Rationale and design of the Medical Research Council's Precision Medicine with Zibotentan in Microvascular Angina (PRIZE) trial.

Microvascular angina is caused by cardiac small vessel disease, and dysregulation of the endothelin system is implicated. The minor G allele of the non-coding single nucleotide polymorphism (SNP) rs9349379 enhances expression of the endothelin 1 gene in human vascular cells, increasing circulating concentrations of ET-1. The prevalence of this allele is higher in patients with ischemic heart disease. Zibotentan is a potent, selective inhibitor of the ETA receptor. We have identified zibotentan as a potential disease-modifying therapy for patients with microvascular angina. METHODS: We will assess the efficacy and safety of adjunctive treatment with oral zibotentan (10 mg daily) in patients with microvascular angina and assess whether rs9349379 (minor G allele; population prevalence ~36%) acts as a theragnostic biomarker of the response to treatment with zibotentan. The PRIZE trial is a prospective, randomized, double-blind, placebo-controlled, sequential cross-over trial. The study population will be enriched to ensure a G-allele frequency of 50% for the rs9349379 SNP. The participants will receive a single-blind placebo run-in followed by treatment with either 10 mg of zibotentan daily for 12 weeks then placebo for 12 weeks, or vice versa, in random order. The primary outcome is treadmill exercise duration using the Bruce protocol. The primary analysis will assess the within-subject difference in exercise duration following treatment with zibotentan versus placebo. CONCLUSION: PRIZE invokes precision medicine in microvascular angina. Should our hypotheses be confirmed, this developmental trial will inform the rationale and design for undertaking a larger multicenter trial.

Impact of established cardiovascular disease on outcomes in the randomized global leaders trial.

OBJECTIVE: To investigate the impact of different anti-platelet strategies on outcomes after percutaneous coronary intervention (PCI) in patients with established cardiovascular disease (CVD). METHODS: GLOBAL LEADERS was a randomized, superiority, all-comers trial comparing one-month dual anti-platelet therapy (DAPT) with ticagrelor and aspirin followed by 23-month ticagrelor monotherapy (experimental treatment) with standard 12-month DAPT followed by 12-month aspirin monotherapy (reference treatment) in patients treated with a biolimus A9-eluting stent. Established CVD was defined as ≥1 prior myocardial infarction, PCI, coronary artery bypass operation, stroke, or established peripheral vascular disease. The primary endpoint was a composite of all-cause death or new Q-wave MI at 2-years. The secondary safety endpoint was BARC 3 or 5 bleeding. Exploratory secondary endpoints were the patient-orientated composite endpoint and net adverse clinical events. RESULTS: Among the 15,761 patients in this cohort were 6,693 patients (42.5%) with established CVD. Compared to those without established CVD, these patients had significantly higher rates of the primary (5.1 vs. 3.3%, HR1.59[1.36-1.86], p < .001) and secondary composite endpoints with no significant differences in bleeding. There was a nonsignificant reduction in the primary endpoint in patients with established CVD receiving the experimental treatment (4.6 vs. 5.6%, HR0.82[0.66-1.02], p = .07). When comparing patients without CVD to those with one or three territories of CVD, the hazard ratio for the primary endpoint increased in unadjusted and adjusted models. CONCLUSIONS: The poorer outcomes in patients with established CVD are not mitigated by prolonged monotherapy with a potent P2Y12 inhibitor suggesting a greater need to focus on modifiable risk factors.

Conservative versus Invasive Strategy in Elderly Patients with Non-ST-Elevation Myocardial Infarction: Insights from the International POPular Age Registry.

This registry assessed the impact of conservative and invasive strategies on major adverse clinical events (MACE) in elderly patients with non-ST-elevation myocardial infarction (NSTEMI). Patients aged ≥75 years with NSTEMI were prospectively registered from European centers and followed up for one year. Outcomes were compared between conservative and invasive groups in the overall population and a propensity score-matched (PSM) cohort. MACE included cardiovascular death, acute coronary syndrome, and stroke. The study included 1190 patients (median age 80 years, 43% female). CAG was performed in 67% (N = 798), with two-thirds undergoing revascularization. Conservatively treated patients had higher baseline risk. After propensity score matching, 319 patient pairs were successfully matched. MACE occurred more frequently in the conservative group (total population 20% vs. 12%, adjHR 0.53, 95% CI 0.37-0.77, p = 0.001), remaining significant in the PSM cohort (18% vs. 12%, adjHR 0.50, 95% CI 0.31-0.81, p = 0.004). In conclusion, an early invasive strategy was associated with benefits over conservative management in elderly patients with NSTEMI. Risk factors associated with ischemia and bleeding should guide strategy selection rather than solely relying on age.

Mental Health Outcomes Among British Healthcare Workers-Lessons From the First Wave of the Covid-19 Pandemic.

