Catherine McGorrian

Antithrombotic Therapy in Peripheral Artery Disease

BACKGROUND This guideline focuses on antithrombotic drug therapies for primary and secondary prevention of cardiovascular disease as well as for the relief of lower-extremity symptoms and critical ischemia in persons with peripheral arterial disease (PAD). METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS The most important of our 20 recommendations are as follows. In patients aged ≥ 50 years with asymptomatic PAD or asymptomatic carotid stenosis, we suggest aspirin (75-100 mg/d) over no therapy (Grade 2B) for the primary prevention of cardiovascular events. For secondary prevention of cardiovascular disease in patients with symptomatic PAD (including patients before and after peripheral arterial bypass surgery or percutaneous transluminal angioplasty), we recommend long-term aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 1A). We recommend against the use of warfarin plus aspirin in patients with symptomatic PAD (Grade 1B). For patients undergoing peripheral artery percutaneous transluminal angioplasty with stenting, we suggest single rather than dual antiplatelet therapy (Grade 2C). For patients with refractory claudication despite exercise therapy and smoking cessation, we suggest addition of cilostazol (100 mg bid) to aspirin (75-100 mg/d) or clopidogrel (75 mg/d) (Grade 2C). In patients with critical limb ischemia and rest pain unable to undergo revascularization, we suggest the use of prostanoids (Grade 2C). In patients with acute limb ischemia due to acute thrombosis or embolism, we recommend surgery over peripheral arterial thrombolysis (Grade 1B). CONCLUSIONS Recommendations continue to favor single antiplatelet therapy for primary and secondary prevention of cardiovascular events in most patients with asymptomatic PAD, symptomatic PAD, and asymptomatic carotid stenosis. Additional therapies for relief of limb symptoms should be considered only after exercise therapy, smoking cessation, and evaluation for peripheral artery revascularization.

Estimating modifiable coronary heart disease risk in multiple regions of the world: the INTERHEART Modifiable Risk Score

AIMS Summating risk factor burden is a useful approach in the assessment of cardiovascular risk among apparently healthy individuals. We aimed to derive and validate a new score for myocardial infarction (MI) risk using modifiable risk factors, derived from the INTERHEART case-control study (n = 19 470). METHODS AND RESULTS Multiple logistic regression was used to create the INTERHEART Modifiable Risk Score (IHMRS). Internal validation was performed using split-sample methods. External validation was performed in an international prospective cohort study. A risk model including apolipoproteins, smoking, second-hand smoke exposure, hypertension, and diabetes was developed. Addition of further modifiable risk factors did not improve score discrimination in an external cohort. Split-sample validation studies showed an area under the receiver-operating characteristic (ROC) curve c-statistic of 0.71 [95% confidence interval (CI): 0.70, 0.72]. The IHMRS was positively associated with incident MI in a large cohort of people at low risk for cardiovascular disease [12% increase in MI risk (95% CI: 8, 16%) with a 1-point increase in score] and showed appropriate discrimination in this cohort (ROC c-statistic 0.69, 95% CI: 0.64, 0.74). Results were consistent across ethnic groups and geographic regions. A non-laboratory-based score is also supplied. CONCLUSIONS Using multiple modifiable risk factors from the INTERHEART case-control study, we have developed and validated a simple score for MI risk which is applicable to an international population.

Sudden cardiac death in 14- to 35-year olds in Ireland from 2005 to 2007: a retrospective registry.

