Fetal cardiomyocytes as cardiac pacemaker

Transplanted fetal cardiomyocytes as cardiac pacemaker

Arjang Ruhparwara, Juergen Tebbenjohannsb, Michael Niehausb, Michael Mengelc, Thiemo Irtela, Theodoros Kofidisa, Andreas M. Pichlmaiera, Axel Havericha
a) Department of Thoracic and Cardiovascular Surgery, Hannover Medical School, Germany; b) Department of Cardiology and Angiology, Hannover Medical School, Germany; c) Department of Pathology, Hannover Medical School, Germany

Background: While morphologic integration of transplanted fetal cardiomyocytes into the ventricular myocardium is a well-known fact, no studies have yet shown transplanted cells to coherently contribute to contraction and electrical excitation of the host myocardium. The aim of this study was to prove the hypothesis that by transplanting cardiomyocytes with a higher intrinsic rhythmic rate into the myocardium of the left ventricle, these cells could act as an ectopic pacemaker by functional coupling with host cardiomyocytes.

Methods and Results: Dissociated fetal canine atrial cardiomyocytes including sinus nodal cells were delivered into the free wall of the left ventricle of adult canine X-linked muscular dystrophy dogs (n=2). These dogs fail to express Dystrophin in both cardiac and skeletal muscle. In the control group (n=2) fetal skin fibroblasts were used for grafting. A total of 3–4 weeks after transplantation the dogs underwent catheter ablation of the atrioventricular node (AV-node) and subsequent electrophysiological mapping studies. Transplanted cells were identified by Dystrophin immunoreactivity, indicating survival and morphological integration in the recipient heart. The expression of Connexin 43 between donor and recipient cells suggested formation of gap junctions between injected and host cardiomyocytes. After catheter ablation of the AV-node, a ventricular escape rhythm emerged driving the pace of the heart and originating from the labeled transplantation site. This effect could not be observed in the control group (n=2).

Conclusions: The results constitute the first observation of phenomena indicating electrical and mechanical coupling between allogeneic donor cardiomyocytes and recipient myocardium in-vivo. Further experiments are necessary to evaluate the technique as a potential therapy for atrioventricular block.

Key Words: Pacemakers • Pacing • Cell grafting • Micro-transplantation

Eur J Cardiothorac Surg 2002;21:853-857

© 2002 Elsevier Science NL

Cell transplantation in myocardium

Cell transplantation in myocardium

Philippe Menasché, MD, PhD
Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, Paris, France

Cell transplantation is gaining a growing interest as a potential new means of improving the prognosis of patients with cardiac failure. The basic assumption is that left ventricular dysfunction is largely due to the loss of a critical number of cardiomyocytes and that it can be partly reversed by implantation of new contractile cells into the postinfarction scars.

Primarily for practical reasons, autologous skeletal myoblasts have been the first to undergo clinical trials but other cell types are also considered, particularly bone marrow stem cells, which are attractive because of their autologous origin and their purported cardiomyocyte/endothelial transdifferentiation potential in response to cues provided by the target organ.

However several key issues still need to be addressed including (1) the optimal type of donor cells, (2) the mechanism by which cell engraftment improves cardiac function, (3) the optimization of cell survival, and (4) the potential benefits of cell transplantation in nonischemic heart failure.

In parallel to the experimental studies designed to address these issues clinical trials are under way and should hopefully allow assessing to what extent cell transplantation may improve the outcome of patients with heart failure.

Ann Thorac Surg 2003;75:S20-S28
© 2003 The Society of Thoracic Surgeons

Are Stem Cells Drugs?

The Regulation of Stem Cell Research and Development

Michael R. Rosen, MD
From the Departments of Pharmacology and Pediatrics, Center for Molecular Therapeutics, College of Physicians and Surgeons of Columbia University, New York, NY.

Stem cell research and its clinical application have become political, social, and medical lightning rods, polarizing opinion among members of the lay community and among medical/scientific professionals. A potpourri of opinion, near-anecdotal observation, and scientifically sound data has sown confusion in ways rarely seen in the medical arts and sciences.

A major issue is regulation, with different aspects of stem cell research falling within the purview of different government agencies and local offices. An overarching clearinghouse to review the field and recommend policy is lacking.

In the following pages, I touch on the societal framework for regulation, the known and potential risks and benefits of cardiovascular stem cell therapies, whether stem cells should be regulated as drugs or in analogy to drugs, and if there is to be regulation, then by whom.

