Annette Maznyczka

Obesity and cardiovascular outcomes: a review

The prevalence of obesity is increasing at an epidemic rate globally with more than 1 billion adults overweight and at least 300 million of them clinically obese. This is expected to rise further in the next 20 to 30 years. Obesity is known to be an independent risk factor for serious health conditions, including hypertension, type 2 diabetes, and cardiovascular diseases. Given the association of obesity with cardiovascular disease, it could be speculated that obese individuals would have adverse outcomes after a cardiovascular event compared to those with normal body mass index (BMI). However, various studies have reported a paradoxical U-shaped relationship between obesity and mortality from various diseases, including myocardial infarction and heart failure, suggesting that patients with higher BMI have similar or lower short- and long-term mortality rates. This phenomenon has been termed the ‘obesity paradox’ or ‘reverse epidemiology’. The goal of this review is to evaluate the potential mechanisms behind the obesity paradox and its implications.

Arachidonate 5-lipoxygenase (5-LO) promoter genotype and risk of myocardial infarction: A case-control study

BACKGROUND Leukotrienes are inflammatory mediators derived from arachidonic acid via the 5-lipoxygenase pathway. Both experimental and clinical studies implicate the 5-lipoxygenase pathway in the pathophysiology of atherosclerosis. In a previous study, a microsatellite polymorphism in the 5-lipoxygenase gene promoter involving the binding site for the transcription factor Sp1, was associated with carotid intima media thickness (CIMT). Compared to subjects carrying the common allele, subjects carrying two variant alleles had significantly greater CIMT. Elevated CIMT is a risk factor for coronary events. In this study we investigated whether carriage of two variants alleles for the 5-lipoxygenase promoter polymorphism is associated with increased risk of myocardial infarction (MI). METHODS 1464 subjects, comprising 746 MI cases (under 65 years of age) and 718 controls, were genotyped for the 5-lipoxygenase microsatellite polymorphism by PCR amplification of the promoter region and allele discrimination by capillary electrophoresis. RESULTS The distribution of subjects grouped into those homozygote for the common allele, subjects carrying one variant allele, and subjects carrying two variant alleles was similar in cases and controls (cases: 66.9%/29.8%/3.3%, controls: 66.0%/29.4%/4.6%, p=0.48). The odds ratio for MI for subjects carrying two variant alleles compared to subjects carrying at least one common allele was 0.72 (95% CI: 0.42-1.22, p=0.22). The odds ratio was not affected by adjustment for other demographic risk factors. CONCLUSIONS Despite their association with a marker of atherosclerosis, variant 5-lipoxygenase promoter genotypes are not a major risk factor for MI, at least in Caucasian subjects of Northern European origin.

Leukotriene B4 production in healthy subjects carrying variants of the arachidonate 5-lipoxygenase-activating protein gene associated with a risk of myocardial infarction

Leukotrienes are implicated in the pathogenesis of coronary artery disease. Recently two haplotypes (HapA and HapB) in the gene encoding ALOX5AP (arachidonate 5-lipoxygenase-activating protein), the main regulator of 5-lipoxygenase, have been associated with a doubling of the risk of myocardial infarction. Studies have also shown that treatment with a leukotriene inhibitor reduces biomarkers of coronary risk in patients carrying HapA, raising the possibility of developing genotype-specific therapy. In the present study, we examined whether carriage of HapA or HapB is associated with increased LTB(4) (leukotriene B(4)) production in healthy subjects. Age- and gender-matched healthy HapA carriers (n=21), HapB carriers (n=20) and non-A/non-B carriers (n=18), with no reported history of cardiovascular disease, were recruited following DNA screening of 1268 subjects from a population-based study. Blood neutrophils were isolated, and LTB(4) production was measured in response to stimulation with 1 mumol/l of the calcium ionophore A23187. There was no difference in the mean level for LTB(4) production in the three groups (non-A/non-B, 24.9+/-8.3 ng/10(6) cells; HapA, 22.2+/-11.9 ng/10(6) cells; HapB, 19.8+/-4.8 ng/10(6); P=0.14). The findings indicate that if either the HapA or the HapB haplotype of ALOX5AP indeed increases cardiovascular risk, then the mechanism is not simply due to a systematically observable effect of the haplotype on LTB(4) production in response to stimulation. The results suggest that knowledge of a patients haplotype may not provide useful information on the probable clinical response to ALOX5AP inhibitors.

