Cardiology

The ESC and AHA point
the way ahead

There is an overwhelming amount of cardiology research emanating from the world’s academic institutions. Attending leading cardiology conferences, such as the annual European Society of Cardiology (ESC) congress and the American Heart Association’s Scientific Sessions is a good way to stay informed. The ESC held their congress in Munich in late August and the AHA Scientific Sessions were held in Louisiana in November. In an effort to keep you informed Middle East Health reports on a handful of key papers presented at the ESC and the Scientific Sessions.

Pre-hospital treatment on the way to PCI

Professor Kurt Huber of the Medical University of Vienna – presenting at the 2008 ESC Congress – outlines a number of pre-treatment strategies for patients on the way to primary Percutaneous Coronary Intervention (PCI) therapy.

For patients with acute STsegment- elevation AMI (STEMI) within 12 hours after symptom onset and with persistent ST-segment elevation, or new or presumed new left bundle-branch block with concomitant ST-segment elevation, restoring coronary blood flow as early as possible is the main goal of reperfusion strategies.

Because it is sometimes (in about 1/3 of patients presenting with signs of STEMI) difficult to determine exactly the time of onset of infarction, reperfusion therapy should be considered when there are clinical or electrocardiographic signs of ongoing ischaemia even if, according to the individual patient, symptoms started over 12 hours ago. Primary Percutaneous Coronary Intervention (PCI) is the recommended therapy of choice if performed by an experienced team as soon as possible after first medical contact. According to recent guidelines, the PCI related delay time should be under two hours in any case and significantly shorter in patients presenting early with an acceptable bleeding risk and with greater non-reperfused areas of myocardium (e.g. anterior wall).

An optimal pre-treatment on the way to primary PCI could thereby help to improve the clinical outcome.

Antiplatelet Agents


Aspirin should be given to all patients with acute STEMI as soon as possible after the diagnosis. Aspirin should be started at a dose of 150-325 mg in a chewable form (enteric-coated aspirin should be avoided. An alternative approach, especially if oral ingestion is not possible, is IV administration of aspirin at a dose of 250 mg. A lower dose (75-160 mg) is given orally daily thereafter for life.

(NSAIDs – apart from aspirin and selective COX-2 inhibitors – have been demonstrated to increase the risk of death, reinfarction, cardiac rupture and other complications in STEMI patients. Accordingly, immediate discontinuation of these drugs is indicated at the time of an STEMI).

Clopidogrel is less studied in patients with acute STEMI treated with primary PCI, but there is clear evidence of its usefulness as an adjunctive antiplatelet therapy in patients undergoing PCI from the CREDO, PCI-CURE, and PCI-CLARITY-trials.

Although the early, prehospital administration of clopidogrel (starting with a loading dose of 600 mg) has only recently being tested in a prospective randomised trial (CIPAMI), the general assumption is that this strategy might be beneficial. In summary, clopidogrel should be given early to all patients with STEMI referred for primary PCI with a 600 mg loading dose, which has been demonstrated to achieve a more rapid and stronger inhibition of platelet aggregation. This should then be followed by a daily dose of 75 mg for up to one year.

Most of the studies on the role of GPIIb/IIIa antagonists in STEMI have focused on abciximab rather than on the lower molecular weight agents: tirofiban and eptifibatide. Several randomised trials have assessed the value of periprocedural administration of intravenous abciximab in this setting. A systematic review of these trials showed that abciximab reduced 30-day mortality by 32% without affecting the risk of haemorrhagic stroke and major bleeding. The mechanism of benefit with abciximab is thought to be the improvement of microcirculation. Although smaller studies – meta-analyses and registries - - reported a benefit of early, pre-hospital administration of abciximab with respect to clinical outcome, the only prospective randomised trial (FINESSE) showed that abciximab did not have a significant impact on the patency of infarct-related arteries. The upstream administration of a planned PCI procedure did not offer advantages compared to the administration in the cath lab (see below). Accordingly, the pre-hospital use of abciximab cannot be recommended at present. Abciximab is given intravenously as a bolus of 0.25 mg/kg bolus, 0.125 g/kg per minute infusion (maximum 10 g/min for 12 hours).