In so doing, I refer to the stem cell literature only as it relates to the discussion of regulation because this is not a review of stem cell research; it is an opinion regarding regulation.

Key Words: cardiovascular diseases • cells • heart failure • myocardial infarction • trials

Circulation. 2006;114:1992-2000.

© 2006 American Heart Association, Inc.

Alternative AV conduction pathway

Cardiac Conduction through Engineered Tissue

Yeong-Hoon Choi, Christof Stamm, Peter E. Hammer, Kevin F. Kwaku , Jennifer J. Marler , Ingeborg Friehs, Mara Jones , Christine M. Rader, Nathalie Roy, Mau-Thek Eddy, John K. Triedman, Edward P. Walsh, Francis X. McGowan, Jr. , Pedro J. del Nido and Douglas B. Cowan
From the Departments of Cardiac Surgery, Anesthesiology, Surgery, and Cardiology, Children’s Hospital Boston, and the Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

In children, interruption of cardiac atrioventricular (AV) electrical conduction can result from congenital defects, surgical interventions, and maternal autoimmune diseases during pregnancy. Complete AV conduction block is typically treated by implanting an electronic pacemaker device, although long-term pacing therapy in pediatric patients has significant complications.

As a first step toward developing a substitute treatment, we implanted engineered tissue constructs in rat hearts to create an alternative AV conduction pathway. We found that skeletal muscle-derived cells in the constructs exhibited sustained electrical coupling through persistent expression and function of gap junction proteins.

Using fluorescence in situ hybridization and polymerase chain reaction analyses, myogenic cells in the constructs were shown to survive in the AV groove of implanted hearts for the duration of the animal’s natural life. Perfusion of hearts with fluorescently labeled lec-tin demonstrated that implanted tissues became vascularized and immunostaining verified the presence of proteins important in electromechanical integration of myogenic cells with surrounding re-cipient rat cardiomyocytes.

Finally, using optical mapping and electrophysiological analyses, we provide evidence of permanent AV conduction through the implant in one-third of recipient animals. Our experiments provide a proof-of-principle that engineered tissue constructs can function as an electrical conduit and, ultimately, may offer a substitute treatment to conventional pacing therapy.

American Journal of Pathology. 2006;169:72-85.
© 2006 American Society for Investigative Pathology

After cardioversion: left atrial function

Abnormalities of left atrial function after cardioversion: an atrial strain rate study

L Thomas1, T Mckay1, K Byth1 and T H Marwick2
1) Department of Cardiology, University of Sydney/Westmead Hospital, Sydney, New South Wales, Australia; 2) Department of Medicine, University of Queensland/Princess Alexandra Hospital, Brisbane, Queensland, Australia

Background and objectives: The role of atrial myocardial dysfunction after cardioversion is unclear. In a comparison of patients after successful cardioversion from chronic atrial fibrillation (CAF) and normal controls, we sought to determine whether Doppler-derived atrial strain rate (A-sr) could be used to measure global left atrial function and whether A-sr was reduced in patients with CAF.
Methods: A-sr was measured from the basal septal, lateral, inferior and anterior atrial walls from the apical four-chamber and two-chamber views in 37 patients with CAF who had been cardioverted to sinus rhythm and followed up for 6 months, and in a cohort of 37 healthy people. Conventional measures of atrial function included peak transmitral A-wave velocity, A-wave velocity time integral, atrial fraction and the left atrial ejection fraction. Doppler tissue imaging was used to estimate atrial contraction velocity (A' velocity). In addition to amplitude parameters, the time to peak A-sr was measured from aortic valve closure.
Results: Immediately after cardioversion, A-sr in the CAF cohort (baseline) was significantly lower than in controls (mean (SD) –0.53 (0.31) v –1.6 (0.75) s–1; p<0.001); the A-sr correlated with A' velocity (r = 0.63; p<0.001) in patients. Atrial function improved over time, with maximal change observed in the initial 4 weeks after cardioversion. The time to peak A-sr was increased in the CAF group compared with controls (0.55 (0.15) v 0.46 (0.12) s), but this failed to normalise over time.
Conclusion: Atrial strain rate is a descriptor of atrial function, which is reduced after cardioversion from chronic atrial fibrillation and subsequently recovers.
Abbreviations: A-sr, atrial strain rate; AVC, aortic valve closure; BSA, body surface area; CAF, chronic atrial fibrillation; DTI, Doppler tissue imaging; LAEF, left atrial ejection fraction; LAESV, left atrial end systolic volume; tA-sr, time to peak A-sr; VTI, velocity time integral

Heart 2007;93:89-95
© 2007 by BMJ Publishing Group Ltd & British Cardiovascular Society

Clopidogrel: pre-operative exposure

Clopidogrel administration prior to coronary artery bypass grafting surgery: the cardiologist's panacea or the surgeon's headache?

