The need for dual antiplatelet therapy following percutaneous coronary intervention (PCI) also imposes a significant bleeding risk. Chronic kidney disease (CKD) is associated with poorer outcomes following PCI, and in addition a detrimental effect on platelet function is well described. In this study the authors investigated the outcomes of patients with chronic renal impairment (defined here as a creatinine clearance [CrCl] <60ml/min) following PCI.

In a retrospective study of single centre registry data the authors identified a total of 166 patients who had undergone PCI and had an indication for oral anticoagulation; of these, 68 also had chronic renal impairment (CrCl<60mL/min). Patients were contacted by telephone to ascertain details about complications and hospital records were also reviewed. Chronic kidney disease was associated with a higher risk for major bleeding (hazard ratio, 3.44; p=0.004) and all-cause mortality (hazard ratio, 3.50; p=0.003). Noticeably, triple antithrombotic therapy (aspirin, clopidogrel, and warfarin) was associated with a significantly increased risk for a major bleeding complication (hazard ratio, 3.29; p=0.043), regardless of renal function.

While this small study suffers from the problems associated with all retrospective studies it is a useful reminder of the hazards associated with extended periods of antiplatelet and anticoagulant therapy in patients with multiple co-morbidities. In addition, it reminds us that using warfarin with dual anti-platelet therapy more than triples the risk of major bleeding.

• Sergio Manzano-Fernández, Francisco Marín, Francisco J. Pastor-Pérez et al. Impact of Chronic Kidney Disease on Major Bleeding Complications and Mortality in Patients With Indication for Oral Anticoagulation Undergoing Coronary Stenting. Chest 2009;135:983-990

Among patients undergoing coronary artery bypass graft surgery (CABG), those with a history of previous myocardial infarction (PMI) have poorer post-operative cardiovascular outcomes than those without. However it remains unclear whether there are differences in outcomes after CABG between patients with anterior PMI versus those with inferior PMI.

Fukui et al. retrospectively reviewed the medical records of 310 patients with a history of PMI whom underwent CABG without valve replacement. PMI was defined as myocardial infarction occurring more than 30 days before surgery. PMI was confirmed most commonly by scintigraphy, although ECG, echocardiography, and MRI were also used. Patients with lateral MI or a combination of anterior and inferior MI were excluded. 151 patients with anterior PMI and 159 patients with inferior PMI were included in the study.

Investigators found that patients with inferior PMI were older (68.3 ± 9.2 vs 65.5 ± 11.0, p = 0.015), had a greater number of diseased vessels per patient (2.9 ± 0.3 vs 2.8 ± 0.5, p = 0.009), had a lower incidence of diabetes (44.0% vs 58.3%, p = 0.02) and a higher rate of mitral regurgitation (18.2% vs 8.6%, p = 0.02) as compared to patients with anterior PMI. There were no differences between groups with respect to operative technique, number of grafts and completeness of revascularisation.

Patients with a history of inferior PMI were observed to have a higher incidence of respiratory failure, requirement for haemodialysis, increased operative mortality and a combined clinical endpoint of operative death and major complications (table).

Multivariate analysis revealed inferior PMI to be the only independent predictor of major postoperative complications including death (p = 0.007). The mechanistic explanation for this remains unclear, however potential right ventricular dysfunction following prior inferior MI may adversely affect respiratory function and renal perfusion. Further large scale randomised control trials may help to explain this observation which, if reproduced, may assist pre-operative risk stratification algorithms.

Fukui T, Shimokawa T, Manabe S et al. Prior Inferior Myocardila Infarction Has Worse Early Outcomes in Patients Undergoing Coronary Artery Bypass Grafting Than Prior Anterior Myocardial Infarction. Ann Thorac Surg 2009;87:475-80

Elevated blood glucose at hospital admission, and elevated fasting blood glucose levels during admission, have been shown to predict worse outcome among patients with STEMI, however, the contribution of glucose levels to risk predictive algorithms involving patients with acute coronary syndromes (ACS) remains unclear.

