

Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene (EDN1) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. Results: A total of 118 participants (mean ±SD; years of age 63.5 [9.2 ]; 71 [60.2% ] females; 25 [21.2% ] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95 ] CI, -19.60 to 11.06] P=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P<0.001). Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.

Novel diagnostic approaches and management of coronary microvascular dysfunction.

The mechanism underlying ischaemic heart disease (IHD) has been primarily attributed to obstructive coronary artery disease (CAD). However, non-obstructive coronary arteries are identified in >50% of patients undergoing elective coronary angiography, recently leading to growing interest in the investigation and management of angina/ischaemia with non-obstructive coronary arteries (ANOCA/INOCA). INOCA is an umbrella term encompassing a multiple spectrum of possible pathogenetic entities, including coronary vasomotor disorders which consist of two major endotypes: coronary microvascular dysfunction (CMD) and vasospastic angina. Both conditions can coexist and be associated with concomitant obstructive CAD. Particularly, CMD refers to myocardial ischaemia due to reduced vasodilatory capacity of coronary microcirculation secondary to structural remodelling or impaired resting microvascular tone (functional) or a combination of both. CMD is not a benign condition and is more prevalent in women presenting with chronic coronary syndrome compared to men. In this setting, an impaired coronary flow reserve has been associated with increased risk of major adverse cardiovascular events. ANOCA/INOCA patients also experience impaired quality of life and associated increased healthcare costs. Therefore, research in this scenario has led to better definition, classification, and prognostic stratification based on the underlying pathophysiological mechanisms. The development and validation of non-invasive imaging modalities, invasive coronary vasomotor function testing and angiography-derived indices provide a comprehensive characterisation of CMD. The present narrative review aims to summarise current data relating to the diagnostic approach to CMD and provides details on the sequence that therapeutic management should follow.

Rethinking False Positive Exercise Electrocardiographic Stress Tests by Assessing Coronary Microvascular Function.

BACKGROUND: Exercise electrocardiographic stress testing (EST) has historically been validated against the demonstration of obstructive coronary artery disease. However, myocardial ischemia can occur because of coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease. OBJECTIVES: The aim of this study was to assess the specificity of EST to detect an ischemic substrate against the reference standard of coronary endothelium-independent and endothelium-dependent microvascular function in patients with angina with nonobstructive coronary arteries (ANOCA). METHODS: Patients with ANOCA underwent invasive coronary physiological assessment using adenosine and acetylcholine. CMD was defined as impaired endothelium-independent and/or endothelium-dependent function. EST was performed using a standard Bruce treadmill protocol, with ischemia defined as the appearance of ≥0.1-mV ST-segment depression 80 ms from the J-point on electrocardiography. The study was powered to detect specificity of ≥91%. RESULTS: A total of 102 patients were enrolled (65% women, mean age 60 ± 8 years). Thirty-two patients developed ischemia (ischemic group) during EST, whereas 70 patients did not (nonischemic group); both groups were phenotypically similar. Ischemia during EST was 100% specific for CMD. Acetylcholine flow reserve was the strongest predictor of ischemia during exercise. Using endothelium-independent and endothelium-dependent microvascular dysfunction as the reference standard, the false positive rate of EST dropped to 0%. CONCLUSIONS: In patients with ANOCA, ischemia on EST was highly specific of an underlying ischemic substrate. These findings challenge the traditional belief that EST has a high false positive rate.

ChaMP-CMD: A Phenotype-Blinded, Randomized Controlled, Cross-Over Trial.

