Over the last three decades a large body of research has investigated the link between emotional distress and myocardial ischaemia; mental stress-induced myocardial ischaemia (MSIMI) is associated with an increased risk of cardiovascular events and death. Recent studies on selective serotonin reuptake inhibitors (SSRIs) has show that they may reduce the mental stress-induced haemodynamic response, metabolic risk factors, and platelet activity. The REMIT (Responses of Mental Stress Induced Myocardial Ischaemia to Escitalopram Treatment) trial aimed to investigate whether SSRI treatment could improve MSIMI.

The study was a randomised, double-blind, placebo-controlled trial that took place between 2007 and 2001 at a tertiary medical centre. Patients with clinically stable coronary heart disease and laboratory diagnosed MSIMI were randomised to receive escitalopram or placebo over 6 weeks. The main outcome measure was the occurrence of MSIMI, defined as the development of regional wall motion abnormality, a reduction in left ventricular ejection fraction of 8% or more, and/or significant ST depression during mental stressor tasks.

56 patients in the escitalopram and placebo groups completed end point assessments. At the end of 6 weeks, more patients taking escitalopram had absence of MSIMI during mental stressor tasks (34.3% vs. 17.5%, odds ratio 2.62). Although rates of exercise-induced ischaemia were also slightly lower at 6 weeks in the escitalopram group, this difference was not statistically significant (P=.56).

Conclusions:

In patients with stable coronary artery disease and mental stress-induced myocardial ischaemia, 6 weeks of escitalopram treatment resulted in lower rates of stress-induced ischaemia when compared with placebo, however no significant difference in exercise-induced ischaemia was seen.

• Jiang W, Velazquez EJ, Kuchibhatla M et al. Effect of Escitalopram on Mental Stress-Induced Myocardial Ischemia. JAMA 2013;309:2139-2149.

Polyunsaturated fatty acids derived from fish oils have been shown to confer benefit following myocardial infarction, and in patients with heart failure. They are thought to be pleiotropic, effecting atherosclerosis, inflammation, thrombosis and arrythmogenesis with a minimal side effect profile. However, the role of these potentially attractive drugs in primary prevention remains unknown.

In this double-blind, placebo-controlled primary care based clinical trial, 12,513 patients with multiple cardiovascular risk factors or atherosclerotic vascular disease who had not had a myocardial infarction were recruited and randomly assigned in a 1:1 ratio to n-3 fatty acids (1 g daily) or placebo (olive oil) and followed for a median of 5 years. The initially specified primary end point was the cumulative rate of death, nonfatal myocardial infarction, and nonfatal stroke. At 1 year, after the event rate was found to be lower than anticipated, the primary end point was revised as time to death from cardiovascular causes or admission to the hospital for cardiovascular causes. The results demonstrated no benefit for the intervention group with the primary end point occurring in 733 (11.7%) of those assigned to n-3 fatty acids and 745 (11.9%) of those receiving placebo (adjusted HR, 0.97; 95% CI, 0.88 to 1.08; P=0.58). The same results were observed for all the secondary endpoints.

Conclusion:

In a large, prospective, double-blind study of patients with multiple cardiovascular risk factors, primary prevention by daily treatment with n-3 fatty acids did not reduce cardiovascular mortality and morbidity.

• Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi V, Longoni P, Marzona I, Milani V, Silletta MG, Tognoni G, Marchioli R. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013 May 9;368(19):1800-8.

Over 1.6 million pacing or cardioverter defibrillator (ICD) devices are implanted worldwide annually and up to 1/3 of this cohort have an indication for long-term anticoagulation therapy. Current guidelines suggest discontinuing the oral anticoagulant and initiating bridging therapy with heparin but this strategy is associated with increased costs, a short but high risk period of normal coagulability, and of itself is associated with a pocket haematoma rate of between 20 to 30%. Small case series have suggested that it may be safe to perform surgery without interrupting warfarin treatment but thus far no adequately powered prospective trial has reported on this strategy.

In the BRUISE-CONTROL study, 681 patients taking warfarin and requiring device implantation were randomly assigned in a 1:1 ratio to continued warfarin treatment or to bridging therapy with heparin. The primary outcome was clinically significant device-pocket haematoma, which was defined as device-pocket haematoma that necessitated prolonged hospitalization, interruption of anticoagulation therapy, or further surgery. The trial was terminated early after a prespecified interim analysis, which strongly favoured continuation of warfarin therapy. Clinically significant pocket haematoma occurred in 12 of 343 patients (3.5%) in the warfarin group, as compared with 54 of 338 (16.0%) in the heparin group (RR, 0.19; 95% CI, 0.10 to 0.36; P<0.001). Major surgical and thromboembolic complications were rare and did not differ significantly between the study groups. They included one episode of cardiac tamponade and one myocardial infarction in the heparin-bridging group and one stroke and one transient ischaemic attack in the warfarin group.