Admission and fasting glucose levels were available for 13 526 patients enrolled in the Global Registry of Acute Coronary Events (GRACE). This included patients with STEMI, NSTEMI and unstable angina admitted to hospital between April 1999 to December 2005 from 106 hospitals in 14 countries.

In-hospital and 6 month mortality was calculated and correlated against the presence and degree of glucose elevation on admission and in a fasting sample during admission. Researchers found that patients who had higher fasting glucose levels were more often female, had a higher Killip class, and had a history of hypertension, previous stroke / TIA or peripheral vascular disease. 39.7% of patients were newly diagnosed as diabetic.

Elevated admission and fasting glucose levels independently predicted higher in-hospital mortality, however 6 month mortality only appeared to correlate with certain levels of fasting glucose elevation (see table) and did not correlate with glucose levels on admission. Congestive cardiac failure, cardiogenic shock and major bleeding complications also appeared to occur more frequently among patients with elevated glucose levels.

These data extend the relationship between elevated fasting glucose level and adverse outcome to the wider spectrum of ACS. Fasting glucose appeared to be a more robust independent marker of adverse outcome than admission glucose, which may represent a severe stress response rather than disturbed glucometabolism. Overall, these data reinforce the importance of categorising diabetic patients with ACS as high risk.

· Sinnaeve P, Steg G, Fox K et al. Association of elevated fasting glucose with increased short-term and 6-month mortality in ST-segment elevation and non-ST segment elevation acute coronary syndromes. The Global Registry of Acute Coronary Events. Arch Intern Med. 2009;169(4):402-9

When cardiac muscle is lost, the heart mostly heals through the formation of scar tissue. Although the heart cannot undergo large-scale tissue regeneration, stem/progenitor cells with the potential to generate cardiomyocytes in vitro remain in the adult human myocardium, and mature cardiomyocytes have been suggested to have the ability to re-enter the cell cycle and duplicate.

To investigate cardiomyocyte turnover in human hearts, Bergmann et al. used a novel system based on radiocarbon dating of DNA. Following nuclear bomb testing during the early period of the cold war (1945-1963), the levels of ¹⁴C (incorporated into ¹⁴CO₂) in the atmosphere rapidly equalized around the world. After being taken up by plants which are subsequently consumed by humans, the ¹⁴C is then incorporated into DNA, and because DNA is stable after a cell has gone through its last cell division, the concentration of ¹⁴C in DNA serves as a date mark for when a cell was born, and can be used to retrospectively date cells in humans. A similar approach has been used in rodent models previously, but never implemented in humans due to safety concerns.

Using mathematical modeling, the authors suggest that cardiomyocyte renewal is an age-dependent process, with a gradual decrease from 1% annual turnover at the age of 25, to 0.45% at the age of 75. By contrast, non-myocytes in the heart turn over at an estimated rate of 18% per year. By the age of 50, 55% of human cardiomyocytes remain from birth, while 45% were generated afterward. However, overall fewer than 50% of cardiomyocytes are rejuvenated during a normal life span.

This remarkable piece of work exploits a dark period of recent human history to make a novel and exciting scientific discovery. The next step lies in determining the origins of new cardiac myocytes, and the pathways that lead to their development, before looking at how they are activated in response to injury. Knowledge of this process may in the long term lead to methods of rejuvenating damaged myocardium, and preventing heart failure.

· Evidence of Cardiomyocyte Renewal in Humans. Bergmann O, Bhardwaj RD, Bernard S et al. Science 2009:324;p98-102

The outcomes of coronary artery bypass grafting (CABG), when compared with percutaneous coronary intervention (PCI) might vary according to the patient characteristics, such as the presence of diabetes or the number of diseased vessels. However, no randomized trial to date has been large enough to provide adequate statistical power for sub-group analysis, and meta-analyses have been hampered by inconsistent reporting in published trials.