Kapetanakis EI, Medlam DA, Boyce SW, Haile E, Hill PC, Dullum MK, Bafi AS, Petro KR, Corso PJ.
Section of Cardiac Surgery, Department of Surgery, Washington Hospital Center, Washington, USA.

AIMS:

Thrombotic complications after percutaneous coronary intervention procedures have decreased in past years mainly due to the use of clopidogrel antiplatelet therapy. However, the risk of bleeding due to enhanced and irreversible platelet inhibition in patients who will require surgical coronary revascularization instead has not been adequately addressed in the literature. The purpose of this study was to evaluate the effect of pre-operative clopidrogel exposure in haemorrhage-related re-exploration rates, peri-operative transfusion requirements, morbidity, and mortality in patients undergoing coronary artery bypass grafting (CABG) surgery.

METHODS AND RESULTS:

A study population of 2359 patients undergoing isolated CABG between January 2000 and June 2002 was reviewed. Of these, 415 (17.6%) received clopidogrel prior to CABG surgery, and 1944 (82.4%) did not. A risk-adjusted logistic regression analysis was used to assess the association between clopidogrel pre-medication (vs. no) and haemostatic re-operation, intraoperative and post-operative blood transfusion rates, and multiple transfusions received. Haemorrhage-related pre-operative risk factors identified from the literature and those found significant in a univariate model were used. Furthermore, a sub-cohort, matched-pair by propensity scores analysis, was also conducted.

CONCLUSION:

Pre-operative clopidogrel exposure increases the risk of haemostatic re-operation and the requirements for blood and blood product transfusion during, and after, CABG surgery.

Eur Heart J. 2005 Mar;26(6):576-83. Epub 2005 Feb 21.

Heart attack: symptoms and treatment

A heart attack (also known as a myocardial infarction) is the death of heart muscle from the sudden blockage of a coronary artery by a blood clot. Coronary arteries are blood vessels that supply the heart muscle with blood and oxygen. Blockage of a coronary artery deprives the heart muscle of blood and oxygen, causing injury to the heart muscle. Injury to the heart muscle causes chest pain and pressure. If blood flow is not restored within 20 to 40 minutes, irreversible death of the heart muscle will begin to occur. Muscle continues to die for 6-8 hours at which time the heart attack usually is "complete." The dead heart muscle is replaced by scar tissue.Approximately one million Americans suffer a heart attack each year. Four hundred thousand of them die as a result of their heart attack.

What are the symptoms of a heart attack?
Although chest pain or pressure is the most common symptom of a heart attack, heart attack victims may experience a diversity of symptoms that include:

• Pain, fullness, and/or squeezing sensation of the chest

• Jaw pain, toothache, headache

• Shortness of breath

• Nausea, vomiting, and/or general epigastric (upper middle abdomen) discomfort

• Sweating

• Heartburn and/or indigestion

• Arm pain (more commonly the left arm, but may be either arm)

• Upper back pain

• General malaise (vague feeling of illness)

• No symptoms (Approximately one quarter of all heart attacks are silent, without chest pain or new symptoms.

Silent heart attacks are especially common among patients with diabetes mellitus) Even though the symptoms of a heart attack at times can be vague and mild, it is important to remember that heart attacks producing no symptoms or only mild symptoms can be just as serious and life-threatening as heart attacks that cause severe chest pain. Too often patients attribute heart attack symptoms to "indigestion," "fatigue," or "stress," and consequently delay seeking prompt medical attention. One cannot overemphasize the importance of seeking prompt medical attention in the presence of symptoms that suggest a heart attack. Early diagnosis and treatment saves lives, and delays in reaching medical assistance can be fatal. A delay in treatment can lead to permanently reduced function of the heart due to more extensive damage to the heart muscle. Death also may occur as a result of the sudden onset of arrhythmias such as ventricular fibrillation.

How is a heart attack treated?

