Thomas J. Ford

Pharmacodynamic effects of a novel prokinetic 5-HT4receptor agonist, ATI-7505, in humans

Abstract  ATI‐7505, an investigational 5‐HT4 receptor agonist, was designed to have similar activity as cisapride without the cardiac adverse effects, i.e. without QT prolongation. In addition, ATI‐7505 is not metabolized by CYP450. The aim of the study was to assess the effect of ATI‐7505 on gastrointestinal (GI) and colonic transit in healthy humans. A randomized, parallel‐group, double‐blind, placebo‐controlled study evaluated effects of 9‐day treatment with ATI‐7505 (3, 10 or 20 mg t.i.d.) on scintigraphic GI and colonic transit in healthy volunteers (12 per group). Primary endpoints were gastric‐emptying (GE) T1/2, colonic geometric centre (GC) at 24 h and ascending colon (AC) emptying T1/2. Daily stool diaries were kept. Analysis of covariance assessed overall treatment group differences, followed by post hoc unadjusted pairwise comparisons. There were borderline overall treatment effects (decrease) on GE T1/2 (P = 0.154); the 20 mg t.i.d. of ATI‐7505‐accelerated GE vs placebo (P = 0.038). ATI‐7505 increased colonic transit (GC24, P = 0.031) with fastest transit at 10 mg t.i.d. vs placebo (P = 0.065). ATI‐7505 accelerated AC emptying T1/2 (overall P = 0.075) with 10 mg dose vs placebo (P = 0.042). There was looser stool (Bristol stool form scale, overall P = 0.056) with the 10 and 20 mg t.i.d. doses. No safety issues were identified. ATI‐7505 accelerates overall colonic transit and tends to accelerate GE and AC emptying and loosen stool consistency.

Stable coronary syndromes: pathophysiology, diagnostic advances and therapeutic need

The diagnostic management of patients with angina pectoris typically centres on the detection of obstructive epicardial CAD, which aligns with evidence-based treatment options that include medical therapy and myocardial revascularisation. This clinical paradigm fails to account for the considerable proportion (approximately one-third) of patients with angina in whom obstructive CAD is excluded. This common scenario presents a diagnostic conundrum whereby angina occurs but there is no obstructive CAD (ischaemia and no obstructive coronary artery disease—INOCA). We review new insights into the pathophysiology of angina whereby myocardial ischaemia results from a deficient supply of oxygenated blood to the myocardium, due to various combinations of focal or diffuse epicardial disease (macrovascular), microvascular dysfunction or both. Macrovascular disease may be due to the presence of obstructive CAD secondary to atherosclerosis, or may be dynamic due to a functional disorder (eg, coronary artery spasm, myocardial bridging). Pathophysiology of coronary microvascular disease may involve anatomical abnormalities resulting in increased coronary resistance, or functional abnormalities resulting in abnormal vasomotor tone. We consider novel clinical diagnostic techniques enabling new insights into the causes of angina and appraise the need for improved therapeutic options for patients with INOCA. We conclude that the taxonomy of stable CAD could improve to better reflect the heterogeneous pathophysiology of the coronary circulation. We propose the term ‘stable coronary syndromes’ (SCS), which aligns with the well-established terminology for ‘acute coronary syndromes’. SCS subtends a clinically relevant classification that more fully encompasses the different diseases of the epicardial and microvascular coronary circulation.

Ankyrin-B syndrome: a case of sinus node dysfunction, atrial fibrillation and prolonged QT in a young adult.

Ankyrin-B protein is involved in regulating expression and localisation of cardiac ion channels and transporters. Mutations of the ANK2 gene in the rare condition Ankyrin-B syndrome result in loss of function of the ankyrin-B protein which in turn leads to abnormal regulation of intracellular sodium and calcium and a predisposition to cardiac arrhythmia including torsades de pointes. We describe a rare case of this condition characterised by sinus node dysfunction, atrial fibrillation and prolonged QT syndrome in a young patient with a family history of sudden death. The management of Ankyrin-B syndrome may include avoidance of QT prolonging medications, insertion of a permanent pacemaker for sinus node dysfunction, or a cardioverter defibrillator for those at high-risk of sudden death from torsades de pointes.

