The new era of cardiac surgery: hybrid therapy for cardiovascular disease

Surgical therapy for cardiovascular disease carries excellent long-term outcomes but it is relatively invasive. With the development of new devices and techniques, modern cardiovascular surgery is trending toward less invasive approaches, especially for patients at high risk for traditional open heart surgery. A hybrid strategy combines traditional surgical treatments performed in the operating room with treatments traditionally available only in the catheterization laboratory with the goal of offering patients the best available therapy for any set of cardiovascular diseases. Examples of hybrid procedures include hybrid coronary artery bypass grafting, hybrid valve surgery and percutaneous coronary intervention, hybrid endocardial and epicardial atrial fibrillation procedures, and hybrid coronary artery bypass grafting/carotid artery stenting. This multidisciplinary approach requires strong collaboration between cardiac surgeons, vascular surgeons, and interventional cardiologists to obtain optimal patient outcomes.     

Evidence-based management of coronary artery disease in the elderly--current perspectives

Cardiovascular disease accounts for significant morbidity and mortality in the elderly. The clinical trial data available to guide therapy in this growing population subset are relatively limited. This review will focus on treatment approaches and recommendations obtained from subgroup analyses of elderly patients from major clinical trials for the management of chronic stable angina, acute coronary syndromes (unstable angina and non-ST-segment elevation myocardial infarction), and coronary revascularization. Recent advances in the treatment of stable angina have shown that use of angiotensin-converting enzyme inhibitors and lipid-lowering therapy as adjunctive measures show benefit in the elderly by reducing the occurrence of death, nonfatal myocardial infarction, and unstable angina. However, if patients experience disabling or unstable anginal symptoms despite effective medical therapy, coronary revascularization must be considered. Several clinical trials have shown a significant reduction in major adverse cardiac events when using intravenous glycoprotein receptor antagonists periprocedurally during percutaneous revascularization approaches in elderly patients with unstable angina or non-ST-segment elevation myocardial infarction, especially when these measures are performed as soon as possible. However, the success of myocardial revascularization by a percutaneous or surgical approach is highly dependent on the patient's associated comorbidities, especially in patients over age 80 years.     

Effects of pool isolation on trophic ecology of fishes in a highland stream

The objective of this study was to examine the effects of pool isolation on fish diet and to answer three questions: Were food resources different or reduced in isolated compared with connected pools? Were fishes more selective and did they increase resource partitioning in isolated pools? Would individuals exhibit increased gastrointestinal tract (GIT) length in isolation to aid nutrient absorption? Benthic macroinvertebrate density and richness were significantly lower in isolated pools compared with connected pools; fishes became more selective and partitioned resources more in isolated pools and all three species showed an increase in GIT length in isolated pools compared with connected pools. With a changing climate predicted to increase intermittency within headwater streams, the results show that these fishes have the adaptive ability to respond and continue to survive.     

Image-based modeling of hemodynamics in coronary artery aneurysms caused by Kawasaki disease

Kawasaki Disease (KD) is the leading cause of acquired pediatric heart disease. A subset of KD patients develops aneurysms in the coronary arteries, leading to increased risk of thrombosis and myocardial infarction. Currently, there are limited clinical data to guide the management of these patients, and the hemodynamic effects of these aneurysms are unknown. We applied patient-specific modeling to systematically quantify hemodynamics and wall shear stress in coronary arteries with aneurysms caused by KD. We modeled the hemodynamics in the aneurysms using anatomic data obtained by multi-detector computed tomography (CT) in a 10-year-old male subject who suffered KD at age 3?years. The altered hemodynamics were compared to that of a reconstructed normal coronary anatomy using our subject as the model. Computer simulations using a robust finite element framework were used to quantify time-varying shear stresses and particle trajectories in the coronary arteries. We accounted for the cardiac contractility and the microcirculation using physiologic downstream boundary conditions. The presence of aneurysms in the proximal coronary artery leads to flow recirculation, reduced wall shear stress within the aneurysm, and high wall shear stress gradients at the neck of the aneurysm. The wall shear stress in the KD subject (2.95-3.81 dynes/sq cm) was an order of magnitude lower than the normal control model (17.10-27.15 dynes/sq cm). Particle residence times were significantly higher, taking 5 cardiac cycles to fully clear from the aneurysmal regions in the KD subject compared to only 1.3 cardiac cycles from the corresponding regions of the normal model. In this novel quantitative study of hemodynamics in coronary aneurysms caused by KD, we documented markedly abnormal flow patterns that are associated with increased risk of thrombosis. This methodology has the potential to provide further insights into the effects of aneurysms in KD and to help risk stratify patients for appropriate medical and surgical interventions.     