Conclusions:

In this large multi-center prospective study, as compared with bridging therapy with heparin, a strategy of continued warfarin treatment at the time of pacemaker or ICD implantation significantly reduced the incidence of pocket haematomas.

• Birnie DH, Healey JS, Wells GA, Verma A, Tang AS, Krahn AD, Simpson CS, Ayala-Paredes F, Coutu B, Leiria TL, Essebag V. Pacemaker or Defibrillator Surgery without Interruption of Anticoagulation. N Engl J Med. 2013 May 9. [Epub ahead of print]

The use of preoperative beta-blockade to minimise the cardiovascular risks of noncardiac surgery has remained controversial for some time, and recent studies have suggested that preoperative beta-blockade may be now decreasing as a result. The purpose of this study was to determine whether early preoperative exposure to beta-blockers could influence 30-day postoperative outcomes in patients undergoing noncardiac surgery.

This was a retrospective analysis examining 136,745 patients (1:1 matched on propensity scores) who were given beta-blockers on the day of or following major non cardiac surgery. 104 VA hospitals were involved. The main outcome measure was 30-day mortality and cardiac morbidity (cardiac arrest or Q-wave myocardial infarction).

55,138 (40.3%) of patients were exposed to beta-blockers, with those undergoing vascular surgery most likely to receive beta-blockade (66.7% of all patients undergoing vascular surgery). 1.1% of patients died and cardiac morbidity occurred among 0.9% of patients. After the propensity matching, beta-blocker use was associated with lower mortality (relative risk 0.73, P<0.001). When stratified by cumulative numbers of Revised Cardiac Risk Index factors, beta-blocker exposure was associated with significantly lower mortality in patients with 2,3, and 4 risk factors, however this association was limited to patients undergoing nonvascular surgery. A lower rate of cardiac arrest and nonfatal Q-wave infarction was seen in patients given beta-blockers (P<0.001), but this again was limited to non-vascular surgery only.

Conclusions:

Following propensity matching, preoperative beta-blockade was associated with lower rates of 30-day mortality in patients with 2 or more Revised Cardiac Risk Index Factors undergoing non-cardiac, non-vascular surgery.

• London MJ, Hur K, Schwartz GG et al. Association of Perioperative Beta-Blockade With Mortality and Cardiovascular Morbidity Following Major Noncardiac surgery. JAMA 2013;309:1704-1713.

Familial hypercholesterolaemia is characterised by substantially raised plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and is associated with a risk of coronary heart disease that is five to eight times higher than average. One charity has estimated a saving of £378.7 million from cardiovascular events avoided if all relatives of index cases were identified and treated optimally over 55 years of age.

The disease is inherited in an autosomal-dominant fashion and is thought to be monogenic, however no mutations are detected in about 60% of patients with the clinical phenotype who are tested. A proportion of these cases of familial hypercholesterolaemia could be polygenic, due to the inheritance of a greater than average number of common LDL-C-rasing alleles. Identification of those individuals with polygenic hyperlipidaemia could improve the efficacy of a testing programme.

Talmud et al. assembled patients with familial hypercholesterolaemia from three UK sources and compared them with a control sample from the UK Whitehall II (WHII) study. Patients from a Belgian lipid clinic were also studied for validation analysis. Participants were genotyped for 12 common LDL-C-raising alleles and a weighted LDL-C-raising gene score was constructed.

The mean weighted LDL-C gene score of the control (Whitehall) participants (0.90) was strongly associated with LDL-C concentration. Mutation-negative UK patients had a significantly higher mean weighted LDL-C score (1.0) than did WHII controls, as did the mutation negative Belgian patients (0.99). The score was also higher in UK (0.95) and Belgian (0.92) mutation-positive patients when compared to Whitehall study controls.

Conclusions:

A substantial number of patients with familial hypercholesterolaemia have no known mutation, and this study suggests that in these patients the raised LDL-C concentrations have a polygenic cause. This finding may explain the variable penetrance of the disease, and has implications for genetic testing strategies.

• Talmud PJ, Shah S, Whittall R et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study. Lancet 2013;381:1291-1301.

20-30% of patients taking oral anticoagulants also have ischaemic heart disease that requires treatment by percutaneous coronary intervention (PCI), thereby necessitating dual anti-platelet therapy to prevent stent thrombosis. However, the combination of dual anti-platelet therapy (DAP) and anti-coagulants is associated with a high annual risk of fatal and non-fatal bleeding episodes. This study hypothesised that in patients who must continue with oral anti-coagulants, clopidogrel alone would reduce the risk of bleeding – while not increasing the risk of thrombotic events – compared to clopidogrel and aspirin.