Hlatky et al. pooled individual patient data from ten randomized trials providing data on 7812 patients. PCI was performed with balloon angioplasty in six trials and bare-metal stents in four trials. 575 of 3889 patients (15%) assigned to CABG died compared with 628 of 3923 (16%) patients assigned to PCI over a median follow-up of 5.9 years. In patients with diabetes, mortality was substantially lower in the CABG group than in the PCI group (hazard ratio 0.70), but mortality was similar in groups without diabetes (hazard ratio, 0.98). 20% of patients aged over 65 died following CABG, compared to a death rate of 24% in the same population following PCI. This interaction remained after adjustment for sex, diabetes, smoking, hypertension, history of myocardial infarction, heart failure and three-vessel disease (p=0.002). No other baseline characteristics were found to significantly alter outcomes.

The results must be interpreted with caution; patients included in the analysis had only single- or double-vessel disease (the recently published SYNTAX trial was not included), a group in which CABG is already known to have no prognostic benefit. Furthermore, internal mammary grafts were underused in the surgical group, and drug-eluting stents were not used in the PCI studies included. Nonetheless, the finding that CABG is the preferred treatment method in diabetics agrees with the findings of the BARI trial. Furthermore, the study suggests that CABG is also preferred for those aged greater than 65 – but it should be noted that only 5% of the patients in this study were aged greater that 75.

• Hlatky MA, Boothroyd DB, Bravata DM, et al. Coronary artery bypass surgery compared with percutaneous coronary interventions for multivessel disease: A collaborative analysis of individual patient data from ten randomised trials. Lancet 2009; DOI:10.1016/S0140-6736(09)60552.
• Taggart DP. PCI or CABG in coronary artery disease? Lancet 2009; DOI:10.1016/S0140-6736(09)60574-2.

Previous studies, such as the World Health Organisation MONICA (monitoring trends and determinants in cardiovascular disease) project, have demonstrated the rapid and progressive uptake of medical care that has been shown in randomised clinical trials to reduce cardiovascular mortality [Lancet 2000;355:688-700]. However, there are relatively few population based studies available that describe how this apparent uptake of evidence-based therapy translates to actual long-term survival following myocardial infarction (MI) or death rates from coronary heart disease in the real world.

In order to address this question Briffa and co-workers examined the impact of evidence based medical treatment and coronary revascularisation on the long term survival of 4,451 patients registered by the MONICA project who were admitted to hospital with acute MI between 1984 to 1993 in Perth, Western Australia. Patients who died in the first 28 days were excluded. The cohort was divided into 3 subgroups according to date of admission (1984-7, 1988-90, and 1991-3), which allowed for temporal changes in the use medical therapy to be identified (table 1).

Over 12 year follow up, patients from the most recent subgroup (1991-3) had a 7.6% (95% CI, 4% to 11%) reduction in absolute events or a 28% lower relative risk reduction (RRR) (16 to 38%) when compared with the cohorts who presented earlier, either 1984-7 or 1988-90.

This improved survival persisted after adjustment for demographic factors, coronary risk factors, severity of disease, and event complications; adjusted RRR, 26% (14% to 37%), but was absent after further adjustment for medical treatments in hospital and coronary revascularisation procedures within 1 year of index presentation, which may provide support for their favourable influence on mortality.

Although observational data must always be interpreted with caution the observations made in the present study suggest improved survival rates which appear to correspond with the initiation evidence based treatment. Consequently, this data describes how improved cardiovascular survival observed in the setting of clinical trials may translate into a ‘real world’ population based setting.

· Briffa T, Hickling S, Knuiman M et al. Long term survival after evidence based treatment of acute myocardial infarction and revascularisation: follow-up of population based Perth MONICA cohort, 1984-2005. BMJ 2009;338:b36

Renal sympathetic efferent and afferent nerves are crucial for the initiation and maintenance of systemic hypertension, and as such renal sympathetic denervation is a potential therapeutic target for hypertension. Krum et al. describe the development of a novel, percutanoeus, catheter-based approach to renal sympathetic denervation. The lumen of the main renal artery is cannulated and the surrounding sympathetic nerves destroyed by radiofrequency waves, and in a swine model this technique has been shown to reduce noradrenaline content in the kidney by as much as 85%.