Clinical trials of gene therapy for atherosclerotic cardiovascular disease

PURPOSE OF REVIEW: To provide an update on clinical trials of gene therapy for atherosclerotic cardiovascular disease published since 1 August 2001 and summarize the general advantages and potential problems of gene transfer in these disorders. RECENT FINDINGS: There are two major areas in which gene therapy has entered clinical trials. The first is angiogenesis for coronary and peripheral arterial disease. Two relatively small placebo-controlled trials for coronary disease were reported, one using intramyocardial plasmid VEGF-2 gene, the other using intracoronary adenoviral FGF-4 gene. The VEGF-2 study in no-option patients showed reduced angina, and significant improvement in perfusion and function, whereas the FGF-4 study in less severely affected patients showed promising results in some subsets. In peripheral artery disease two phase 1 studies of adenoviral NV1FGF and VEGF showed some objective improvement in pain, ulcer size and ankle:brachial index in one study and endothelial function in the other. Both adenoviral and plasmid VEGF gene transfer at angioplasty increased vascularity in a phase 2 double-blind study. The other major area is the prevention of graft disease and restenosis using antisense oligodeoxynucleotides. E2F decoy led to a significant reduction in venous graft complications after ex-vivo transfection at the time of coronary bypass surgery, whereas the c-Myc oligodeoxynucleotide was ineffective in preventing in-stent coronary restenosis. SUMMARY: There are more reviews of gene therapy for atherosclerosis in the literature than publications with original data or trials, but in the past year the imbalance is being redressed, with some promising results from controlled studies.     

Prolactinomas, Cushing's disease and acromegaly: debating the role of medical therapy for secretory pituitary adenomas

Pituitary adenomas are associated with a variety of clinical manifestations resulting from excessive hormone secretion and tumor mass effects, and require a multidisciplinary management approach. This article discusses the treatment modalities for the management of patients with a prolactinoma, Cushing's disease and acromegaly, and summarizes the options for medical therapy in these patients. First-line treatment of prolactinomas is pharmacotherapy with dopamine agonists; recent reports of cardiac valve abnormalities associated with this class of medication in Parkinson's disease has prompted study in hyperprolactinemic populations. Patients with resistance to dopamine agonists may require other treatment. First-line treatment of Cushing's disease is pituitary surgery by a surgeon with experience in this condition. Current medical options for Cushing's disease block adrenal cortisol production, but do not treat the underlying disease. Pituitary-directed medical therapies are now being explored. In several small studies, the dopamine agonist cabergoline normalized urinary free cortisol in some patients. The multi-receptor targeted somatostatin analogue pasireotide (SOM230) shows promise as a pituitary-directed medical therapy in Cushing's disease; further studies will determine its efficacy and safety. Radiation therapy, with medical adrenal blockade while awaiting the effects of radiation, and bilateral adrenalectomy remain standard treatment options for patients not cured with pituitary surgery. In patients with acromegaly, surgery remains the first-line treatment option when the tumor is likely to be completely resected, or for debulking, especially when the tumor is compressing neurovisual structures. Primary therapy with somatostatin analogues has been used in some patients with large extrasellar tumors not amenable to surgical cure, patients at high surgical risk and patients who decline surgery. Pegvisomant is indicated in patients who have not responded to surgery and other medical therapy, although there are regional differences in when it is prescribed. In conclusion, the treatment of patients with pituitary adenomas requires a multidisciplinary approach. Dopamine agonists are an effective first-line medical therapy in most patients with a prolactinoma, and somatostatin analogues can be used as first-line therapy in selected patients with acromegaly. Current medical therapies for Cushing's disease primarily focus on adrenal blockade of cortisol production, although pasireotide and cabergoline show promise as pituitary-directed medical therapy for Cushing's disease; further long-term evaluation of efficacy and safety is important.     

Debate: PCI vs CABG: a moving target, but we are gaining

The treatment of patients with coronary artery disease continues to evolve; all three strategies – medical therapy, surgical revascularization, and percutaneous coronary intervention – have changed. Medical therapy with intense risk-factor modification and treatment with a statin, aspirin, and angiotensin-converting enzyme (ACE) inhibitors, should be used unless contraindicated. Surgical therapy has also changed with the introduction of minimally invasive, beating heart surgery. Percutaneous coronary intervention has perhaps changed the most radically with adjunctive therapy – glycoprotein IIb/IIIa inhibitors, thienopyridines, and reliance on stent implantation. The future, with new distal protection devices and drug-coated stents, should continue to see increased numbers of patients who can benefit from percutaneous intervention.     