The What is the Optimal antiplatElet and anticoagulant therapy in patients with oral anticoagulation and coronary StenTing (WOEST) study was an open-label, randomised, controlled trial carried out at 15 sites in the Netherlands and Belgium between 2008 and 2011. Patients taking oral anti-coagulants and undergoing PCI were assigned to clopidogrel alone, or clopidogrel plus aspirin. The primary outcome measure was any bleeding episode within one year of PCI; analysis was by intention to treat.

Of the 573 patients enrolled in the study, one-year data were available for 279 (98.2%) of patients assigned double therapy (clopidogrel and oral anticoagulant) and for 284 (98.3%) of patients assigned triple therapy (aspirin, clopidogrel, and oral anticoagulant). In patients receiving double therapy, bleeding episodes were noted in only 54 (19.4%) of patients, compared to 126 (44.4%) in patients receiving triple therapy (hazard ration 0.36, p<0.0001). Multiple bleeding episodes were also more common in the triple therapy group (2.2% vs 12.0%), as were blood transfusions (3.9% vs. 9.5%).

Conclusions:

In patients taking oral anticoagulants who underwent PCI, the use of clopidogrel without aspirin was associated with a significant reduction in bleeding complications and no increase in the rate of thrombotic events.

• DeWilde WJM, Oirbans T, Verheugt FWA et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet 2013;381:1107-1115.

Implantable cardioverter-defibrillators (ICDs) are now the standard of care in primary and secondary prevention of malignant arrhythmias, however with their increasing use it has been noted that ICD therapies – both appropriate and inappropriate – are associated with an increased risk of death and worsening of heart failure. The recent Multicenter Automatic Defibrillator Implantation Trial to Reduce Inappropriate Therapy (MADIT-RIT) found that for primary prevention, prolonging the arrhythmia detection interval or setting a high cut-off rate reduced inappropriate therapies.

The purpose of the ADVANCE III (Avoid Delivering Therapies for Nonsustained Arrhythmias in ICD Patients III) trial was to assess whether increasing the number of detection intervals was beneficial in any type of ICD with the capability of delivering antitachycardia pacing (ATP) during capacitor charge, in this case among patients with both primary and secondary indications for an ICD implant. Specifically the trial looked at whether using 30 of 40 intervals to detect ventricular arrythmias, as opposed to standard detection with 18 of 24 intervals, could reduce ATP and shock delivery during spontaneous fast VT episodes.

1902 primary and secondary prevention patients with ischaemic and nonischaemic indications for first ICD implantation were enrolled, and randomised in a single-blind fashion to programming with long- (30 of 40) or standard-detection (18 of 24) intervals. The main outcome measure was the total number of ATPs and shocks delivered for all episodes; inappropriate shocks, mortality, and syncopal rates were secondary outcomes.

Over a median follow-up of 12 months, patients in the long-detection group had 346 delivered therapies compared to 557 in the standard-detection group (P<.001). The long- vs. standard-detection group also had fewer ATPs (23 per 100 person-years vs. 37 per 100 person-years; P<.001), fewer shocks (19 vs. 30; P=.06), and a reduction in the first occurrence of inappropriate shocks. However, mortality (P=.50) and arrhythmic syncope rates (P=.22) did not differ significantly between groups.

Conclusions:

Among patients undergoing first ICD implantation, the use of long- vs standard-detection intervals resulted in lower rates of ATP and shocks. This programming strategy may therefore be a useful alternative approach for ICD recipients.

• Gasparini M, Proclemer A, Klersy C et al. Effect of Long-Detection Interval vs Standard-Detection Interval for Implantable Cardioverter-Defibrillators on Antitachycardia Pacing and Shock Delivery. The ADVANCE III Randomized Clinical Trial. JAMA 2013;309:1903-1911.

Intrauterine fetal death occurs in approximately 1 in every 160 pregnancies; postmortem evaluation often fails to find an underlying cause.  The objective of this paper was to determine the spectrum and prevalence of mutations in the three most common Long QT syndrome (LQTS) susceptible genes in a cohort of cases of unexplained intrauterine death.

Retrospective post-mortem genetic testing was carried out on 91 unexplained intrauterine fetal deaths collected between 2006 and 2012.  Publically available exome databases were assessed for the general population frequency of identified genetic variants.  Mutations analysis was performed by liquid chromatography and DNA sequencing.  Functional analysis of novel mutations was performed using heterologous expression and patch-clamp recording.