BACKGROUND: Angina with nonobstructive coronary arteries is a common condition for which no effective treatment has been established. We hypothesized that the measurement of coronary flow reserve (CFR) allows identification of patients with angina with nonobstructive coronary arteries who would benefit from anti-ischemic therapy. METHODS: Patients with angina with nonobstructive coronary arteries underwent blinded invasive CFR measurement and were randomly assigned to receive 4 weeks of amlodipine or ranolazine. After a 1-week washout, they crossed over to the other drug for 4 weeks; final assessment was after the cessation of study medication for another 4 weeks. The primary outcome was change in treadmill exercise time, and the secondary outcome was change in Seattle Angina Questionnaire summary score in response to anti-ischemic therapy. Analysis was on a per protocol basis according to the following classification: coronary microvascular disease (CMD group) if CFR<2.5 and reference group if CFR≥2.5. The study protocol was registered before the first patient was enrolled (International Standard Randomised Controlled Trial Number: ISRCTN94728379). RESULTS: Eighty-seven patients (61±8 years of age; 62% women) underwent random assignment (57 CMD group and 30 reference group). Baseline exercise time and Seattle Angina Questionnaire summary scores were similar between groups. The CMD group had a greater increment (delta) in exercise time than the reference group in response to both amlodipine (difference in delta, 82 s [95% CI, 37-126 s]; P<0.001) and ranolazine (difference in delta, 68 s [95% CI, 21-115 s]; P=0.005). The CMD group reported a greater increment (delta) in Seattle Angina Questionnaire summary score than the reference group in response to ranolazine (difference in delta, 7 points [95% CI, 0-15]; P=0.048), but not to amlodipine (difference in delta, 2 points [95% CI, -5 to 8]; P=0.549). CONCLUSIONS: Among phenotypically similar patients with angina with nonobstructive coronary arteries, only those with an impaired CFR derive benefit from anti-ischemic therapy. These findings support measurement of CFR to diagnose and guide management of this otherwise heterogeneous patient group.

Characterizing Mechanisms of Ischemia in Patients With Myocardial Bridges.

BACKGROUND: Myocardial bridges (MBs) are prevalent and can be associated with acute and chronic ischemic syndromes. We sought to determine the substrates for ischemia in patients with angina with nonobstructive coronary arteries and a MB in the left anterior descending artery. METHODS: Patients with angina with nonobstructive coronary arteries underwent the acquisition of intracoronary pressure and flow during rest, supine bicycle exercise, and adenosine infusion. Coronary wave intensity analysis was performed, with perfusion efficiency defined as accelerating wave energy/total wave energy (%). Epicardial endothelial dysfunction was defined as a reduction in epicardial vessel diameter ≥20% in response to intracoronary acetylcholine infusion. Patients with angina with nonobstructive coronary arteries and a MB were compared with 2 angina with nonobstructive coronary arteries groups with no MB: 1 with coronary microvascular disease (CMD: coronary flow reserve, <2.5) and 1 with normal coronary flow reserve (reference: coronary flow reserve, ≥2.5). RESULTS: Ninety-two patients were enrolled in the study (30 MB, 33 CMD, and 29 reference). Fractional flow reserve in these 3 groups was 0.86±0.05, 0.92±0.04, and 0.94±0.05; coronary flow reserve was 2.5±0.5, 2.0±0.3, and 3.2±0.6. Perfusion efficiency increased numerically during exercise in the reference group (65±9%-69±13%; P=0.063) but decreased in the CMD (68±10%-50±10%; P<0.001) and MB (66±9%-55±9%; P<0.001) groups. The reduction in perfusion efficiency had distinct causes: in CMD, this was driven by microcirculation-derived energy in early diastole, whereas in MB, this was driven by diminished accelerating wave energy, due to the upstream bridge, in early systole. Epicardial endothelial dysfunction was more common in the MB group (54% versus 29% reference and 38% CMD). Overall, 93% of patients with a MB had an identifiable ischemic substrate. CONCLUSIONS: MBs led to impaired coronary perfusion efficiency during exercise, which was due to diminished accelerating wave energy in early systole compared with the reference group. Additionally, there was a high prevalence of endothelial and microvascular dysfunction. These ischemic mechanisms may represent distinct treatment targets.

Coronary microvascular dysfunction and heart failure with preserved ejection fraction: what are the mechanistic links?

PURPOSE OF REVIEW: Heart failure with preserved ejection fraction (HFpEF) accounts for half of all heart failure presentations and is associated with a dismal prognosis. HFpEF is an umbrella term that constitutes several distinct pathophysiological entities. Coronary microvascular dysfunction (CMD), defined as the inability of the coronary vasculature to augment blood flow adequately in the absence of epicardial coronary artery disease, is highly prevalent amongst the HFpEF population and likely represents one distinct HFpEF endotype, the CMD-HFpEF endotype. This review appraises recent studies that have demonstrated an association between CMD and HFpEF with an aim to understand the pathophysiological links between the two. This is of significant clinical relevance as better understanding of the pathophysiology underlying CMD-HFpEF may result in more targeted and efficacious therapeutic options in this patient cohort. RECENT FINDINGS: There is a high prevalence of CMD, diagnosed invasively or noninvasively, in patients with HFpEF. Patients with HFpEF who have an impaired myocardial perfusion reserve (MPR) have a worse outcome than those with a normal MPR. Both MPR and coronary flow reserve (CFR) are associated with measures of left ventricular diastolic function and left ventricular filling pressures during exercise. Impaired lusitropy and subendocardial ischaemia link CMD and HFpEF mechanistically. SUMMARY: CMD-HFpEF is a prevalent endotype of HFpEF and one that is associated with adverse cardiovascular prognosis. Whether CMD leads to HFpEF, through subendocardial ischaemia, or whether it is secondary to the impaired lusitropy that is characteristic of HFpEF is not known. Further mechanistic work is needed to answer this pertinent question.