Treatment of heart attacks include:

• Anti-platelet medications to prevent formation of blood clots in the arteries

• Anti-coagulant medications to prevent growth of blood clots in the arteries

• Coronary angiography with either percutaneous transluminal coronary angioplasty (PTCA) with or without stenting to open blocked coronary arteries

• Clot-dissolving medications to open blocked arteries

• Supplemental oxygen to increase the supply of oxygen to the heart's muscle

• Medications to decrease the need for oxygen by the heart's muscle

• Medications to prevent abnormal heart rhythms

The primary goal of treatment is to quickly open the blocked artery and restore blood flow to the heart muscle, a process called reperfusion. Once the artery is open, damage to heart muscle ceases, and the patient becomes pain free. By minimizing the extent of heart muscle damage, early reperfusion preserves the pumping function of the heart. Optimal benefit is obtained if reperfusion can be established within the first 4-6 hours of a heart attack. Delay in establishing reperfusion can result in more widespread damage to heart muscle and a greater reduction in the ability of the heart to pump blood. Patients with hearts that are unable to pump sufficient blood develop heart failure, decreased ability to exercise, and abnormal heart rhythms. Thus, the amount of healthy heart muscle remaining after a heart attack is the most important determinant of the future quality of life and longevity.

Cardiac syndrome X: Prognosis

Cardiac syndrome X: Prognosis

G A Lanza
Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Largo A Gemelli, 8, 00168 Rome, Italy

All studies on patients with CSX have consistently reported an excellent clinical outcome at long-term follow up, with a total absence of major acute coronary events (that is, cardiac death or acute myocardial infarction).

The favourable prognosis of patients with CSX can be challenged by some recent data showing increased occurrence of events among patients with chest pain and normal or near normal coronary arteries who had evidence of coronary endothelial dysfunction. However, these studies included patients with characteristics (for example, with LV dysfunction or subcritical coronary artery stenoses) clearly different from those of CSX. Thus, these studies cannot be taken as a clue to a possible prognostic value of endothelial dysfunction in patients with CSX. In fact, a recent study showed no spontaneous acute coronary events at the 12-year follow up of women with CSX who also had evidence of coronary endothelial dysfunction at enrolment.
Although studies have consistently shown a good prognosis for patients with CSX, no attempts have been made to understand whether this finding may have some specific explanation. Indeed, these patients present a risk profile largely similar to that of patients with obstructive CAD, including, together with a significant prevalence of traditional cardiovascular risk factors, a higher prevalence of inflammation, insulin resistance and endothelial dysfunction.

Thus, a challenging clinical question is whether patients with CSX may have some protective factor that, despite the evidence of coronary microvascular dysfunction, may delay the development of critical atherosclerotic lesions in large coronary vessels and prevent acute coronary events. This possibility is suggested by our data showing a reduction in platelet reactivity after stress stimuli (for example, exercise or mental stress) in patients with CSX, in contrast to patients with CAD and to normal subjects, in whom an increase and no changes in platelet reactivity, respectively, are observed. Whether these findings really imply vascular protection and whether other potential protective factors against acute thrombotic coronary events exist in patients with CSX are challenging issues that would merit investigation in future studies.

Quality of life

In contrast to the excellent prognosis, patients with CSX may have a significantly impaired quality of life. Symptoms improve over time in only about one third of patients. In 10–20% of patients, on the other hand, anginal symptoms worsen progressively during follow up, becoming more frequent and long lasting, ensuing at lower levels of exercise or even at rest and becoming less sensitive or refractory to drug treatment, thus impairing usual daily activities, which also results in high rates of absence and retirement from work. The most symptomatic patients also may often have recurrent medical visits, emergency room admissions and hospital admissions, and have repeat non-invasive diagnostic tests and coronary angiography. Thus, although prognostically benign, CSX is an individually, socially and economically relevant condition.

Although a psychological component has been suggested to be involved in patients with CSX with severe chest pain, it is not clear whether psychological disturbances have a causal role or are rather a consequence of the persistent invalidating symptoms. Some data, indeed, suggest that the prevalence of psychological disorders is similar in patients with CSX and in those with obstructive CAD, thus supporting the second hypothesis.

Heart 2007;93:159-166 (“Cardiac syndrome X: a critical overview and future perspectives”)
© 2007 by BMJ Publishing Group Ltd & British Cardiovascular Society

Happy Valentine's Day!

