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.

Anaemia is common in patients with systolic heart failure and is associated with lower functional capacity, worse quality of life, and higher rates of hospitalization and death. The cause of anaemia in these patients is often unclear but may be related to an absolute or relative deficiency of, or resistance to, erythropoietin. In this study Swedberg et al. evaluated the effects of erythropoietin replacement with darbepoetin alfa on clinical outcomes in patients with systolic heart failure and anaemia.

In a multi-centre international randomized, double-blind trial, 2278 patients with systolic heart failure and mild-to-moderate anaemia (haemoglobin level, 9.0 to 12.0 g/dL) and no evidence of iron deficiency were randomised to receive either darbepoetin alfa (to achieve a haemoglobin target of 13 g/dL) or placebo. The primary outcome was a composite of death from any cause or hospitalization for worsening heart failure.

The primary outcome occurred in 576 of 1136 patients (50.7%) in the darbepoetin group and 565 of 1142 patients (49.5%) in the placebo group (HR in the darbepoetin group, 1.01; 95% CI, 0.90 to 1.13; P=0.87). There was no significant between-group difference in any of the secondary outcomes which included death, hospitalisation and a quality of life index. The neutral effect of darbepoetin was also consistent across all prespecified subgroups. Looking at the safety end-points, there was no difference in fatal or nonfatal stroke which occurred in 42 patients (3.7%) in the darbepoetin group and 31 patients (2.7%) in the placebo group (P=0.23) but thromboembolic events were significantly increased in the darbepoetin group (153 patients (13.5%) vs. 114 patients (10.0%) (P=0.01)).

Conclusions:

In this large randomised trial, treatment with darbepoetin alfa did not improve clinical outcomes in patients with systolic heart failure and mild-to-moderate anaemia.

• Swedberg K, Young JB, Anand IS, Cheng S, Desai AS, Diaz R, Maggioni AP, McMurray JJ, O’Connor C, Pfeffer MA, Solomon SD, Sun Y, Tendera M, van Veldhuisen DJ. Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure. N Engl J Med. 2013;368:2010-2019.

Breast cancer remains the commonest cancer in women with approximately 1 million new cases diagnosed annually. However, survival rates have increased year-on-year with 5 year disease free survival as high as 90% in women in whom the tumour is diagnosed early. Large numbers of cancer survivors are therefore present in the population – an estimated three million women in North America alone. While anthracyclines and therapies targeting the HER2 receptor are known to cause cardiac muscle disease, the long term cardiac effects of radiotherapy – a common component of many treatment strategies – is less well explored.

In this population-based case-control study Darby et al. utilised comprehensive registry data from Sweden and Denmark following 2168 women who underwent radiotherapy for breast cancer between 1958 and 2001. The primary end-point was a major coronary event (i.e., myocardial infarction, coronary revascularization, or death from ischemic heart disease). Individual patient information was obtained from hospital records and the mean radiation doses to the whole heart and to the left anterior descending coronary artery were estimated from radiotherapy charts.

963 women had major coronary events during follow up. Mean dose to the whole heart was 4.9 Gy (range, 0.03 to 27.72). Rates of major coronary events increased linearly with mean dose by 7.4% per gray (95% CI, 2.9 to 14.5; P<0.001), with no apparent threshold. The increase started within the first 5 years after radiotherapy and continued into the third decade after radiotherapy. The proportional increase in the rate of major coronary events per gray was similar in women with and women without cardiac risk factors at the time of radiotherapy.

Conclusions:

Exposure of the heart to ionizing radiation during radiotherapy for breast cancer increases the subsequent rate of ischemic heart disease with the risk being proportional to the mean dose to the heart.

• Darby SC, Ewertz M, McGale P et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013 Mar 14;368(11):987-98.

Heart failure with preserved ejection fraction (HFPEF) is now felt to be the most common form of heart failure in the community, and is associated with significant morbidity and mortality. Currently, effective therapies are needed as trials of traditional renin-angiotensin antagonists have failed to show an improvement in outcomes or clinical status. Experimental work has suggested that phosphodiesterase-5 inhibitors may be able to enhance cardiovascular function and this exercise capacity in HFPEF.

The RELAX (Phoshphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction) trial compared the effects of the PDE-5 inhibitor sildenafil with placebo in patients with HFPEF. 216 stable outpatients with heart failure, an ejection fraction of >50%, elevated N-terminal brain-type natriuretic peptide or elevated invasively measured filling pressures, and reduced exercise capacity were recruited between 2008 and 2012. 113 patients were given Sildenafil, and 103 placebo, 20mg three times a day for 12 weeks, followed by 60mg, three times a day for 12 weeks. The primary endpoint was the change in peak oxygen consumption after 24 weeks of therapy.

At 24 weeks follow-up, the median changes in peak oxygen consumption were not significantly different (P=0.90) between the sildenafil and the placebo groups.  Similarly, the mean clinical status rank scores were not significantly different (P=.85), nor were changes in 6-minute walk distance (P=.92). Serious adverse events occurred in 16 placebo patients (16%), and 25 sildenafil (22%) patients.

Conclusions:

The use of the phosphodiesterase-5 inhibitor sildenafil in patients with HFPEF did not result in significant improvement in exercise capacity or clinical status when compared to placebo.

• Redfield MM, Chen HH, Borlaug BA et al. Phodiesterase-5 Inhibition on Exercise Capacity and Clinical Status in Heart Failure With Preserved Ejection Fraction. A Randomized Clinical Trial. JAMA 2013;309:1268-1277.