Coronary Slow Flow Is Not Diagnostic of Microvascular Dysfunction in Patients With Angina and Unobstructed Coronary Arteries.

Background Guidelines recommend that coronary slow flow phenomenon (CSFP), defined as corrected thrombolysis in myocardial infarction frame count (CTFC) >$$ > $$27, can diagnose coronary microvascular dysfunction (CMD) in patients with angina and nonobstructed coronary arteries. CSFP has also historically been regarded as a sign of coronary endothelial dysfunction (CED). We sought to validate the utility of CTFC, as a binary classifier of CSFP and as a continuous variable, to diagnose CMD and CED. Methods and Results Patients with angina and nonobstructed coronary arteries had simultaneous coronary pressure and flow velocity measured using a dual sensor-tipped guidewire during rest, adenosine-mediated hyperemia, and intracoronary acetylcholine infusion. CMD was defined as the inability to augment coronary blood flow in response to adenosine (coronary flow reserve <2.5) and CED in response to acetylcholine (acetylcholine flow reserve ≤1.5); 152 patients underwent assessment using adenosine, of whom 82 underwent further acetylcholine testing. Forty-six patients (30%) had CSFP, associated with lower flow velocity and higher microvascular resistance as compared with controls (16.5±$$ \pm $$6.9 versus 20.2±$$ \pm $$6.9 cm/s; P=0.001 and 6.26±$$ \pm $$1.83 versus 5.36±$$ \pm $$1.83 mm Hg/cm/s; P=0.009, respectively). However, as a diagnostic test, CSFP had poor sensitivity and specificity for both CMD (26.7% and 65.2%) and CED (21.1% and 56.0%). Furthermore, on receiver operating characteristics analyses, CTFC could not predict CMD or CED (area under the curve, 0.41 [95% CI, 0.32%-0.50%] and 0.36 [95% CI, 0.23%-0.49%], respectively). Conclusions In patients with angina and nonobstructed coronary arteries, CSFP and CTFC are not diagnostic of CMD or CED. Guidelines supporting the use of CTFC in the diagnosis of CMD should be revisited.

Prospective RandOmised Trial of Emergency Cardiac Computerised Tomography (PROTECCT).

OBJECTIVE: Many patients presenting with suspected acute coronary syndrome (ACS) have high-sensitivity cardiac troponin (hs-cTn) concentrations between rule-in and rule-out thresholds and hence need serial testing, which is time consuming. The Prospective RandOmised Trial of Emergency Cardiac Computerised Tomography (PROTECCT) assessed the utility of coronary CT angiography (CCTA) in patients with suspected ACS, non-ischaemic ECG and intermediate initial hs-cTn concentration. METHODS: Patients were randomised to CCTA-guided management versus standard of care (SOC). The primary outcome was hospital length of stay (LOS). Secondary outcomes included cost of in-hospital stay and major adverse cardiac events (MACE) at 12 months of follow-up. Data are mean (SD); for LOS harmonic means, IQRs are shown. RESULTS: 250 (aged 55 (14) years, 25% women) patients were randomised. Harmonic mean (IQR) LOS was 7.53 (6.0-9.6) hours in the CCTA arm and 8.14 (6.3-9.8) hours in the SOC arm (p=0.13). Inpatient cost was £1285 (£2216) and £1108 (£3573), respectively, p=0.68. LOS was shorter in the CCTA group in patients with <25% stenosis, compared with SOC; 6.6 (5.6-7.8) hours vs 7.5 (6.1-9.4) hours, respectively; p=0.021. More referrals for cardiology outpatient clinic review and cardiac CT-related outpatient referrals occurred in the SOC arm (p=0.01). 12-month MACE rates were similar between the two arms (7 (5.6%) in the CCTA arm and 8 (6.5%) in the SOC arm-log-rank p=0.78). CONCLUSIONS: CCTA did not lead to reduced hospital LOS or cost, largely because these outcomes were influenced by the detection of ≥25% grade stenosis in a proportion of patients. TRIAL REGISTRATION NUMBER: NCT03583320.