Peripheral Arterial Disease: Risk Factors

Peripheral Arterial Disease

Approximately 12 million Americans suffer from Peripheral Arterial Disease (PAD), often referred to as hardening of the arteries or atherosclerosis.
This narrowing of the blood vessels in the legs is caused by the buildup of fatty plaque and is a strong predictor of heart disease. Peripheral Arterial Disease may show up in leg arteries before there are any signs or symptoms. Many people experience discomfort while walking that is relieved by rest, but are unaware that it is due to blocked arteries.

Peripheral Arterial Disease Risk Factors
The following are contributing factors that often lead to peripheral arterial disease.
Controllable Peripheral Arterial Disease Risk Factors:

High blood pressure

Smoking

High cholesterol

Excessive alcohol use

Poor diet

Heart disease

Diabetes

Lack of exercise

Obesity

Uncontrollable Peripheral Arterial Disease Risk Factors: Family history and Age

Peripheral Arterial Disease Warning Signs

Unfortunately, there are often no symptoms or warning signs for peripheral arterial disease.

You may want to keep these symptoms in mind in the event that you or a loved one experience the following:

- Constant leg pain, tingling, burning or loss of sensation
- Pain during exercise, which is relieved during rest
- Cold legs
- Poor wound healing

Fontan palliation in women

Pregnancy and delivery in women after Fontan palliation

W Drenthen1, P G Pieper1, J W Roos-Hesselink2, W A van Lottum1, A A Voors1, B J M Mulder3, A P J van Dijk4, H W Vliegen5, K M Sollie6, P Moons7, T Ebels6, D J van Veldhuisen1, for the ZAHARA Investigators
1) Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; 2) Department of Cardiology, Erasmus Medical Centre, Rotterdam, The Netherlands; 3) Department of Cardiology, Academic Medical Centre, Amsterdam, The Netherlands; 4) Department of Cardiology, Radboud University Medical Centre Nijmegen, Nijmegen, The Netherlands; 5) Department of Obstetrics and Gynaecology, University Medical Center Groningen, Groningen, The Netherlands; 6) Department of Thoracic Surgery, University Medical Center Groningen, Groningen, The Netherlands; 7) Department of Cardiology, University Hospitals Leuven, Leuven, Belgium

Objectives: To evaluate the outcome of pregnancy in women after Fontan palliation and to assess the occurrence of infertility and menstrual cycle disorders.
Design and patients: Two congenital heart disease registries were used to investigate 38 female patients who had undergone Fontan palliation (aged 18–45 years): atriopulmonary anastomosis (n = 23), atrioventricular connection (n = 5) and total cavopulmonary connection (n = 10).
Results: Six women had 10 pregnancies, including five miscarriages (50%) and one aborted ectopic pregnancy. During the remaining four live-birth pregnancies clinically significant complications were encountered: New York Heart Association class deterioration; atrial fibrillation; gestational hypertension; premature rupture of membranes; premature delivery; fetal growth retardation and neonatal death. Four of seven women who had attempted to become pregnant reported female infertility: non-specified secondary infertility (n = 2), uterus bicornis (n = 1) and related to endometriosis (n = 1). Moreover, several important menstrual cycle disorders were documented. In particular, the incidence of primary amenorrhoea was high (n = 15, 40%), which resulted in a significant increase in age at menarche (14.6 (SD 2.1) years, p < 0.0001, compared with the general population).
Conclusion: Women can successfully complete pregnancy after adequate Fontan palliation without important long-term sequelae, although it is often complicated by clinically significant (non-)cardiac events. In addition, subfertility or infertility and menstrual disorders were common.

Heart 2006;92:1290-1294
© 2006 by BMJ Publishing Group Ltd & British Cardiovascular Society

Familial combined hyperlipidaemia

Impaired endothelium-dependent vascular reactivity in patients with familial combined hyperlipidaemia

M De Michele1, A Iannuzzi2, A Salvato3, P Pauciullo3, M Gentile3, G Iannuzzo3, S Panico3, A Pujia4, G M Bond5 and P Rubba3
1) Division of Cardiology, Moscati Hospital, Aversa, Italy; 2) Division of Internal Medicine, Cardarelli Hospital, Naples, Italy; 3) Department of Clinical and Experimental Medicine, Federico II University, Naples, Italy; 4) Department of Clinical and Experimental Medicine "G Salvatore", University of Catanzaro Magna Graecia, Catanzaro, Italy; 5) Division of Vascular Ultrasound Research, Wake Forest University, Winston Salem, North Carolina, USA

Background: Familial combined hyperlipidaemia (FCHL) is associated with a markedly increased risk of premature coronary artery disease. This study was designed to evaluate whether preclinical atherosclerotic functional abnormalities are detectable in the arteries of patients with FCHL.