OBJECTIVE: To ascertain the level of psychological distress, using validated psychology tools, among British National healthcare workers (HCW) during the first wave of the Covid-19 crisis. METHODS: A multi-centre, anonymized, all-comer staff survey across 3 hospitals in Lancashire, England during the Covid-19 first wave (April to June 2020), consisting of Patient Health Questionnaire (PHQ-9), Perceived Stress Scale-10 (PSS-10), Generalized Anxiety Disorder-7 (GAD-7), and Impact of Events Scale (IES-6). RESULTS: Among 1113 HCW, median (IQR) PHQ-9, GAD-7, PSS-10, and IES-6 score was 7 (3 to 11), 6 (3 to 11), 19 (13 to 24), and 9 (5 to 14), respectively. Potential predictors of higher levels of psychological distress included living alone, disabled dependents, history of depression/anxiety, and being female. CONCLUSIONS: The study indicates a high prevalence of psychological distress during the acute Covid-19 period among HCW, identifies groups at risk and areas of future research.

Balloon-assisted tracking technique as 'a way forward' for transradial intervention.

BACKGROUND: In percutaneous coronary interventions, use of the radial artery may be limited by vascular anatomy or vascular complications, such as radial artery spasm, dissection or perforation. The balloon-assisted tracking (BAT) technique is a novel and innovative method to successfully perform transradial procedures in patients with difficult vascular anatomy, severe tortuosity or radial artery spasm. In addition, the BAT technique can serve as a bail-out technique when vascular complications such as artery dissection or perforation occur. OBJECTIVE: We analysed data of all percutaneous coronary intervention patients in whom the BAT technique was undertaken in daily practice and report acute and long-term outcomes. RESULTS: A total of 62 patients were included and, in most patients, the BAT technique was performed for radial spasm. Most patients were administered benzodiazepines or nitrates before the BAT technique was performed. The primary end point, defined as successful passage of the catheter through the artery of the arm using the BAT technique, was 98%. 11% of patients developed a complication within 24 h (haematoma, prolonged pain or visible vascular damage at the end of procedure); all completely recovered at follow-up. No complications occurred during long-term follow-up. CONCLUSION: BAT is a low-risk and easy-to-use technique that increases the success rate of radial artery access and may prevent vascular complications.

Comparison of the clinical utility of atrial and B type natriuretic peptide measurement for the diagnosis of systolic dysfunction in a low-risk population.

BACKGROUND: Measurement of B type natriuretic peptide and its N terminal prohormone (NTproBNP) can now be performed routinely by automated high-throughput immunoassays. The study compared measurement of NTproBNP with measurement of N terminal pro-atrial natriuretic peptide (NTproANP) for detection of ventricular systolic dysfunction in primary care. METHODS: 734 subjects aged >45 years (349 men and 385 women, median age 58 years, range 45-89, interquartile range 51-67 years) from seven representative general practices attended for echocardiography with determination of ejection fraction and completed a questionnaire. Blood samples were collected into gel serum separation tubes (Becton-Dickinson, Franklin Lakes, New Jersey, USA), the serum separated and aliquots stored frozen at -70 degrees C until analyses. Samples were analysed for NTproBNP (Roche Diagnostics, Lewes, UK; coefficient of variation (CV) 3.2-2.4%) and for NTproANP (Biomedica, Vienna, Austria; CV 5.6-10.1%). Echocardiography was used as the diagnostic "gold standard", with ventricular systolic dysfunction defined as abnormal when there was an ejection fraction of

Energy drinks give you wings but also an abnormal exercise test.

This is the case of a 53-year-old man with known coronary artery disease who underwent two exercise treadmill tests (ETT). The first test, which yielded an abnormal result, was undertaken shortly after he had drunk two cans of Red Bull, a popular energy drink (ED). A second ETT was undertaken 1 week later by the same team without EDs on board and the test result was normal. This case suggests that drinking EDs prior to an ETT could lead to a false positive result and should be discouraged prior to exercise testing.

Wasp sting induced STEMI with complete coronary artery occlusion: a case of Kounis syndrome.

A 45-year-old previously healthy man with minimal coronary artery disease on imaging presented with an acute MI after sustaining a wasp sting following previous non-eventful exposures throughout his life. This is the first case of Kounis syndrome with optical coherence tomography imaging and proven IgE wasp venom hypersensitivity. The Hymenoptera venom is composed of allergenic proteins and vasoactive amines which are responsible for venom toxicity. This patient also has a history of atopy giving a predisposition for developing IgE-mediated allergic reactions. Hymenoptera stings can be severe in atopic individuals and anaphylaxis may ensue. However, it is a rare cause of myocardial infarction (MI) (Kounis syndrome). Multiple wasp stings in the past may have contributed to sensitisation. Kounis syndrome is a rare clinical manifestation which should remain in the minds of physicians, especially with younger patients with no history of ischaemic heart disease or few risk factors.

Cost-effective strategies to screen for left ventricular systolic dysfunction in the community--a concept.

Early detection of heart failure caused by left ventricular systolic dysfunction (LVSD) is important, since early treatment has been shown to retard the progression of heart failure. While traditional echocardiography remains the standard for the detection of LVSD, electrocardiography and serum brain natriuretic peptide have also been shown to predict LVSD. Recently, hand-held echocardiography systems have been shown to have high predictive accuracy for assessment of LVSD. With the availability of the above bedside and relatively less-costly techniques, compared with traditional echocardiography, the major question now is what is the most cost-effective strategy for screening subjects for LVSD. To date, no studies have systematically addressed this issue, but preliminary data are becoming available. This review article discusses the pros and cons of various investigative strategies and likely cost-effectiveness of each strategy to screen for LVSD.