Antithrombins

Unfractionated heparin (UFH) is the standard antithrombotic therapy during PCI in STEMI. Unfractionated heparin is given as an intravenous bolus at a usual starting dose of 100 U/kg weight (60 U/kg if GPIIb/IIIa antagonists are used). Lowmolecular weight heparins have not specifically been evaluated in conjunction with primary PCI in STEMI patients. An ongoing trial investigates the role of 0.5 U enoxaparin/kg body weight in comparison with UFH (ATOLL). Thus, there is at present no direct evidence to support their use instead of UFH in this setting. Accordingly, a pre-treatment with UFH (with 60 U/kg to enable the later use of abciximab during PCI) on the way to the cath lab, as frequently performed, would not complicate the procedure and potentially add benefit, although this has not been proven prospectively.

Bivalirudin, a direct thrombin inhibitor, has been investigated intensively as adjunct antithrombotic therapy in patients undergoing PCI. In the HORIZONS-AMI trial, 3,602 patients undergoing PCI were randomly assigned to receive either bivalirudin with provisional use of GP IIb/IIIa inhibitor or heparin (or enoxaparin) as well as a GP IIb/IIIa inhibitor. At the primary combined endpoint of 30 days, major adverse cardiac events or major bleeding was significantly reduced by bivalirudin with a 40% reduction in major bleeding, while the composite ischemic endpoint was similar in both groups. Bivalirudin is given as an intravenous bolus of 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hr and usually terminated at the end of the procedure. The early use of bivalirudin (either prehospital or in the emergency room in the organisation phase for the cath lab) is still not investigated and therefore not recommended at present.

(Fondaparinux, a factor Xa inhibitor, has been compared with heparin or placebo in 12,092 STEMI patients treated with fibrinolytic agents or primary PCI or no reperfusion therapy. In the PCI subset, fondaparinux was associated with a non-significant 1% higher incidence of death or recurrent AMI at 30 days and a higher catheter thrombois rate. It is not recommended for primary PCI neither during the catheter procedure nor before).

Facilitated PCI

Facilitated PCI is defined as a pharmacologic reperfusion treatment delivered prior to a planned PCI, in order to bridge the PCI-related time delay and to increase the quality of thrombolysis in myocardial infarction (TIMI) flow in the diagnostic angiogram of the infarct related artery before intervention.

Full-dose lytic therapy, half dose lytic therapy with a GPIIb/IIIa inhibitor and GPIIb/IIIa inhibitors alone have been tested for this indication. No evidence of a benefit with either of these agents could be demonstrated in the ASSENTIV PCI trial (with TNK-tPA), in the meta-analysis of Keeley et al. (with GP IIb/IIIa-antagonsits), and in the FINESSE trial (with abciximab or a combination of half-dose lytic and fulldose abcicimab). In spite of the fact that pre-PCI patency rates were higher with lytic based treatments no mortality benefit, but more bleeding complications were observed. The pre-PCI patency rates with upfront GPIIb/IIIa antagonist alone were not higher than with placebo and there was also a trend towards more bleeding. Accordingly, facilitated PCI as it has been tested in the trials cannot be recommended.

Obese kids’ artery plaque similar to middle-aged adults

The neck arteries of obese children and teens look more like those of 45-year-olds, according to research presented at the American Heart Association’s Scientific Sessions 2008.

“There’s a saying that ‘you’re as old as your arteries’, meaning that the state of your arteries is more important than your actual age in the evolution of heart disease and stroke,” said Geetha Raghuveer, MD, MPH, associate professor of paediatrics at the University of Missouri Kansas City School of Medicine and cardiologist at Children’s Mercy Hospital. “We found that the state of the arteries in these children is more typical of a 45- year-old than of someone their own age.”