Coronary artery disease: physiology and prognosis

The ‘stenosis centric’ approach to the diagnosis of coronary artery disease (CAD) neglects the broader pathophysiology of angina and disorders of coronary artery function (Figure 1). Accordingly, we propose the term ‘stable coronary artery syndrome’ in order to reflect the distinct and related pathologies of focal and diffuse CAD, as well as coronary microvascular and vasospastic disorders, that may reduce myocardial perfusion and provoke ischaemia in individual patients. Evidence linking parameters of coronary artery function with prognosis has evolved substantially in the last four decades. Coronary flow reserve (CFR) was first described as the ratio of maximum stress flow to rest flow for a given arterial distribution with or without a stenosis or diffuse narrowing. CFR determined non-invasively using positron emission tomography (PET) is associated with the risk of major adverse cardiac events (MACE) in the future, independent of clinical variables and the number of ischaemic myocardial segments. Fractional flow reserve (FFR) was subsequently described as a pressure-derived index to quantify the relative reduction in coronary artery blood flow due to a coronary stenosis as compared with the flow in the same artery in the absence of the stenosis. Invasively measured CFR (via thermodilution or Doppler wire methods) is reported to be prognostically important even when FFR is preserved. van de Hoef et al. demonstrated the potential clinical relevance of discordant CFR and FFR values, showing that in a pooled group of patients with stable coronary artery disease patients with a reduced Doppler-derived CFR (defined as <2.0) but preserved FFR (>_0.75) were at a higher risk of adverse clinical events at 5-year follow-up, compared with patients with concordantly preserved CFR and FFR values [relative risk = 5.0, 95% confidence interval (CI) 2.4–10.2; P < 0.001). Invasively measured CFR and FFR are discordant in 40% of patients, which reflects the distinct compartments of the coronary circulation. Johnson et al. demonstrated that discordant CFR and FFR values may be explained by fundamental differences in coronary pathophysiology at the extremes of focal and diffuse CAD. For example, severe focal epicardial coronary disease may be reflected by a reduced FFR (<0.80) and a preserved CFR (>2.0), whereas diffuse coronary plaque without a focal stenosis may be reflected by a preserved FFR (>0.8) and a reduced CFR (<2.0) (Figure 1). In this issue of the journal, Park et al. report their analysis of the comparative prognostic utility of FFR and ‘pressure-bounded’ coronary flow reserve (pb-CFR) in a study involving 1837 patients (2088 coronary lesions) enrolled in a multicentre South Korean clinical registry. pb-CFR is a novel parameter determined by estimating the upper and lower physiological limits of CFR values using resting and hyperaemic pressure data integrated into a mathematical model of pressure and flow. Pb-CFR was shown to have reasonable diagnostic accuracy of 84.4% in a recent validation study based on individual patient haemodynamic data from the DEFER trial. Patients in the current study were dichotomized into two groups based on a low (<2.0) or high (>_2.0) CFR. A key strength of this analysis is the comparatively large samples size reflecting a prospectively enrolled population of invasively managed patients with a broad range of CAD severities. Further, the pb-CFR values were determined post-hoc; therefore, the data were not available to treating clinicians and so could not have influenced their clinical decisions. The clinical endpoints were adjudicated by a central committee blind to the pb-CFR values. The investigators found that the composite primary endpoint of MACE (cardiac death, myocardial infarction, and repeat revascularization) was predicted by FFR but not by pb-CFR, which had a neutral prognostic implication when adjusted for clinical variables. In a per-lesion analysis, during a median follow-up of 1.9 years (interquartile range: 1.0– 3.0 years), the incidence of MACE did not differ between lesions with pb-CFR <2 vs. pb-CFR >_2 [4.0% vs. 4.0%; adjusted hazard ratio (aHR) = 0.93, 95% CI 0.59–1.48; P = 0.76). FFR was predictive of future

Selective anti-scatter grid removal during coronary angiography and PCI: a simple and safe technique for radiation reduction

Objectives The aim of this study was to quantify the radiation dose reduction during coronary angiography and percutaneous coronary intervention (PCI) through removal of the anti-scatter grid (ASG), and to assess its impact on image quality in adult patients with a low body mass index (BMI). Methods A phantom with different thicknesses of acrylic was used with a Westmead Test Object to simulate patient sizes and assess image quality. 129 low BMI patients underwent coronary angiography or PCI with or without the ASG in situ. Radiation dose was compared between both patient groups. Results With the same imaging system and a comparable patient population, ASG removal was associated with a 47% reduction in total dose-area product (DAP) (p < 0.001). Peak skin dose was reduced by 54% (p < 0.001). Operator scatter was reduced to a similar degree and was significantly reduced through removal of the ASG. Using an image quality phantom it was demonstrated that image quality remained satisfactory. Conclusions Removal of the ASG is a simple and effective method to significantly reduce radiation dose in coronary angiography and PCI. This was achieved while maintaining adequate diagnostic image quality. Selective removal of the ASG is likely to improve the radiation safety of cardiac angiography and interventions.

Pulmonary hypertension and hepatic encephalopathy: lethal complications of Rendu-Osler-Weber disease

Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterised by epistaxis, mucocutaneous telangiectasia with systemic manifestations due to visceral telangiectasia and arterio-venous malformations (AVMs). We describe unusual complications of HHT in a 68-year-old male who developed high-output cardiac failure with pulmonary hypertension in combination with hepatic encephalopathy due to hepatic AVMs. This case shows the importance of a multi-system approach to HHT and considers the treatment of its hepatic complications.