Current clinical perspectives on myocardial angiogenesis

Currently accepted modalities of treatment for atherosclerotic coronary artery disease (CAD) include pharmacological therapy, and revascularization with either bypass surgery or percutaneous coronary intervention (PCI). Similarly, conventional treatment of congestive heart failure (HF) is limited to medical therapy, temporary assist devices and in a select few, cardiac transplantation. A significant subset of patients with severe symptomatic CAD and end stage HF is not eligible for these traditional methods of treatment. In spite of maximal medical and revascularization therapy, these patients may not get adequate symptomatic relief. After a decade of investigations, gene therapy is emerging as a promising therapeutic option for this group of patients. This review discusses myocardial angiogenesis as a therapeutic modality in these patients including therapeutic angiogenesis with growth factors and cell transplantation.     

HDL-raising strategies in the treatment of coronary artery disease: perspectives from the Armed Forces Regression Study

PURPOSE OF REVIEW: Even with the aggressive reduction of LDL-cholesterol, the risk of cardiovascular events in patients with coronary artery disease remains substantial. The Armed Forces Regression Study was a randomized, double-blind, placebo-controlled trial of combination drug therapy aimed at raising HDL-cholesterol in patients with angiographically evident coronary artery disease. Drug therapy ultimately resulted in regression of the angiographic lesions and a reduction in cardiovascular events. This review places the Armed Forces Regression Study within the context of other recent studies. RECENT FINDINGS: In the past few years a number of other important papers have further defined the important role HDL-cholesterol plays in the pathobiology of atherosclerosis. These studies have focused on three general areas: HDL-cholesterol metabolism and the reverse cholesterol transport pathway; novel therapeutic interventions and their effects on coronary artery disease as assessed through non-invasive imaging modalities; and finally a re-analysis of previous outcomes trials with established HDL-cholesterol modifying agents. SUMMARY: The results of the Armed Forces Regression Study fit nicely within the evolving paradigm of targeting HDL-cholesterol in patients at risk of cardiovascular events. The use of niacin and well-tolerated fibrates as an adjunct to statins or as primary therapy in patients intolerant of statins appears reasonable in patients with low levels of HDL-cholesterol and at high risk of cardiovascular events. The further development of novel therapeutic approaches, in addition to broadening our pharmacological armamentarium, should further advance our understanding of HDL-cholesterol.     

Modification of coronary artery disease progression by cholesterol-lowering therapy: the angiographic studies

Large randomized placebo-controlled trials have demonstrated that cholesterol lowering with statin therapy reduces the incidence of adverse cardiac events. Smaller angiographic studies have shown that coronary artery disease progression can be slowed and, in some cases, reversed by cholesterol-lowering interventions. These anatomical changes, however, are small and occur too slowly to account for the early clinical benefit. Current evidence suggests that plaque stabilization is the most important mechanism, by which cholesterol-lowering therapy reduces both the incidence of adverse cardiac events and coronary artery disease progression.     

Delayed diagnosis of symptomatic coronary artery disease in young men

Delay in making the diagnosis of symptomatic coronary artery disease was determined by studying the medical histories of 265 men aged 24.7 to 49.9 (mean 40.1) years with angiographically proven obstructive coronary atherosclerosis. The diagnosis of angina pectoris was delayed three times as often as the diagnosis of myocardial infarction, and for five times as long. The diagnosis of symptomatic coronary artery disease was delayed three and a half times more often in patients less than 35 years of age, than in patients over 45; the average time from presentation with symptoms to diagnosis was 30 times longer in patients under 35 years of age than in patients over 45.     

The discovery of the selective If current inhibitor ivabradine (Procoralan): a new therapeutic approach to ischemic heart disease