Fifty patients received percutaneous radiofrequency catheter-based treatment between June 2007 and November 2008, with subsequent follow-up to 1 year. The primary endpoints were office blood pressure and safety data at 1,3,6,9, and 12 months after the procedure. Both renal and magnetic resonance angiography were performed to ensure no anatomical damage from the procedure, and blood-pressure lowering effectiveness was assessed by repeated measures ANOVA. 5 patients were excluded from treatment for anatomical reasons (such as the presence of dual renal artery systems).

Following the procedure, a significant and progressive reduction in blood pressure was observed over the 12 months since treatment (figure 1); by comparision the 5 patients not treated showed a mean rise in blood pressure. Baseline and six-moth glomerular filtraion rate data were available for 25 patients, and showed a mean increase from 79 to 83mL/min/1.73m2. One intraprocedural renal artery dissection occurred before radiofrequency energy delivery, without further sequelae, and there were no other renovascular complications.

This was a proof-of-concept study, and as such lacks a control group. Furthermore, in an age of advanced pharmacotherapy for hypertension, can an invasive approach ever be completely justifiable? It is most likely that this technique will evolve to have a role in those with truly resistant hypertension.

· Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet 2009; published online March 30. DOI:10.1016/S0140-6736(09)60566-3

· Interventional management of resistant hypertension. Doumas M, Douma S. Lancet 2009; published online March 30. DOI:10.1016/S0140-6736(09)60624-3

The diagnosis and management of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) can be problematic – the disease has a highly variable clinical presentation, and cardiac arrhythmias and sudden cardiac death occur frequently. Currently the diagnosis is usually made clinically using criteria that have been defined by an international task force -whilst these are specific they are not very sensitive. Furthermore, the structural changes in ARVC generally spare the sub-endocardium and do not tend to involve the inter-ventricular septum and therefore the pathological features of ARVC may not be identified on conventional endomyocardial biopsy. Additionally, the pathological features are more pronounced in patients with severe disease, but may not be observed in patients with early disease.

Genetic testing offers an alternative method of diagnosis, and mutations in desmosomal proteins including desmoplakin, plakoglobin, plakophilin 2, desmocollin 2 and desmoglein 2 have been identified in approximately 40% of patients with ARVC. The authors of this paper had previously observed that levels of plakoglobin (also known as γ-catenin) were greatly reduced at intercalated disks in patients with rare recessive forms of ARVC. They further studied commoner forms of ARVC related to a variety of desmosomal genes and observed a decreased plakoglobin (a protein which links adhesion molecules at the intercalated disk to the cytoskeleton) signal level. Following this they sought to identify whether a decreased plakoglobin signal-level, identified at the myocardial cell-cell junctions was a sensitive and specific marker of ARVC using immunohistochemical techniques on human myocardial samples.

Myocardial samples from 11 patients with ARVC were tested for desmosomal gene mutations and of these 8 had the mutation. Myocardial autopsy samples from 10 patients with no evidence of clinical or pathological heart disease were used as a control. All ARVC samples but no controls demonstrated a marked reduction in levels of plakoglobin. Other desmosomal proteins showed variable changes but levels of the non-desmosomal adhesion molecule N-cadherin were normal in all patients with ARVC. In order to ascertain whether a decreased plakoglobin level was specific for ARVC, myocardial samples from 15 subjects with either dilated, ischaemic or hypertrophic cardiomyopathy were analysed. In all of these, N-cadherin and plakoglobin levels were indistinguishable from controls. Additionally, blinded immunohistochemical analysis of cardiac biopsy samples from the Johns Hopkins ARVC registry was performed. The correct diagnosis was made in 10/11 subjects with a definite diagnosis of ARVC on clinical criteria. The authors also ruled out ARVC in 10/11 subjects without ARVC, overall sensitivity 91%, specificity 82%, positive predictive value 83%, negative predictive value 90%. The plakoglobin level was diffusely reduced in ARVC samples including in those obtained from the left ventricle and inter-ventricular septum.