Methods: 60 subjects were recruited for the study: 30 probands of families with FCHL (mean (standard deviation (SD)) age 48 (10) years, 77% men), defined by fasting total plasma cholesterol or triglyceride concentration >250 mg/dl (>6.5 mmol/l cholesterol, >2.8 mmol/l triglyceride) and by the occurrence of multiple lipoprotein phenotypes within a family, and 30 age-matched and sex-matched healthy controls. All subjects underwent high-resolution B-mode ultrasound examination and the brachial arterial reactivity, a marker of endothelial function, was measured by a semiautomated computerised program. Lipid profile, resting blood pressure, body mass index (BMI), smoking status, insulin and homocysteine levels were also determined.

Results: Compared with controls, patients with FCHL had significantly higher BMI, diastolic blood pressure and insulin levels. No difference was observed in baseline brachial diameter between the two groups (mean (SD) 3.45 (0.51) mm for FCHL v 3.60 (0.63) mm for controls; p = 0.17). In response to flow increase, the arteries of the controls dilated (mean (SD) 8.9% (4.9%), range 2.3–20.8%), whereas in the patients with FCHL, brachial arterial reactivity was significantly impaired (5.5% (2.5%), range 0–10.1%; p = 0.002). In multivariate linear regression analysis, apolipoprotein B and BMI were independent determinants of brachial artery response to reactive hyperaemia.

Conclusions: The findings of our study suggest that vascular reactivity is impaired in the arteries of patients with FCHL.

Abbreviations: apo, apolipoprotein; BMI, body mass index; FCHL, familial combined hyperlipidaemia; LDL, low-density lipoprotein

Heart 2007;93:78-81
© 2007 by BMJ Publishing Group Ltd & British Cardiovascular Society

Previous myocardial infarction

The coronary risk of cyclo-oxygenase-2 inhibitors in patients with a previous myocardial infarction

J M Brophy*, L E Lévesque and B Zhang
Department of Epidemiology and Biostatistics, McGill University Health Centre, McGill University, Montréal, Canada

Background: Cyclo-oxygenase-2 selective inhibitors have been associated with cardiovascular side effects, but previous studies have generally excluded people with previous myocardial infarction, thereby limiting our knowledge of their cardiotoxicity in this population.
Objectives: To determine whether a history of myocardial infarction modified the risk of acute myocardial infarction associated with the use of various non-steroidal anti-inflammatory drugs (NSAIDs).
Methods: A population-based cohort of 122 079 elderly people with and without previous myocardial infarction newly treated with an NSAID between 1 January 1999 and 30 June 2002 were identified using the computerised health databases of Québec, Canada. A nested-case–control approach was used for the analysis, with controls matched by cohort entry and age. Current users of NSAIDs, those whose last prescription overlapped with the index date, were compared with those who were not exposed to NSAIDs in the year preceding the event. Rate ratios of acute myocardial infarction were estimated using conditional logistic regression and adjusted for potential confounders.
Results: Users of rofecoxib, both with and without previous myocardial infarction, were at increased risk of myocardial infarction, with a trend for greater risk among those with a previous event (rate ratio (RR) 1.59, 95% confidence interval (CI) 1.15 to 2.18 v RR 1.23, 95% CI 1.05 to 1.45; p = 0.14 for interaction). By contrast, celecoxib was only associated with an increased risk in people with previous myocardial infarction (RR 1.40, 95% CI 1.06 to 1.84 v RR 1.03, 95% CI 0.88 to 1.20; p = 0.04 for interaction). The available power was insufficient to reliably assess risks among patients with previous myocardial infarction treated with other NSAIDs, dose–response relationships or interaction with aspirin.
Conclusions: Although only rofecoxib use was associated with an increased risk of myocardial infarction in those without a previous event, both rofecoxib and celecoxib were associated with an excess risk of acute myocardial infarction for current users with a history of myocardial infarction. A large randomised trial is required to more completely and reliably assess the cardiovascular safety of celecoxib and traditional NSAIDs in this population of high-risk patients.
Abbreviations: Cox-2, cyclo-oxygenase-2; NSAID, non-steroidal anti-inflammatory drug