Therapeutic hypothermia in patients with out-of-hospital arrest

Therapeutic hypothermia (TH) is increasingly used in patients presenting with out-of-hospital cardiac arrest (OHCA). Such strategies derive from data that suggest TH may improve survival and attenuate adverse neurological outcomes associated with the cardiac arrest. Consequently, TH has been integrated into various guidelines for the management of OHCA and has become a focussed strategy, particularly in patients with ST-segment elevation myocardial infarction. However, there remains uncertainty over the true impact of TH. In patients with OHCA due to asystole or pulseless electrical activity, overall available evidence suggests that TH does not improve neurological outcomes and survival. While in patients with OHCA due to ventricular fibrillation or ventricular tachycardia, observational studies and small, randomised studies have suggested there may be survival benefits and improved neurological recovery. However, even here, trial data robustness has been questioned, with ongoing debate regarding the optimum temperature for managing patients with OHCA and optimal timing of its initiation. More uniform and robust guidelines for the application of TH for patients with OHCA are required, but can only be formulated on appropriately sized robust trials. This review examines the current status of TH.

Distribution of lifespan gain from primary prevention intervention.

Objective When advising patients about possible initiation of primary prevention treatment, clinicians currently do not have information on expected impact on lifespan, nor how much this increment differs between individuals. Methods First, UK cardiovascular and non-cardiovascular mortality data were used to calculate the mean lifespan gain from an intervention (such as a statin) that reduces cardiovascular mortality by 30%. Second, a new method was developed to calculate the probability distribution of lifespan gain. Third, we performed a survey in three UK cities on 11 days between May–June 2014 involving 396 participants (mean age 40 years, 55% male) to assess how individuals evaluate potential benefit from primary prevention therapies. Results Among numerous identical patients, the lifespan gain, from an intervention that reduces cardiovascular mortality by 30%, is concentrated within an unpredictable minority. For example, men aged 50 years with national average cardiovascular risk have mean lifespan gain of 7 months. However, 93% of these identical individuals gain no lifespan, while the remaining 7% gain a mean of 99 months. Many survey respondents preferred a chance of large lifespan gain to the equivalent life expectancy gain given as certainty. Indeed, 33% preferred a 2% probability of 10 years to fivefold more gain, expressed as certainty of 1 year. Conclusions People who gain lifespan from preventative therapy gain far more than the average for their risk stratum, even if perfectly defined. This may be important in patient decision-making. Looking beyond mortality reduction alone from preventative therapy, the benefits are likely to be even larger.

A propensity matched comparison of return to work and quality of life after stenting or coronary artery bypass surgery

Objectives We sought to determine (1) return to work (RTW) rates, (2) long-term employment (>12 months postprocedure), (3) time taken to RTW, and (4) quality of life (QoL), in patients treated with percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Methods Questionnaires regarding RTW were sent to 689 PCI and 169 CABG patients who underwent PCI or CABG at University Hospitals of Leicester Trust, UK, from May 2012 to May 2013. QoL was also measured using the European QoL 5-dimensions questionnaire (EQ-5D). Responses from patients employed preprocedure were analysed using multivariate logistic regression. Propensity score-matching was further used to compare similar patient populations receiving PCI or CABG. Results The response rate was 38% (235 PCI and 88 CABG patients). 241 respondents (75%) were employed preprocedure. Of these 162 (93%) PCI and 51 (77%) CABG patients returned to work, whereas 147 (85%) PCI and 41 (62%) CABG patients were still employed at >12 months postprocedure. After propensity analysis, there was no significant difference between PCI and CABG patients in RTW, long-term employment, nor QoL. The median time taken to RTW was 6 weeks after PCI and 13 weeks after CABG (p=0.001). The effect remained significant after multivariate analysis (p=0.001) and propensity analysis (p=0.001). Conclusions In this first propensity score-matched study comparing RTW and QoL after PCI or CABG strict propensity matching indicates that RTW or QoL, is similar for PCI or CABG, albeit the number of matched pairs was small. There are differences, however, in delay in RTW.

Discontinuation of metformin in the setting of coronary angiography: clinical uncertainty amongst physicians reflecting a poor evidence base.