Coronary artery disease is still a major cause of morbidity and mortality in the industrialized countries and its prevalence is predicted to grow with the current aging of the population in these countries. In spite of the rapid pace of progress and increasing use of myocardial revascularization procedures, in particular percutaneous coronary interventions, the medical treatment of coronary artery disease has lost none of its relevance in the majority of patients, though conventional drugs have their limitations and the pharmacological approach to ischemic heart disease needs to be improved in terms of efficacy and tolerance to ensure better prevention of mortality and improvement in quality of life. Since increased heart rate plays a major role in coronary artery disease, not only as a trigger of most ischemic episodes, but also as an independent predictor of mortality, inhibition of the pacemaker If current in view of inducing a direct and selective decrease in heart rate represents an ideal conceptual target and an attractive therapeutic approach to coronary artery disease. The screening of original benzocycloalkane compounds at the Servier Research Institute resulted in the selection of ivabradine (Procoralan) for clinical development. Preclinical data showed that ivabradine inhibits the If current originating in the sinus node, induces a selective reduction in heart rate both at rest and during exercise, preserves myocardial contractility, atrioventricular conduction and ventricular repolarization and prevents exercise-induced myocardial ischemia as effectively as a b-blocker while offering better protection of regional myocardial contractility. These data were confirmed in humans, in particular the anti-ischemic efficacy of ivabradine, at least as effective as that of a b-blocker in patients with stable angina. Large ongoing clinical trials are seeking to assess the therapeutic value of ivabradine in ischemic heart failure and its potential for improving the prognosis of coronary artery disease by reducing mortality and the occurrence of major cardiovascular events.     

Lipid management after acute coronary syndrome

PURPOSE OF REVIEW: Despite advances in medical therapy and percutaneous revascularization, patients with acute coronary syndrome face a high risk of early, recurrent cardiovascular events. Interventions targeting atherogenic lipoproteins may favorably modify this risk. RECENT FINDINGS: Two randomized clinical trials, MIRACL and PROVE-IT, demonstrated efficacy of early, intensive statin therapy after acute coronary syndrome. Recent observational and meta-analyses corroborate the findings of these trials. The benefit of intensive statin treatment appears to apply broadly to elderly as well as younger patients, and to patients with or without diabetes or metabolic syndrome. Randomized trials demonstrating the efficacy of early, intensive statin treatment after acute coronary syndrome employed fixed statin dosages, and there does not appear to be an initial or achieved LDL-cholesterol level below which benefit is absent. As such, broad application of intensive statin therapy after acute coronary syndrome may be preferable to titration of statin dose to achieve specific LDL goals. Low HDL-cholesterol predicts risk after acute coronary syndrome; therefore, pharmacologic interventions to raise HDL concentration or mimic its function may help reduce that risk. SUMMARY: Early, intensive statin therapy is safe and effective after acute coronary syndrome. Future research will determine whether drugs that raise or mimic HDL-cholesterol are effective adjuncts to statin therapy.     

Cardiac evaluation and risk reduction in patients undergoing major vascular operations.

Occult coronary artery disease often accompanies symptomatic peripheral vascular disease and has an important effect on survival. Most perioperative and late fatalities after peripheral vascular operations are due to cardiac causes. Noninvasive cardiac testing can identify patients at increased risk for postoperative cardiac complications, although controversy exists regarding the optimal preoperative evaluation. Risk reduction strategies for patients known to be at high risk are also controversial. Some authors advocate coronary revascularization with coronary artery bypass grafting or percutaneous transluminal coronary angioplasty before the vascular procedure. Others believe that the combined morbidity and mortality of 2 operations exceed those of a peripheral vascular operation performed with aggressive monitoring and medical therapy. Continuous electrocardiographic monitoring after an operation has identified silent myocardial ischemia as a powerful predictor of cardiac complications. Ongoing research is likely to provide insights into the pathogenesis of postoperative cardiac complications and may lead to specific therapeutic interventions. Few prospective studies have been done in this area, and the threshold for preoperative and postoperative intervention is unknown. I review the literature and present an algorithm to guide cardiac testing and risk reduction in patients undergoing elective vascular surgical procedures.     

Current clinical perspectives on myocardial angiogenesis

Currently accepted modalities of treatment for atherosclerotic coronary artery disease (CAD) include pharmacological therapy, and revascularization with either bypass surgery or percutaneous coronary intervention (PCI). Similarly, conventional treatment of congestive heart failure (HF) is limited to medical therapy, temporary assist devices and in a select few, cardiac transplantation. A significant subset of patients with severe symptomatic CAD and end stage HF is not eligible for these traditional methods of treatment. In spite of maximal medical and revascularization therapy, these patients may not get adequate symptomatic relief. After a decade of investigations, gene therapy is emerging as a promising therapeutic option for this group of patients. This review discusses myocardial angiogenesis as a therapeutic modality in these patients including therapeutic angiogenesis with growth factors and cell transplantation. (Mol Cell Biochem 264: 157–167, 2004)     

Coronary computed tomographic angiography as gatekeeper for new-onset stable angina

Patients with new-onset stable angina constitute a substantial part of the population seen by cardiologists. Currently, the diagnostic workup of these patients depends on the pre-test probability of having obstructive coronary artery disease. It consists of either functional testing for myocardial ischaemia or anatomical testing by using coronary computed tomographic angiography (CCTA) or invasive coronary angiography. In case the pre-test probability is > 5%, the current guidelines for the management of chronic coronary syndromes do not state a clear preference for one of the noninvasive techniques. However, based on the recently published cost-effectiveness analysis of the PROMISE trial and considering the diagnostic yield in patients with angina and nonobstructive coronary artery disease, we argue a more prominent role for CCTA as a gatekeeper for patients with new-onset stable angina.     