Rapid risk stratification of acute coronary syndrome: adoption of an adapted European Society of Cardiology 0/1-hour troponin algorithm in a real-world setting.

Aims: To evaluate the clinical feasibility of implementing the 2020 ESC 0/1 hr algorithm for rapid rule-out/rule-in of acute coronary syndrome (ACS). Methods and results: Data were collected retrospectively from 5496 patients in 2020 and 7363 patients in 2021 who received cardiac troponin measurements through the ACS algorithm in acute care settings within a large tertiary cardiac centre in the United Kingdom. This period overlapped the introduction of the 2020 ESC 0/1 hr algorithm. After exclusion of haemolysis, 1905 patients underwent repeat troponin measurement within the study period in 2020 and 2658 in 2021. Median time to repeat was significantly reduced from 3 h 14 min for intermediate low risk patients (5-12 ng/L) in 2020 to 1 h 22 min in 2021, and from 3 h 30 min to 1 h 59 min in intermediate high-risk patients (12-51 ng/L). Less than 15% of patients requiring repeat testing had dynamic changes in troponin of sufficient magnitude to change their initial risk category. Of all patients, 58.1% of patients in 2020 were ultimately classified as 'low risk', 19.2% deemed 'ACS likely', and 22.7% as 'ACS possible', with similar distributions in 2021. Conclusion: Whilst an efficient algorithm, our study demonstrates multi-faceted, practical limitations of achieving the 1 h target for the triage of patients with suspected ACS. Despite challenges predominantly of logistic nature, the algorithm enables rapid, streamlined, and efficient triage of large patient cohorts. Further work is required to streamline this process and achieve the targeted 1 h repeat in a resource-constrained healthcare environment, which would invariably require second blood draw before the result of first, as recommended by the ESC.

Evaluation of the causes of sex disparity in heart failure trials.

OBJECTIVES: Cardiovascular disease is one of the leading causes of mortality and morbidity in women. Despite this, even in contemporary research, female patients are poorly represented in trials. This study aimed to explore reasons behind the sex disparity in heart failure (HF) trials. METHODS: HF trials published in seven high-impact clinical journals (impact factor >20), between 2000 and 2020, were identified. Trials with over 300 participants of both sexes were included. Large HF registries, as well as population statistics, were also identified using the same criteria. RESULTS: We identified 146 HF trials, which included 248 620 patients in total. The median proportion of female patients was 25.8%, with the lowest proportions seen in trials enrolling patients with ischaemic cardiomyopathy (17.9%), severe systolic dysfunction (left ventricular ejection fraction (LVEF) <35%) (21.4%) and those involving an invasive procedure (21.1%). The highest proportion of women was seen in trials assessing HF with preserved LVEF (51.6%), as well as trials including older participants (40.5%). Significant differences were seen between prevalence of female trial participants and population prevalence in all LVEF categories (25.8% vs 49.0%, p<0.01). CONCLUSIONS: A significant sex disparity was identified in HF trials, most visible in trials assessing patients with severely reduced LVEF and ischaemic aetiology. This is likely due to a complex interplay between enrolment bias and biological variation. Furthermore, the degree of both these aspects may vary according to trial type. Going forward, we should encourage all HF trials to appraise their recruitment log and suggest reasons for any reported sex disparity.

Invasive coronary physiology in patients with angina and non-obstructive coronary artery disease: a consensus document from the coronary microvascular dysfunction workstream of the British Heart Foundation/National Institute for Health Research Partnership.

Nearly half of all patients with angina have non-obstructive coronary artery disease (ANOCA); this is an umbrella term comprising heterogeneous vascular disorders, each with disparate pathophysiology and prognosis. Approximately two-thirds of patients with ANOCA have coronary microvascular disease (CMD). CMD can be secondary to architectural changes within the microcirculation or secondary to vasomotor dysfunction. An inability of the coronary vasculature to augment blood flow in response to heightened myocardial demand is defined as an impaired coronary flow reserve (CFR), which can be measured non-invasively, using imaging, or invasively during cardiac catheterisation. Impaired CFR is associated with myocardial ischaemia and adverse cardiovascular outcomes.The CMD workstream is part of the cardiovascular partnership between the British Heart Foundation and The National Institute for Health Research in the UK and comprises specialist cardiac centres with expertise in coronary physiology assessment. This document outlines the two main modalities (thermodilution and Doppler techniques) for estimation of coronary flow, vasomotor testing using acetylcholine, and outlines a standard operating procedure that could be considered for adoption by national networks. Accurate and timely disease characterisation of patients with ANOCA will enable clinicians to tailor therapy according to their patients' coronary physiology. This has been shown to improve patients' quality of life and may lead to improved cardiovascular outcomes in the long term.