Researchers used ultrasound to measure the thickness of the inner walls of the neck (carotid) arteries that supply blood to the brain. Increasing carotid artery intima-media thickness (CIMT) indicates the fatty build-up of plaque within arteries feeding the heart muscle and the brain, which can lead to heart attack or stroke.

Investigators calculated CIMT in 34 boys and 36 girls who were “at-risk,” (average age 13, 89% white) and found:

● These children had abnormal levels of one or more types of cholesterol – elevated levels of low-density lipoprotein (LDL), which is known as “bad cholesterol;” low levels of high-density lipoprotein (HDL), which is the “good cholesterol;” or high triglyceride levels.

● Forty (57%) had a body mass index (BMI, a calculation of weight for height) above the 95th percentile.

Their average CIMT was 0.45 millimetres (mm), with a maximum of 0.75 mm.

The children’s “vascular age” – the age at which the level of thickening would be normal for their gender and race – was about 30 years older than their actual age, Raghuveer said.

The children were deemed at high risk for future heart disease because of obesity, abnormal cholesterol, and/or a family history of early heart disease. On average, these children had:

● total cholesterol levels of 223.4 milligrams per decilitre (mg/dL) (less than 170 is considered acceptable by American Heart Association recommendations);

● LDL cholesterol levels of 149.8 mg/dL (less than 110 is considered acceptable); and

● triglycerides levels of 151.9 mg/dL (below 150 is considered acceptable).

Researchers found that having a higher BMI and higher systolic blood pressure had the most impact on CIMT.

Of the various risk factors, the children with triglycerides over 100 mg/dL were most likely to have an advanced vascular age. Thirty-eight children with high triglycerides had a CIMT above the 25th percentile for 45-year-olds, while only five in the group were below the 25th percentile. Children with lower triglycerides were evenly divided between those who scored below (13) or above (14) the 25th percentile on the charts for 45-year-olds.

“Vascular age was advanced the furthest in the children with obesity and high triglyceride levels, so the combination of obesity and high triglycerides should be a red flag to the doctor that a child is at high risk of heart disease,” Raghuveer said.

Further studies are needed to determine whether artery build-up will decrease if children lose weight, exercise, or are treated for abnormal lipids. Some studies have shown that CIMT can be reduced when children at extremely high risk are treated with cholesterollowering statin medications, and that exercise can improve blood vessel function in children with a high BMI.

“I’m optimistic that something can be done,” Raghuveer said. “In children, the build-up in the vessels is not hardened and calcified. We can improve the vessel walls and blood flow in adults through treatment, and I’m sure we can help children even more.”

Other risk factors for high CIMT in children are high blood pressure, exposure to secondhand smoke and insulin resistance – which is frequently seen in obese children.

● Co-authors are: Joseph Le, medical student; Menees Spencer, medical student; David McCrary, M.D.; Danna Zhang, M.S.; and Chen Jie, PhD. Individual author disclosures are available on the abstract.

The Sarah Morrison Medical Student Research Grant from the University of Missouri, Kansas City, funded the research.

Transcatheter aortic valve replacement
– a new frontier in cardiovascular medicine

Replacing heart valves without the substantial trauma of opening the chest and the heart were little known concepts until the groundbreaking pulmonary and aortic transcatheter valve replacements performed during 2000 and 2002, respectively by Philipp Bonhoeffer and Alain Cribier. However, according to Professor Jan Kovac advanced development programmes for less invasive treatment of the aortic, mitral and pulmonary valves are coming to fruition and herald a period of great transformation in cardiovascular medicine both for patients and for their physicians.