The results from this study demonstrate that reduced plakoglobin at intercalated disks is a consistent feature of ARVC and is not seen in other forms of heart muscle disease. It also shows that levels of the non-desmosomal adhesion molecule N-cadherin is normal in patients with ARVC or other forms of heart disease. Further validation studies will be necessary before this new test can be used clinically. In addition, it is also unknown whether all causes of ARVC result in decreased levels of plakoglobin at the intercalated disks – viral infection causing myocarditis has been associated with ARVC in some patients. This would suggest that acquired causes may also lead to the disease. Finally, although in ARVC myocardial degeneration and fibro-fatty replacement occur preferentially in the right ventricle, a diffuse reduction in plakoglobin levels was observed. This might suggest that it is not necessary to biopsy the heart in areas showing structural change to make the diagnosis. Moreover, it could be possible to obtain comparable information from more accessible tissues containing desmosomes such as hair follicles and buccal mucosa

· Asimaki A, Tandri H, Huang H et al. A New Diagnostic Test for Arrhythmogenic Right Ventricular Cardiomyopathy. N Engl J Med 2009;360:1075-84

The role of Computed Tomography (CT) of the coronary arteries in the diagnosis and treatment of coronary artery disease remains is in evolution. Yet in several areas of the world, this technique is already in widespread use, and it is not yet known what effect this has had on other areas of the diagnosis and management of coronary artery disease. This study looked at the impact of the utlization of coronary CT on other diagnostic modalities in the same centre.

1053 consecutive patients underwent coronary CT after the installation of a new 64-slice Siemens Somatom in Columbus, Ohio. The yearly procedural volumes in cardiac catheterization and noninvasive stress testing were reviewed both before and after the introduction of the CT machine. Overall, only 91 patients (8.6%) of the 1053 patients scanned went on to have invasive diagnostic catheterization, and of these, 48% required percutaneous or surgical intervention. This did not represent an increase in procedures over previous years. However, a 30% decrease was noted in patients referred for non-invasive stress testing.

As very few patients who underwent coronary CT went on to cardiac catheterization, the study highlights the high negative predictive value of coronary CT. However, current guidelines recommend noninvasive stress testing to confirm myocardial ischaemia before percutaneous coronary intervention. This small study also reminds cardiologists that even if coronary disease is detected using CT, other non-invasive stress testing must still be used when appropriate.

· Alex J. Auseon, DO, Sunil S. Advani, MD, Charles A. Bush, MD, Subha V. Raman, MD, MSEE. Impact of 64-Slice Multidetector Computed Tomography on Other Diagnostic Studies for Coronary Artery Disease. Am J Med 122(4);388-391.

Elevated blood glucose at hospital admission, and elevated fasting blood glucose levels during admission, have been shown to predict worse outcome among patients with STEMI, however, the contribution of glucose levels to risk predictive algorithms involving patients with acute coronary syndromes (ACS) remains unclear.

Admission and fasting glucose levels were available for 13 526 patients enrolled in the Global Registry of Acute Coronary Events (GRACE). This included patients with STEMI, NSTEMI and unstable angina admitted to hospital between April 1999 to December 2005 from 106 hospitals in 14 countries.

In-hospital and 6 month mortality was calculated and correlated against the presence and degree of glucose elevation on admission and in a fasting sample during admission. Researchers found that patients who had higher fasting glucose levels were more often female, had a higher Killip class, and had a history of hypertension, previous stroke / TIA or peripheral vascular disease. 39.7% of patients were newly diagnosed as diabetic.

Elevated admission and fasting glucose levels independently predicted higher in-hospital mortality, however 6 month mortality only appeared to correlate with certain levels of fasting glucose elevation (see table) and did not correlate with glucose levels on admission. Congestive cardiac failure, cardiogenic shock and major bleeding complications also appeared to occur more frequently among patients with elevated glucose levels.

These data extend the relationship between elevated fasting glucose level and adverse outcome to the wider spectrum of ACS. Fasting glucose appeared to be a more robust independent marker of adverse outcome than admission glucose, which may represent a severe stress response rather than disturbed glucometabolism. Overall, these data reinforce the importance of categorising diabetic patients with ACS as high risk.

· Sinnaeve P, Steg G, Fox K et al. Association of elevated fasting glucose with increased short-term and 6-month mortality in ST-segment elevation and non-ST segment elevation acute coronary syndromes. The Global Registry of Acute Coronary Events. Arch Intern Med. 2009;169(4):402-9