INTRODUCTION Sudden cardiac death (SCD) in young people is a rare but devastating event for families and communities. Ireland has previously had no measure of the incidence of SCD in young people. We report the incidence and causes of SCD in persons <35 years of age. METHODS AND RESULTS We undertook a retrospective study of SCD between 2005 and 2007 in persons aged 15-35 years in the Republic of Ireland. We identified potential cases of out of hospital SCD through the Central Statistics Office (CSO) death certificate records. Autopsy, toxicology, and inquest reports were then obtained and analysed by an expert panel who adjudicated on the cause of death. A total of 342 potential SCD cases were identified through the CSO. Fifty were younger than 15 years of age, and 86 had either incomplete or unavailable post-mortem reports. Of 206 full reports obtained, 116 were adjudicated as cases of SCD. Cases were predominantly male (75%), with a mean age of 25.8 years (standard deviation 6.3). The incidence of SCD in this age range was 2.85 per 100,000 person-years (4.36 for males and 1.30 for females) and the incidence of sudden arrhythmic death syndrome (SADS) was 0.76 per 100,000 person-years. The commonest causes were SADS, 26.7% (31 of 116), followed by coronary artery disease, 20.7% (24 of 116), hypertrophic cardiomyopathy (HCM), 14.7% (17 of 116), and idiopathic left ventricular hypertrophy not fulfilling criteria for HCM, 10.3% (12 of 116). CONCLUSIONS The incidence of SCD in the young in Ireland was 4.96 (95% CI 3.06, 6.4) for males and 1.3 (95% CI 0.62, 2.56) for females per 100 000 person-years. Sudden arrhythmic death syndrome was the commonest cause of SCD in the young, and the incidence of SADS was more than five times that in official reports of the Irish CSO.

A global perspective on psychosocial risk factors for cardiovascular disease.

Worldwide, there is variation in the incidence CVD with the greater burden being borne by low and middle-income countries. Traditional risk factors do not fully explain the CVD risk in populations, and there is increasing awareness of the impact the social environment and psychological factors have on CVD incidence and outcomes. The measurement of psychosocial variables is uniquely complex as variables are difficult to define objectively and local understanding of psychosocial risk factors may be subject to cultural influences. Notwithstanding this, there is a growing evidence base for the independent role they play in the pathogenesis of CVD. Consistent associations have been seen for general psychological stress, work-related stress, locus of control and depression with CVD risk. Despite the strength of this association the results from behavioural and pharmacological interventions have not clearly resulted in improved outcomes.

Cardiovascular risk age: concepts and practicalities

Objectives A young person with many risk factors may have the same level of risk as an older person with no risk factors. Thus a high-risk 40-year-old may have a risk age of 60 years or more. The aim of the study was to derive a generic equation for risk age, construct risk age charts, and explore the hypothesis that risk age is similar regardless of the cardiovascular disease (CVD) end point used. Methods The equation was generated by equating the generic formula for 10-year CVD risk (with unknown risk factor levels) to the generic formula for 10-year CVD risk in a person with age = x and ideal risk factor levels (total cholesterol 4 mmol/l, systolic blood pressure 120 mm Hg, and non-smoker) and solving for x. To examine the consistency between risk ages for different end points, a risk age based on risk of CVD fatal events and based on risk of fatal and non-fatal CVD events was derived for each of the participants in the FINRISK population study. The correlation between these risk ages was examined. Results A generic equation for risk age was derived. The generic equation could not be used for SCORE (Systematic COronary Risk Evaluation), because the age is included in the baseline. Therefore a table of SCORE risk ages was developed by looking up the risk age corresponding to each combination of risk factors in the chart. Risk age remains similar regardless of the cardiovascular end point used, which bypasses the dilemma of whether to use a risk-estimation system based on CVD mortality or on the more attractive but less reliable end point of total CVD events. On the basis of the equation, risk age is not dependent on baseline survival and therefore recalibration is not required. Conclusions Risk age is an intuitive and easily understood method for communicating about risk, particularly in younger patients, and may facilitate lifestyle change in younger patients. However, treatment decisions should be based on absolute risk, as recommended by guidelines on CVD prevention.