Current experiences with one of the two CE Marked devices, the CoreValve ReValving System for Percutaneous Aortic Valve Replacement (PAVR) have proved to be an overall success. This device consists of a porcine pericardial valve prosthesis mounted on a self-expanding Nitonol frame, which is delivered by means of an 18 French size (6mm) catheter. Today, the procedure can be performed in the cath lab by the interventional cardiologist under local anaesthesia, without the use of surgical cut-down/repair (with pre-closing), without heartlung bypass, and with the heart at normal sinus rhythm during valve placement.

A first safety & efficacy study (August 2005 – August 2006) enrolled 65 patients. A second study (October 2006 – June 2007) enrolled 112 patients. The study criteria focused on severe aortic stenosis (AVAI≤0.6cm2/m2) in patients older than 75 years, or with Logistic EuroSCORE (LE) ≥15%, or older than 65 years with multiple comorbidities. Endpoints considered procedural success/ morbidity/mortality, as well as 30-day and long-term outcomes.

Preliminary analysis of 175 patients enrolled in the combined studies (21F+18F) represent a combined mean theoretical surgical risk level of LE 24%, a mean age of 82 years, a mean pre-procedural AVA of 0.61cm2, and Mean Gradient (MG) 44.3mmHg. About one quarter of patients were deemed totally inoperable and 60% were female. 79% of patients were in NYHA class III/IV.

Overall procedural success was 91%. MG decreased to 7.9mmHg while AVA increased to 1.62cm2, with 86% of patients moving to NYHA class I/II. Procedural and procedure related mortality were <1% and 8% respectively. Total 30-day mortality was 15%. Mean follow-up to 12 months (range 10 to 32 months) detects a further 16% mortality among these octogenarians, none valve related. At last follow-up, substantially improved quality of life was documented for 85% of surviving patients with MG at 11mmHg, Ejection Fraction of 56%, and 88% in NYHA class I/II. No valve dysfunction or migration was observed either post procedurally or at long term follow up.

● This is a summary by Professor Jan Kovac of his presentation to the European Society of Cardiology Congress 2008.

Daily rhythms in blood vessels may explain morning peak in heart attacks

It’s not just the stress of going to work. Daily rhythms in the activity of cells that line blood vessels may help explain why heart attacks and strokes occur most often in early morning hours, researchers from Emory University School of Medicine have found.

Endothelial cells serve as the interface between the blood and the arteries, controlling arterial tone and helping to prevent clots that lead to strokes and heart attacks, says Ibhar Al Mheid, MD, a postdoctoral cardiology researcher at Emory.

Dr Al Mheid presented his findings at the American Heart Association Scientific Sessions in New Orleans, 10 November 2008.

“One of the important ways the lining of our blood vessels is maintained is by progenitor cells that come from the bone marrow,” Dr Al Mheid says. “These are essentially stem cells that help replace endothelial cells at sites of injury and build new vessels at sites deprived of adequate blood supply. The aim of our research was to look at the circadian pattern of both endothelial function – the ability of blood vessels to relax – and the abundance of the progenitor cells.”

Working with Arshed Quyyumi, MD, professor of medicine and director of the Emory Cardiovascular Research Group, and colleagues, Dr Al Mheid examined a dozen healthy middle-aged subjects every four hours for 24 hours. They drew blood while the subjects were asleep at 4am. Blood vessel relaxation is assessed by cuff occlusion, a standard technique in measuring blood pressure – and was not measured at 4am.

The researchers measured the ability of subjects’ blood vessels to relax, the abundance of endothelial progenitor cells (EPCs) and their ability to grow in culture. Both the ability of blood vessels to relax and EPCs’ ability to grow peaked (roughly 40% more than the middle of the day) at midnight, while cell numbers peaked at 8pm.

“The lining of our vessels appears to function better at night than in the day. Endothelial function is particularly depressed in the early morning hours,” Dr Al Mheid says.

He hypothesises that an innate circadian timer in the brain, which other scientists have shown to be influenced by light and dark and daily activities, drives the cyclical variations in EPCs and endothelial function.