Single‐ Versus 2‐Stent Strategies for Coronary Bifurcation Lesions: A Systematic Review and Meta‐Analysis of Randomized Trials With Long‐Term Follow‐up

Background The majority of coronary bifurcation lesions are treated with a provisional single‐stent strategy rather than an up‐front 2‐stent strategy. This approach is supported by multiple randomized controlled clinical trials with short‐ to medium‐term follow‐up; however, long‐term follow‐up data is evolving from many data sets. Methods and Results Meta‐analysis of randomized controlled trials evaluating long‐term outcomes (≥1 year) according to treatment strategy for coronary bifurcation lesions. Nine randomized controlled trials with 3265 patients reported long‐term clinical outcomes at mean weighted follow‐up of 3.1±1.8 years. Provisional single stenting was associated with lower all‐cause mortality (2.94% versus 4.23%; risk ratio: 0.69; 95% confidence interval, 0.48–1.00; P=0.049; I2=0). There was no difference in major adverse cardiac events (15.8% versus 15.4%; P=0.79), myocardial infarction (4.8% versus 5.5%; P=0.51), target lesion revascularization (9.3% versus 7.6%; P=0.19), or stent thrombosis (1.8% versus 1.6%; P=0.28) between the groups. Prespecified sensitivity analysis of long‐term mortality at a mean of 4.7 years of follow‐up showed that the provisional single‐stent strategy was associated with reduced all‐cause mortality (3.9% versus 6.2%; risk ratio: 0.63; 95% confidence interval, 0.42–0.97; P=0.036; I2=0). Conclusions Coronary bifurcation percutaneous coronary intervention using a provisional single‐stent strategy is associated with a reduction in all‐cause mortality at long‐term follow‐up.

Arterial access for invasive coronary angiography: the 'left backhander'

A 73-year-old male underwent invasive coronary angiography for investigation of ventricular tachycardia 12 years after coronary artery bypass grafting including use of left internal mammary artery. The left distal radial artery was punctured as it traverses inside the anatomical snuffbox (Figure 1A). The sheath insertion near the base of thumb (on the dorsal forearm Figure 1B) is distal to the typical palmar radial approach. Most operators prefer the right radial approach (RRA) because it is more ergonomic for them working on the patient’s right side. However, a left radial approach is helpful in patients with prior left internal mammary grafting, short stature, short aortic roots, tortuous or aberrant subclavian anatomy. The ‘traditional’ left radial approach is often painful for both patient and operator. The patient must supinate their arm whilst the operator leans over to manipulate the catheter. This can be particularly challenging in obese patients or those with restricted upper limb movement. Left distal transradial access (LDTRA) is the source of ongoing clinical trials (NCT03292367) but is gaining traction as a safe, feasible and ergonomic alternative access site [1].

Rationale and design of the British Heart Foundation (BHF) Coronary Microvascular Angina CorMicA) stratified medicine clinical trial

Background Coronary angiography is performed to assess for obstructive coronary artery disease (CAD), but “nonobstructive CAD” is a common finding. Microvascular or vasospastic angina may be relevant, but routine confirmatory testing is not evidence based and thus rarely performed. Aim The aim was to assess the effect of stratified medicine guided by coronary function testing on the diagnosis, treatment, and well-being of patients with angina and nonobstructive CAD. Design The BHF CorMicA trial is a prospective, multicenter, randomized, blinded, sham-controlled trial of stratified medicine (NCT03193294). All-comers referred for elective coronary angiography for investigation of suspected CAD will be screened. Following informed consent, eligible patients with angina and nonobstructive CAD will be randomized 1:1 immediately in the catheter laboratory to either coronary artery function–guided diagnosis and treatment (intervention group) or not (control group). Coronary function will be assessed using a pressure-temperature–sensitive guidewire and adenosine followed by pharmacological testing with intracoronary acetylcholine. Patients will be stratified into endotypes with linked therapy. The primary outcome is change in Seattle Angina Questionnaire score at 6 months. Secondary outcomes include safety, feasibility, diagnostic utility (impact on diagnosis and diagnostic certainty), and clinical utility (impact on treatment and investigations). Health status is a key secondary outcome assessed according to the following domains: quality of life, treatment satisfaction, illness perception, physical activity, and anxiety-depression score. Patients with obstructive disease who are not randomized will form a registry group who will be followed up as a comparator for secondary outcomes including health status. Health and economic outcomes will be evaluated in the longer term using electronic health record linkage. Value CorMicA is a proof-of-concept clinical trial of a disruptive stratified intervention with potential benefits to patients and health care providers.

Strategies in Stable Chronic Coronary Disease

Stable coronary artery syndromes include patients with angina caused by obstructive coronary artery disease, by a disorder of coronary vascular function, or by a combination of these two clinical entities. The diagnostic pathway in patients presenting with chest pain and suspected stable coronary artery disease (SCAD) can be challenging because of variations in the pre-test probability of CAD and in the accuracy and local availability of diagnostic tests. There is uncertainty regarding the comparative effectiveness of non-invasive imaging-based diagnostic strategies for the detection of CAD and their role in directing ongoing management. In this chapter, we review the evidence base and clinical practice guideline recommendations underpinning non-invasive and invasive diagnostic strategies.