Family-based associations in measures of psychological distress and quality of life in a cardiac screening clinic for inheritable cardiac diseases: a cross-sectional study

BackgroundFamily-based cardiac screening programmes for persons at risk for genetic cardiac diseases are now recommended. However, the psychological wellbeing and health related quality of life (QoL) of such screened patients is poorly understood, especially in younger patients. We sought to examine wellbeing and QoL in a representative group of adults aged 16 and over in a dedicated family cardiac screening clinic.MethodsProspective survey of consecutive consenting patients attending a cardiac screening clinic, over a 12 month period. Data were collected using two health measurement tools: the Short Form 12 (version 2) and the Hospital Anxiety and Depression Scale (HADS), along with baseline demographic and screening visit-related data. The HADS and SF-12v.2 outcomes were compared by age group. Associations with a higher HADS score were examined using logistic regression, with multi-level modelling used to account for the family-based structure of the data.ResultsThere was a study response rate of 86.6%, with n=334 patients providing valid HADS data (valid response rate 79.5%), and data on n=316 retained for analysis. One-fifth of patients were aged under 25 (n=61). Younger patients were less likely than older to describe significant depression on their HADS scale (p<0.0001), although there were overall no difference between the prevalence of a significant HADS score between the younger and older age groups (18.0% vs 20.0%, p=0.73). Significant positive associates of a higher HADS score were having lower educational attainment, being single or separated, and being closely related to the family proband. Between-family variance in anxiety and depression scores was greater than within-family variance.ConclusionsHigh levels of anxiety were seen amongst patients attending a family-based cardiac screening clinic.Younger patients also had high rates of clinically significant anxiety. Higher levels of anxiety and depression tends to run in families, and this has implications for family screening and intervention programmes.

Increased incidence of QT interval prolongation in a population receiving lower doses of methadone maintenance therapy.

AIMS The aim of this study was to investigate the frequency of corrected QT interval (QTc) prolongation in a methadone maintenance therapy (MMT) population, and to examine potential associations between this QTc interval and methadone dose as well as concurrent use of opiates, cocaine and benzodiazepines. DESIGN Cross-sectional study of patients attending a specialist drug treatment clinic from July 2008 to January 2009. SETTING Single-centre inner-city specialist drug treatment clinic, Ireland. PARTICIPANTS A total of 180 patients on stable MMT attending for daily methadone doses, over a 6-month period, where a total of 376 patients were attending during the study period. MEASUREMENTS All patients agreeing to participate in the study underwent 12-lead electrocardiograms and QTc analysis, as well as analysis of urine toxicology screen results for opiates, benzodiazepines and cocaine. ECGs were carried out prior to methadone dose being received, regardless of time of day (trough ECG). FINDINGS The average age was 32.6 ± 7.1 years, with mean [standard deviation (SD)] methadone dose 80.4 ± 27.5 mg. The mean (SD) QTc was 420.9 ± 21.1 ms, range 368-495 ms. Patients who had a positive toxicology screen for opiates were receiving significantly lower doses of methadone (77.8 ± 23.5 mg versus 85.0 ± 21.4 mg, P = 0.04). No significant association was noted between QTc interval prolongation and presence of cocaine metabolites in the urine (P = 0.13) or methadone dose (P = 0.33). 8.8% of patients had evidence of prolonged QTc interval (8.3% male QTc ≥ 450 ms and 0.5% female QTc ≥ 470 ms), with 11.1% (n = 20) having QTc intervals > 450 ms. CONCLUSIONS Drug-induced corrected QT interval prolongation is evident (ranging from 8.8-11.1%, depending on definition applied) in patients receiving relatively low daily doses of methadone therapy, with no evidence of a dose-response relationship. The presence of cocaine metabolites in urine does not appear to be associated with increased corrected QT interval. Increased awareness of cardiac safety guidelines, including relevant clinical and family history, baseline and trough dose ECG monitoring, should be incorporated into methadone maintenance therapy protocols.