Vasospastic Angina: A Contemporary Review of its Pathophysiology, Diagnosis and Management.

Nearly 40% of patients presenting to the catheter laboratory with angina have non-obstructed coronary arteries (ANOCA), an umbrella term that encompasses distinct pathophysiological entities, such as coronary artery spasm. Coronary artery spasm leads to sudden reversible coronary flow attenuation, which clinically manifests as vasospastic angina (VSA). VSA is associated with poor quality of life and an increased risk of major adverse cardiac events. However, the pathophysiological mechanisms underlying this phenomenon are incompletely understood, which has resulted in limited therapeutic options for patients afflicted with this condition. The past decade has seen a surge in new research being conducted in the field of ANOCA and VSA. This review article provides a comprehensive summary of the underlying pathophysiological mechanisms of VSA and the current therapeutic options. We also appraise the current diagnostic approach in patients with suspected VSA.

Untangling the pathophysiologic link between coronary microvascular dysfunction and heart failure with preserved ejection fraction.

Coronary microvascular disease (CMD), characterized by impaired coronary flow reserve (CFR), is a common finding in patients with stable angina. Impaired CFR, in the absence of obstructive coronary artery disease, is also present in up to 75% of patients with heart failure with preserved ejection fraction (HFpEF). Heart failure with preserved ejection fraction is a heterogeneous syndrome comprising distinct endotypes and it has been hypothesized that CMD lies at the centre of the pathogenesis of one such entity: the CMD-HFpEF endotype. This article provides a contemporary review of the pathophysiology underlying CMD, with a focus on the mechanistic link between CMD and HFpEF. We discuss the central role played by subendocardial ischaemia and impaired lusitropy in the development of CMD-HFpEF, as well as the clinical and research implications of the CMD-HFpEF mechanistic link. Future prospective follow-up studies detailing outcomes in patients with CMD and HFpEF are much needed to enhance our understanding of the pathological processes driving these conditions, which may lead to the development of physiology-stratified therapy to improve the quality of life and prognosis in these patients.

Coronary microvascular disease: current concepts of pathophysiology, diagnosis and management.

Coronary microvascular disease (CMD) is present in 30% of patients with angina and is associated with increased morbidity and mortality. We now have an improved understanding of the pathophysiology of CMD and the invasive and noninvasive tests that can be used to make the diagnosis. Recent studies have shown that management of CMD guided by physiological testing yields better results than empirical treatment. Despite major advances in diagnosing and stratifying this condition, therapeutic strategies remain limited and poorly defined. This review article discusses recent advances in understanding the pathophysiology of CMD, the modalities that are available to diagnose it clinically, current management options and a look at what is in store for the future.

Dizziness in an avid cyclist: an unusual presentation of a common problem.

BACKGROUND: Presyncope and syncope are common presentations with a wide range of differential diagnoses; when it occurs primarily on exertion, a cardiovascular cause is more likely. Structural abnormalities and primary rhythm disturbances are the usual culprits in these patients. CASE SUMMARY: A 75-year-old gentleman presented with a history of progressive exertional presyncope. His investigations demonstrated normal cardiac structure, function, and rhythm. He underwent an exercise stress test, which demonstrated a significant reduction in peak blood pressure with equivocal electrocardiogram changes and absence of ischaemic symptoms. In view of his age and gender, a computerized tomography coronary angiogram (CTCA) was organized to exclude obstructive coronary artery disease (CAD). Intriguingly, the CTCA demonstrated a severe proximal left anterior descending (LAD) artery stenosis. This stenosis was confirmed to be functionally significant using invasive coronary physiology and was treated with percutaneous coronary intervention. At follow-up, there was no recurrence of exertional presyncope and the patient was continuing to return to his baseline function. CONCLUSION: Presyncope and/or syncope as the sole manifestation of obstructive CAD, in the presence of normal ventricular function and valves, has rarely been reported. Myocardial ischaemia-mediated presyncope and/or syncope may be secondary to numerous mechanisms, which are described in this case report. Revascularization of the functionally significant proximal LAD stenosis resulted in cessation of exertional presyncope in our patient. The long-term outcome of revascularization in patients with presyncope and syncope needs to be further investigated.