CTCA for detection of significant coronary artery disease in routine TAVI work-up

Transcatheter aortic valve implantation (TAVI) has evolved to standard treatment of severe aortic stenosis in patients with an intermediate to high surgical risk. Computed tomography coronary angiography (CTCA) could partially replace invasive coronary angiography to diagnose significant coronary artery disease in the work-up for TAVI. A literature search was performed in MEDLINE and EMBASE for papers comparing CTCA and coronary angiography in TAVI candidates. The primary endpoint was the diagnostic accuracy of CTCA, compared to coronary angiography, for detection of significant (>50% diameter stenosis) coronary artery disease, measured as sensitivity, specificity, positive—(PPV) and negative predictive value (NPV). Seven studies were included, with a cumulative sample size of 1,275 patients. The patient-based pooled sensitivity, specificity, PPV and NPV were 95, 65, 71 and 94% respectively. Quality assessment revealed excellent and good quality in terms of applicability and risk of bias respectively, with the main concern being patient selection. In conclusion, on the basis of a significance cut-off value of 50% diameter stenosis, CTCA provides acceptable diagnostic accuracy for the exclusion of coronary artery disease in patients referred for TAVI. Using the routinely performed preoperative computed tomography scans as a gatekeeper for coronary angiography could decrease additional coronary angiographies by 37% in this high-risk and fragile population.     

Performance of WHO Angina Questionnaire in measuring burden of coronary heart disease in human isolate populations

Isolated human populations represent good candidates for studying genetic and environmental causes of common complex diseases because of their decreased genetic and environmental diversity. The possibility of inexpensive and reliable detection of disease prevalence in such populations is therefore of considerable importance, as comprehensive routine health data and disease registries are rarely available in these populations. In this study, we validated the performance of the WHO Rose Angina Questionnaire (RQ) in measuring the burden of coronary heart disease (CHD) in 9 settlements in these Croatian Adriatic islands. CHD was defined as myocardial infarction (MI) diagnosed by a specialist in the local general hospital, or angina pectoris (AP) by a local general practitioner (GP). The true prevalence of CHD in 1,001 adult persons was 10.5%. The results of the RQ screening based on the first 3, 5 and 6 questions were compared with medical record of CHD. Increasing the number of RQ questions from 3 to 6 resulted in decreasing test sensitivity (from 59.0% to 30.5%) and increasing test specificity (from 86.3% to 93.0%) in the prediction of true CHD status. CHD prevalence was overestimated by 76% when subset of the first 3 questions of RQ was used and by 25% when the first 5 questions were used. However, it was underestimated by 10% when the first 6 questions were used. We conclude that RQ is a useful screening method for measuring burden of CHD in isolate human populations, and that the result based on the first 6 questions is a good approximation of the true CHD prevalence in the population, although it should be considered a slight underestimate.     

Emerging relations between infectious diseases and coronary artery disease and atherosclerosis

Cardiovascular disease is the leading cause of death in developed countries. The cause is multifactorial. A substantial proportion of patients with coronary artery disease (CAD) do not have traditional risk factors. Infectious diseases may play a role in these cases, or they may intensify the effect of other risk factors. The association of CAD and Chlamydia pneumoniae infection is firmly established, but causality is yet to be proven. The link with other infectious agents or conditions, such as cytomegalovirus, herpes simplex virus, Helicobacter pylori and periodontitis, is more controversial. Cytomegalovirus infection is more strongly linked than native CAD to coronary artery restenosis after angioplasty and to accelerated CAD after cardiac transplantation. However, new data on this topic are appearing in the literature almost every month. The potential for novel therapeutic management of cardiovascular disease and stroke is great if infection is proven to cause or accelerate CAD or atherosclerosis. However, physicians should not "jump the gun" and start using antibiotic therapy prematurely for CAD. The results of large randomized clinical trials in progress will help establish causality and the benefits of antimicrobial therapy in CAD.