Family-based cardiac screening in relatives of victims of sudden arrhythmic death syndrome

AIMS Sudden arrhythmic death syndrome (SADS) occurs when a person suffers a sudden, unexpected death, with no cause found at postmortem examination. We aimed to describe the cardiac screening outcomes in a population of relatives of SADS victims METHODS AND RESULTS Prospective and retrospective cohort study of consecutive families attending the Family Heart Screening clinic at the Mater Misericordiae Hospital in Dublin, Ireland, from January 2007 to September 2011. Family members of SADS victims underwent a standard screening protocol. Adjunct clinical and postmortem information was sought on the proband. Families who had an existing diagnosis, or where the proband had epilepsy, were excluded. Of 115 families identified, 73 were found to fit inclusion criteria and were retained for analysis, with data available on 262 relatives. Over half of the screened family members were female, and the mean age was 38.6 years (standard deviation 15.6). In 22 of 73 families (30%), and 36 of 262 family members (13.7%), a potentially inheritable cause of SADS was detected. Of the population screened, 32 patients (12.2%) were treated with medication, and 5 (1.9%) have received implantable cardiac defibrillators. Of the five families with long QT syndrome (LQTS) who had a pathogenic gene mutation identified, three carried two such mutations. CONCLUSION In keeping with international estimates, 30% of families of SADS victims were found to have a potentially inherited cardiac disease. The most common positive finding was LQTS. Advances in postmortem standards and genetic studies may assist in achieving more diagnoses in these families.

Getting to the heart of cardiac remodeling; how collagen subtypes may contribute to phenotype

The objective of this study was to investigate the nature and biomechanical properties of collagen fibers within the human myocardium. Targeting cardiac interstitial abnormalities will likely become a major focus of future preventative strategies with regard to the management of cardiac dysfunction. Current knowledge regarding the component structures of myocardial collagen networks is limited, further delineation of which will require application of more innovative technologies. We applied a novel methodology involving combined confocal laser scanning and atomic force microscopy to investigate myocardial collagen within ex-vivo right atrial tissue from 10 patients undergoing elective coronary bypass surgery. Immuno-fluorescent co-staining revealed discrete collagen I and III fibers. During single fiber deformation, overall median values of stiffness recorded in collagen III were 37±16% lower than in collagen I [p<0.001]. On fiber retraction, collagen I exhibited greater degrees of elastic recoil [p<0.001; relative percentage increase in elastic recoil 7±3%] and less energy dissipation than collagen III [p<0.001; relative percentage increase in work recovered 7±2%]. In atrial biopsies taken from patients in permanent atrial fibrillation (n=5) versus sinus rhythm (n=5), stiffness of both collagen fiber subtypes was augmented (p<0.008). Myocardial fibrillar collagen fibers organize in a discrete manner and possess distinct biomechanical differences; specifically, collagen I fibers exhibit relatively higher stiffness, contrasting with higher susceptibility to plastic deformation and less energy efficiency on deformation with collagen III fibers. Augmented stiffness of both collagen fiber subtypes in tissue samples from patients with atrial fibrillation compared to those in sinus rhythm are consistent with recent published findings of increased collagen cross-linking in this setting.

NAA10 mutation causing a novel intellectual disability syndrome with Long QT due to N-terminal acetyltransferase impairment

We report two brothers from a non-consanguineous Irish family presenting with a novel syndrome characterised by intellectual disability, facial dysmorphism, scoliosis and long QT. Their mother has a milder phenotype including long QT. X-linked inheritance was suspected. Whole exome sequencing identified a novel missense variant (c.128 A > C; p.Tyr43Ser) in NAA10 (X chromosome) as the cause of the family’s disorder. Sanger sequencing confirmed that the mutation arose de novo in the carrier mother. NAA10 encodes the catalytic subunit of the major human N-terminal acetylation complex NatA. In vitro assays for the p.Tyr43Ser mutant enzyme showed a significant decrease in catalytic activity and reduced stability compared to wild-type Naa10 protein. NAA10 has previously been associated with Ogden syndrome, Lenz microphthalmia syndrome and non-syndromic developmental delay. Our findings expand the clinical spectrum of NAA10 and suggest that the proposed correlation between mutant Naa10 enzyme activity and phenotype severity is more complex than anticipated; the p.Tyr43Ser mutant enzyme has less catalytic activity than the p.Ser37Pro mutant associated with lethal Ogden syndrome but results in a milder phenotype. Importantly, we highlight the need for cardiac assessment in males and females with NAA10 variants as both patients and carriers can have long QT.