Heart 2007;93:189-194
© 2007 by BMJ Publishing Group Ltd & British Cardiovascular Society

Vascular implantation: new therapeutic approach

Granulation encapsulated stent: a new therapeutic approach for vascular implantation

Lilong Tang1, Xiaochao Chen1, Shuangbo Tang3, Thomas LaLonde2 and Julius M Gardin2
1) Division of Cardiology, The Fifth Affiliated Hospital to Sun Yat-Sen University, Zhuhai, Guangdong, China
2) Division of Cardiology, St. John Hospital and Medical Center, Detroit, MI, USA
3) Division of Forensic Pathology, Preclinical School of Sun Yat-Sen, Guangzhou, Guangdong, China

Objectives: To determine if stents could be encapsulated with immunocompatible granulation tissue for the treatment of vascular diseases.
Methods: Bare metal stents were implanted in New Zealand white rabbits so they would be encapsulated with immunocompatible granulation tissue. The granulation encapsulated stents (GES) were then treated with either mitomycin C or saline, and implanted into rabbit iliac arteries for 4 weeks. To test whether the effect of mitomycin C was retained, we co-cultured smooth muscle cells for 3 h with subcutaneous tissue (as control) or with granulation tissue from GES treated with mitomycin C and saline.
Results: Vessels with GES treated with mitomycin C (MS) and washed with saline had significantly less neointimal area (NA) after 4 weeks (0.27 (SD 0.03) mm2 than vessels containing bare metal stents (B) (1.15 (SD 0.10) mm2, n = 5, p<0.05) or GES treated with saline (S) (4.78 (SD 0.72) mm2, n = 5, p<0.05). The average vessel injury score was not significantly different among these three groups (S: 1.98 (SD 0.51), MS: 1.46 (SD 0.18) and B: 1.51 (SD 0.32)). GES treated with saline had significantly less NA than the other two groups and also blocked blood flow in the contralateral iliac artery in the abdominal aortic bifurcation immediately after implantation and 4 weeks later. Histology also showed neointimal overgrowth in the vessel wall over the contralateral iliac artery.
Conclusions: GES treated with mitomycin C can significantly inhibit neointimal formation in rabbit arteries due to the formation of granulation tissue. GES treated with saline demonstrated significantly increased NA and resisted normal rabbit artery pressures.
Abbreviations: DMEM, Dulbecco’s modified Eagle’s medium; EIA, external iliac artery; GES, granulation encapsulated stent; GT, granulation tissue; NA, neointimal area; VIS, vessel injury scores; VSMC, vascular smooth muscle cells
Keywords: aneurysm; granulation tissue; restenosis; stent

Heart 2007;93:238-243
© 2007 by BMJ Publishing Group Ltd & British Cardiovascular Society

Cardiac syndrome X: Diagnosis

Cardiac syndrome X: Diagnosis

G A Lanza
Istituto di Cardiologia, Università Cattolica del Sacro Cuore, Rome, Italy

The classic definition of cardiac syndrome X (CSX) is angina-like pain on effort, ST segment depression on exercise stress test and totally normal coronary arteries at angiography in the absence of any other cardiac or systemic diseases (for example, hypertension or diabetes) known to influence vascular function.

Although the origin of the syndrome is still debated, several studies have suggested that CSX is mainly caused by coronary microvascular dysfunction, and indeed the term is often used as a synonym for microvascular angina.

DIAGNOSIS

According to the proposed definition (see above), the diagnosis of CSX would require, together with the presence of typical angina and normal (or near normal) coronary arteries at angiography, some findings compatible with myocardial ischaemia or coronary microvascular dysfunction, or both.

A major diagnostic challenge for the cardiologist, however, is whether patients with CSX can be distinguished with sufficient reliability from those with obstructive CAD on the basis of a careful assessment of clinical findings and non-invasive investigation, which would avoid subjecting the patient to the small but definite risk associated with coronary angiography and would also have favourable effects on costs and use of medical resources.

General data are of limited diagnostic help in individual patients. Compared with those with obstructive CAD, patients with CSX are more commonly women, in whom angina often appears after menopause (either spontaneous or surgical); however, female patients with CAD are also more likely to have angina symptoms after menopause.