Cardiac troponins a prerequisite for myocardial infarction diagnosis

In conjunction with clinical assessment and the ECG, simple and rapid blood tests have become the standard for the detection of myocardial infarction. Starting in the year 2000, recommendations by the European Society of Cardiology and other major cardiology societies worldwide have begun to state uniformly that a rise in cardiac troponins – sensitive and specific markers for dying cells in the heart – is a prerequisite for the clinical diagnosis of myocardial infarction. Professor C Meuller, of the University Hospital Basel, summarises his presentation to the ESC.

Myocardial infarction is the major cause of death worldwide. With effective treatment within our grasp, accurate and rapid diagnosis is of major medical and economic importance. With the development of sensitive trials depicting either cardiac troponin I or cardiac troponin T, the only current biomarkers thought to be unique to the heart, the diagnosis of myocardial infarction has been revolutionised. In a patient presenting with chest pain, a rise in cardiac troponin has become a mandatory feature for the clinical diagnosis of myocardial infarction.

Cardiac troponins are our current gold standard for the detection of myocardial necrosis. The more sensitive the cardiac troponin essay used, the smaller the number of dying myocardial cells necessary for this signal to be detected. This has enabled us to detect high risk acute coronary syndrome patients with only minor myocardial damage. Unfortunately, current cardiac troponin essays have one major limitation in common with their predecessor (CKMB): it takes three to four hours after symptom onset until cardiac troponin becomes detectable. Ongoing large clinical multicenter studies, including the Advantageous Predictors of Acute Coronary Syndromes Evaluation (APACE), are assessing whether novel cardiac troponin assays with even higher sensitivity or other biomarkers reflecting different pathophysiological processes such as, for example, copeptin (reflecting endogenuous stress) or myeloperoxidase (reflecting plaque instability and inflammation) will significantly shorten the “troponin-blind” period. Obviously, this would constitute a major medical and economic improvement in clinical practice.

However, the development of high sensitivity cardiac troponin assays also poses dilemmas: First, many physicians are reluctant to use the term “myocardial infarction” in patients with unstable coronary artery disease and tiny elevations of cardiac troponin. As these patients still seem to be at increased risk of death as compared to patients without detectable cardiac troponin levels, the current ESC/AHA/ACC guidelines encourage us to do so. Second, elevations in cardiac troponin I and T reflect myocardial injury, but do not indicate its mechanism.

Myocardial infarction can only be diagnosed when cardiac troponin I or T are increased in the clinical setting of myocardial ischemia – this means the myocardial cells suffer from a lack of oxygen and are “suffocating” due to reduced oxygen supply usually related to a clot in the coronary arteries or less commonly due to other causes of decreased supply such as coronary spasm or hypotension or due to increased oxygen demand such as septic shock. As we currently lack a biomarker that reliably detects clot formation in the coronary arteries, we are left with our basic clinical tools, including patient history, to differentiate myocardial infarction from other causes of myocardial injury. Third, once a diagnostic test is declared “gold standard”, it becomes virtually impossible to rule out definitely false positive test results. This is currently the case with cardiac troponins. We strongly believe that the heart is invariably the exclusive source of cardiac troponin elevations, regardless of the specific patient conditions. However, as both the ECG and imaging techniques have far lower sensitivity to myocardial necrosis than cardiac troponin, scientific proof cannot be provided.

In clinical practice we currently do not have a validated biomarker to assess myocardial ischemia. Cardiac troponins are blind for ischemia without necrosis. In both patients with myocardial ischemia at rest (unstable coronary artery disease) and exercise- induced myocardial ischemia (stable coronary artery disease) elevated B-type natriuretic peptides are associated with the presence of myocardial ischemia. However, the accuracy of B-type natriuretic peptides does not seem to be high enough for use in clinical practice. The ability to identify a patient at risk of myocardial cell death, before it actually occurs, is still a major unmet clinical need.



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ate of upload: 25th January 2009

                                  
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