The three LQTS missense mutations (KCNQ1,p.A283T; KCNQ1, p.R397W; and KCNH2[1b], p.R25W) were discovered in three intrauterine fetal deaths.  Both KV7.1-A283T (16-week male) and KV7.1- R397W (16-week female) mutations were associated with marked KV7.1 loss-of- function consistent with in utero LQTS type 1, while the HERG1b-R25W mutation (33.2-week male) exhibited a loss of function consistent with in utero LQTS type 2. Furthermore, 5 intrauterine fetal deaths hosted SCN5A rare nonsynonymous genetic variants that conferred in vitro electrophysiological characteristics consistent with potentially pro-arrhythmic phenotypes.

Conclusions:

This analysis found that 3 of 91 unexplained intrauterine deaths were associated with missense LQTS mutations, and genetic variants leading to dysfunctional LQTS-associated ion channels were found in 8 cases.  Although preliminary, these results may provide insights into possible mechanisms of stillbirth.

• Crotti L, Tester DJ, White WM et al.  Long QT Syndrome–Associated Mutations in Intrauterine Fetal Death.  JAMA. 2013;309(14):1473-1482

As life expectancy doubled between 1800 and 2000, atherosclerosis replaced infectious diseases as the main cause of death in the developed world. But is atherosclerosis a purely modern phenomenon, precipitated by lifestyle changes and an ageing population, or was it common in ancient societies too?

Thompson et al. performed whole-body CT scans on 137 mummies from four different geographical areas to look for calcification and therefore atherosclerosis. Atherosclerosis was present in the aorta in 28 (20%) mummies, iliac or femoral arteries in 25 (18%), popliteal or tibial arteries in 25 (18%), carotid arteries in 17 (12%), and coronary arteries in six (4%). Of the five vascular beds examined, atherosclerosis was present in one to two beds in 34 (25%) mummies, in three to four beds in 11 (8%), and in all five vascular beds in two (1%). Of note the age at the time of death was positively correlated with atherosclerosis (mean age at death 43 years for mummies with atherosclerosis vs 32 years for those without; p<0·0001) and with the number of arterial beds involved (p<0·0001).

Conclusions:

This unique study performed CT imaging of mummies from different geographical regions and found that atherosclerosis was common in four ancient populations, and therefore challenges the assumption that it is a largely modern disease.

• Thompson RC, Allam AH, Lombardi GP et al. Atherosclerosis across 4000 years of human history: the Horus study of four ancient populations. Lancet 2013; published online March 10, 2013. http://dx.doi.org/10.1016/ S0140-6736(13)60598-X

In patients with chronic postinfarction heart failure, bone marrow-derived mononuclear cell (BMC) therapy has demonstrated mixed results to date.  One possible reason for this is that cell retention by the heart is more difficult in the stable setting in comparison to therapies given following acute myocardial infarction, however a recent discovery found that extracorporeal application of focused low-energy shock waves can upregulate chemokine expression and improve homing and attachment of cell therapies.  The purpose of this study was to determine whether this new technique could improve left ventricular ejection fraction (LVEF) in patients with chronic heart failure.

CELLWAVE was a radomised, double-blind, placebo-controlled trial.  Patients were given single-blind low-dose (n=42), high-dose (n=40), or placebo (n=21) shock wave pretreatment targeted to the left ventricular anterior wall.    The following day, patients receiving shock wave pretreatment were randomised to then receive a double-blind intracoronary infusion of BMCs or placebo, while patients receiving placebo shock wave therapy received intracoronary infusion of BMCs.  The primary endpoint was a change in LVEF from baseline to four months, and secondary endpoints included regional left ventricular function assessed by MRI, and clinical events.

In patients who received shock wave treatment followed by BMCs, the primary endpoint was significantly improved (absolute change in LVEF, 3.2%), compared with the shock wave and placebo infusion group (1.0%; P=.02).  Regional wall thickening also improved significantly in the former group but not the latter.  Furthermore, the shock wave and BMC group had fewer major adverse clinical events compared to both treatment groups (P=.02).

Conclusions:

This study of patients with chronic heart failure found that shock wave therapy augmented treatment with intracoronary bone-marrow cells, leading to a small but significant improvement in left ventricular function.  Further work will investigate whether this translates into improved clinical outcomes.

• Assmus B, Walter DH, Seeger FH et al.  Effect of Shock Wave-Facilitated Intracoronary Cell Therapy on LVEF in Patients with Chronic Heart Failure.  The CELLWAVE Randomized Clinical Trial.  JAMA 2013;309:1622-1631.