The non-invasive assessment of hibernating myocardium in ischaemic cardiomyopathy--a myriad of techniques.

Heart failure is placing an ever-increasing burden on society. Many subjects with heart failure and underlying coronary artery disease have a significant amount of akinetic but viable myocardium that is able to contract should myocardial perfusion improve (hibernating myocardium). Non-randomised studies have shown prognostic benefit in subjects with hibernating myocardium undergoing revascularisation. Several non-invasive techniques have been developed to assess the presence or absence of hibernating myocardium. This review will examine the epidemiology and underlying pathogenesis of hibernating myocardium; evaluate the non-invasive techniques for diagnosing hibernating myocardium, and look at therapeutic intervention in subjects with hibernating myocardium.

Community screening for left ventricular hypertrophy in patients with hypertension using hand-held echocardiography.

Left ventricular (LV) hypertrophy (LVH) confers increased cardiovascular risk on patients with hypertension. Echocardiography using new hand-held devices might allow community-based cost-effective screening for LVH in a targeted hypertensive population. Thus, the aim of this study was to test the validity of hand-held ultrasound devices to screen for LVH in the community. Accordingly, 189 patients with hypertension attending a community-based heart failure screening program underwent echocardiography by both hand-held and standard devices by an experienced echocardiographer. LVH was defined as LV mass index >/=134 g.m(-2) for men and >/=110 g.m(-2) for women using the Devereux-modified American Society of Echocardiography cube equation. No significant differences were noted between the 2 devices in the measurement of LV wall thickness or LV mass index. Agreement for estimation of LVH between the 2 devices was 86% (kappa = 0.63). The sensitivity, specificity, and positive and negative predictive values of the hand-held device for predicting LVH were 72%, 91%, 73%, and 90%, respectively. Thus, hand-held echocardiography devices accurately assessed LVH and may be used for community-based screening for LVH in targeted patients with hypertension.

What is the most cost-effective strategy to screen for left ventricular systolic dysfunction: natriuretic peptides, the electrocardiogram, hand-held echocardiography, traditional echocardiography, or their combination?

AIMS: To assess the screening characteristics and cost-effectiveness of screening for left ventricular systolic dysfunction (LVSD) in community subjects. METHODS AND RESULTS: A total of 1392 members of the general public and 928 higher risk subjects were randomly selected from seven community practices. Attending subjects underwent an ECG, N-terminal pro-brain natriuretic peptide (NTproBNP) serum levels, and traditional echocardiography (TE). A total of 533 consecutive subjects underwent hand-held echocardiography (HE). The screening characteristics and cost-effectiveness (cost per case of LVSD diagnosed) of eight strategies to predict LVSD (LVSD <45% on TE) were compared. A total of 1205 subjects attended. Ninety six per cent of subjects with LVSD in the general population had identifiable risk factors. All screening strategies gave excellent negative predictive value. Screening high-risk subjects was most cost-effective, screening low-risk subjects least cost-effective. TE screening was the least cost-effective strategy. NTproBNP screening gave similar cost savings to ECG screening; HE screening greater cost-savings, and HE screening following NTproBNP or ECG pre-screening the greatest cost-savings, costing approximately 650 Euros per case of LVSD diagnosed in high-risk subjects (63% cost-savings vs.TE). CONCLUSION: Thus several different modalities allow cost-effective community-based screening for LVSD, especially in high-risk subjects. Such programmes would be cost-effective and miss few cases of LVSD in the community.

What is the normal range for N-terminal pro-brain natriuretic peptide? How well does this normal range screen for cardiovascular disease?

AIMS: To define the N-terminal pro-brain natriuretic peptide (NTpBNP) normal range, assessing its cardiovascular screening characteristics in general population and higher risk subjects. METHODS AND RESULTS: A total of 2320 subjects (1392 general population and 928 high-risk) > or =45 years old, selected randomly from seven community practices, were invited to undergo clinical assessment and echocardiography and to assess NTpBNP serum levels. Of these, 1205 attended. The NTpBNP normal range was calculated and its cardiovascular screening characteristics were assessed. Age (P<0.0001) and female gender (P<0.0001) independently predicted NTpBNP levels in normal subjects. In the general population, age- and gender-stratified normal NTpBNP levels gave a negative-predictive value (NPV) of 99% in excluding left ventricular systolic dysfunction, atrial fibrillation, and valvular heart disease, and a positive predictive value of 56% in detecting any cardiovascular disease assessed. In high-risk subjects, these values were 98 and 62%, respectively. Ninety-five per cent of subjects with NTpBNP levels over four times the normal had significant cardiovascular disease with the others having renal dysfunction. CONCLUSION: Normal NTpBNP levels should be stratified by age and gender. Normal NTpBNP levels give high NPV in excluding significant cardiovascular disease. Most subjects with raised NTpBNP levels and almost all subjects with NTpBNP levels over four times the normal have significant cardiovascular disease.