The characteristics of chest pain also do not often permit distinguishing between the two groups of patients. However, the presence of some findings strongly orient the diagnosis towards CSX. These, in particular, are a prolonged (> 15–20 min) dull persistence of chest discomfort after resolution of typical chest pain induced by exercise and a lack of response, or a slow or incomplete response, to administration of short-acting nitrates to relieve pain, both features occurring in about 50% of patients.

Among diagnostic stress tests, the careful analysis of abnormal exercise and stress scintigraphic results also does not usually help to identify patients with CSX. In contrast, the induction of typical, often severe angina during echocardiographic stress test (for example, with dipyridamole or dobutamine) in the presence of ST segment depression, but in the absence of LV contractile abnormalities, strongly suggests CSX, although LV dysfunction can also be undetectable in patients with mild forms of CAD.

Repeating exercise testing after giving sublingual nitrates may also help to identify patients with CSX. Indeed, preventive administration of short-acting nitrates usually improves exercise-induced ST segment changes and symptoms in patients with CAD, whereas short-acting nitrates may paradoxically induce earlier ST segment changes during the test in some patients with CSX.

Lastly, although unpractical for clinical use, assessing platelet reactivity in response to ADP/collagen after exercise may provide a further clue to CSX diagnosis in patients with angina. Indeed, by using the platelet function analyser-100 method, we have recently found that a lengthening by =" type="#_x0000_t75">10 s of the aggregation time after exercise (implying a reduction of platelet reactivity) was detectable only in patients with CSX, whereas a reduction =" type="#_x0000_t75">10 s (implying an increase of platelet reactivity) was detectable only in patients with CAD.

Thus, careful clinical and non-invasive diagnostic assessment of patients with effort angina can find strong clues to the diagnosis of CSX, which may lead to a sufficiently reliable diagnosis of probable CSX, in particular when more suggestive findings are detected together in individual patients.

In the presence of probable CSX, when a definitive diagnosis is required, the preferred test to document the presence of normal coronary arteries should perhaps now be considered to be multislice spiral computed tomography coronary angiography, which has a high negative predictive value for significant CAD (> 95%) and would avoid the small but definite risk of invasive coronary angiography to the patient.

Heart 2007;93:159-166
© 2007 by BMJ Publishing Group Ltd & British Cardiovascular Society

Small-vessel vasculitis

Increased prevalence of subclinical atherosclerosis in patients with small-vessel vasculitis

G Chironi1, C Pagnoux2, A Simon1, M Pasquinelli-Balice1, M Del-Pino1, J Gariepy1 and L Guillevin2
1) Centre de Médecine Préventive Cardiovasculaire, Groupe Hospitalier Broussais-HEGP, Université Paris V, Paris, France; 2) Service de Médecine Interne, Hôpital Cochin, Université Paris V, Paris, France

Background and objective: Although changes in smaller vessels is the hallmark of medium-sized and small-vessel vasculitis, it has been suggested that large arteries of such patients may also be affected by the early atherosclerotic process because of coexisting risk factors or systemic inflammation. This study aimed to bring additional arguments supporting this hypothesis.
Design, setting and patients: 50 consecutive patients with primary systemic necrotising vasculitis and 100 controls matched for age and sex underwent ultrasonic detection of plaque in three peripheral vessels (carotid and femoral arteries and abdominal aorta). Cardiovascular risk factors and inflammation (C reactive protein (CRP)) were concomitantly measured in all participants, and diagnosis of high-risk status was defined by the presence of known history of cardiovascular disease, type 2 diabetes or 10-year-Framingham Risk Score =" src="http://heart.bmj.com/math/ges.gif" border=0>20%.
Results: Patients had higher frequency of plaque than controls in the carotid arteries (p<0.05), in the aorta (p<0.01) and in the three vessels examined (p<0.001), and adjustment for high-risk status did not confound such difference in the aorta and in the three vessels. In the overall population of patients and controls, vasculitis was associated with a higher frequency of three-vessel plaques (p<0.05), independently of high-risk status and CRP. In patients, the higher frequency of three-vessel plaques was associated with high-risk status (p<0.05) but not with CRP, or disease and treatment characteristics.
Conclusions: Small-vessel vasculitis is associated with more frequent subclinical atherosclerosis, especially extended to multiple peripheral vessels, and such association is not entirely explained by cardiovascular risk factors and systemic inflammation.

Heart 2007;93:96-99
© 2007 BMJ Publishing Group Ltd & British Cardiovascular Society