AIMS Metformin is widely prescribed for the treatment of type 2 diabetes mellitus and is associated with a reduction in diabetes-induced cardiovascular morbidity and mortality. Concerns about metformin-associated lactic acidosis (M-ALA) in patients undergoing contrast-based angiographic procedures have led to the development and publication of a number of guidelines to improve the management of this patient cohort. METHODS AND RESULTS This review focuses on the evidence behind these guidelines and, in particular, that concerning metformin discontinuation in diabetic patients undergoing coronary angiography and percutaneous intervention. This review addresses and compares guideline-directed management of such patients and includes the results of a UK physician survey to highlight variations in clinical practice. CONCLUSIONS We conclude that evidence for M-ALA in diabetics on metformin undergoing coronary intervention is lacking and existing guidance on the management of such patients is inconsistent. More robust evidence is needed in the form of a large, adequately-sized randomised trial or extensive registry so that we can optimally manage those patients requiring contrast-based coronary interventions who are also taking metformin.

Outcomes following primary percutaneous coronary intervention in the setting of cardiac arrest: A registry database study

Background: The mortality rate among patients undergoing primary percutaneous coronary intervention (PPCI) in the setting of cardiac arrest (CA) and whether the location where the patient sustains CA influences the outcome is not known in the contemporary era. Methods: Prospectively collected data at a tertiary cardiac centre on all patients undergoing PPCI for ST elevation myocardial infarction (STEMI) in the setting of CA was analysed. Results: In total, 484/4118 (11.8%) patients sustained CA during the study period. Of these, 91/484 (18.8%) sustained CA prior to ambulance arrival, the remainder occurred either after ambulance arrival or in hospital. The overall in-hospital mortality was 20.5% in this cohort. Those sustaining CA before ambulance arrival experienced the highest unadjusted mortality compared to those that had CA after ambulance arrival, in hospital and in the catheterisation laboratory (29.7% versus 12.0%, 16.1% and 23.8% respectively, p=0.03). Multiple logistic regression analysis showed that the following parameters are independent predictors of in-hospital mortality: age (odds ratio (OR) for each year increment of age 1.05; 95% confidence interval (CI) 1.02–1.08, p=0.0009); female gender (OR 2.42; 95% CI 1.17–4.99, p=0.0173); previous PCI (OR 7.59; 95% CI 1.72–33.53, p=0.0075); asystole/ electromechanical dissociation (EMD) (OR 13.43; 95% CI 5.34–33.80, p<0.0001); and patient location at arrest (OR 5.77 for before ambulance arrival; 95% CI 2.55–13.07, p<0.0001). Conclusions: In conclusion, in-hospital mortality remains high among patients undergoing PPCI in the context of CA, particularly among those that arrest prior to ambulance arrival.

Troponins and other biomarkers in the early diagnosis of acute myocardial infarction.

Chest pain is a common presenting symptom; however, the majority of emergency chest pain admissions are not due to acute myocardial infarction (AMI). AMI can be life threatening and early diagnosis or rule out of AMI might potentially improve morbidity and mortality, as well as reduce time to decision and therefore overall treatment costs. High-sensitivity troponin (hs-troponin) assays have been developed that enable precise quantification of extremely low troponin concentrations. Such hs-troponin assays are recommended in early rule-out protocols for AMI, when measured at presentation and again at 3–6 h. However, troponin is less than ideally suited for early diagnosis of acute myocardial injury because of its slow rise, late peak and low specificity for coronary plaque rupture. A new biomarker with a more rapid elevation to peak concentration than hs-troponin and lower background levels in patients with chronic cardiovascular conditions would be a preferred diagnostic test. This review discusses the development of hs-troponin assays and other biomarkers, evaluates their place in the early diagnosis of AMI, discusses troponin elevation without AMI and discusses current guideline recommendations.

The ischaemic constellation: an alternative to the ischaemic cascade—implications for the validation of new ischaemic tests

The ischaemic cascade is the concept that progressive myocardial oxygen supply–demand mismatch causes a consistent sequence of events, starting with metabolic alterations and followed sequentially by myocardial perfusion abnormalities, wall motion abnormalities, ECG changes, and angina. This concept would suggest that investigations that detect expressions of ischaemia earlier in the cascade should be more sensitive tests of ischaemia than those that detect expressions appearing later in the cascade. However, careful review of the studies on which the ischaemic cascade is based suggests that the ischaemic cascade concept may be less well supported by the literature than assumed. In this review we explore this, discuss an alternative method for conceptualising ischaemia, and discuss the potential implications of this new approach to clinical studies and clinical practice.