Placebo and nocebo in cardiovascular health: implications for healthcare, research, and the doctor-patient relationship.

Despite treatments proven effective by sound study designs and robust end points, placebos remain integral to elicit effective medical care. The authenticity of the placebo response has been questioned, but placebos likely affect pain, functionality, symptoms, and quality of life. In cardiology, placebos influence disability, syncope, heart failure, atrial fibrillation, angina, and survival. Placebos vary in strength and efficacy. Compliance to placebo affects outcomes. Nocebo responses can explain some adverse clinical outcomes. A doctor may be an unwitting contributor to placebo and nocebo responses. Placebo and nocebo mechanisms, not well understood, are likely multifaceted. Placebo and nocebo use is common in practice. A successful doctor-patient relationship can foster a strong placebo response while mitigating any nocebo response. The beneficial effects of placebo, generally undervalued, hard to identify, often unrecognized, but frequently used, help define our profession. The role of the doctor in healing, above the therapy delivered, is immeasurable but powerful. An effective placebo response will lead to happy and healthy patients. Imagine instead the future of healthcare relegated to a series of guidelines, tests, algorithms, procedures, and drugs without the human touch. Healthcare, rendered by a faceless, uncaring army of protocol aficionados, will miss an opportunity to deliver an effective placebo response. Wise placebo use can benefit patients and strengthen the medical profession.     

Implantable Dual-Chamber Defibrillator for the Selective Treatment of Spontaneous Atrial and Ventricular Arrhythmias: Arrhythmia Incidence and Device Performance

Introduction: Atrial tachyarrhythmias are a common co-morbidity in patients with an ICD indication. Recently introduced ICDs are equipped to independently detect and treat atrial and ventricular tachyarrhythmias. The purpose of this prospective study was to evaluate the incidence and termination of spontaneous atrial and ventricular tachyarrythmias in patients with a history of atrial tachyarrhythmias.Methods and Results: Ninety patients, 70% male with an ICD indication and history of atrial tachyarrhythmia (LVEF 45 ± 6%, [AT/AF indication 55 ± 10, AT/VT 45 ± 16], 46% CAD) were enrolled and 89 were implanted with a VENTAK PRIZM AVT (Guidant). Spontaneous atrial and ventricular tachyarrhythmias were printed and evaluated during an average follow-up period of 272 ± 72 days utilizing the stored intracardial electrogram function of the device. Nineteen patients (21%) presented had only atrial tachyarrhythmias, 32 patients (36%) had both atrial and ventricular tachyarrhythmias and 18 patients (20%) had only ventricular tachyarrhythmias. Patients with only atrial tachyarrhythmias had a total of 3274 atrial episodes; 2002 terminated spontaneously, 1264 were treated with ATP and 8 with shock therapy. ATP was successful in 735 (58%) of 1264 episodes. Patients with both atrial and ventricular tachyarrhythmias had 7277 documented atrial tachyarrhythmias, 5231 terminated spontaneously, 1153 of 2009 were terminated by ATP (57.4%) and 37 by shock therapy (20 patient controlled). Atrial tachyarrhythmias identified as atrial flutter (AT) by the atrial rhythm classification (ARC) algorithm had a higher ATP conversion success rate than episodes identified as atrial fibrillation (AF); 66.7% for AT and 26.4% for AF. Patients with only ventricular tachyarrhythmias had 690 documented episodes, 401 terminated spontaneously, 248 (85.8%) were terminated by ATP and 41 by shock.Conclusion: Seventy-seven percent of patients with an ICD indication had spontaneous atrial and/or ventricular tachyharrhythmias within the first 6 months after ICD implantation. ATP therapy terminated 58% of all atrial tachyarrhytmias and 66.7% of the atrial flutters. The dual chamber ICD detected, classified and terminated all ventricular tacharrhythmias appropriately.     

Plaque neovascularization and antiangiogenic therapy for atherosclerosis

The concept that neovascularization of the vessel wall may play a fundamental role in the pathophysiology of atherosclerosis was proposed more than a century ago. In recent years, supportive experimental evidence for this hypothesis (such as the finding that neointimal microvessels may increase delivery of cellular and soluble lesion components to the vessel wall) has been underscored by clinical studies associating plaque angiogenesis with more rapidly progressive high-grade disease. Attention has also focused on a possible role for microvessel-derived intraplaque hemorrhage in the development of acute lesion instability. The interest of clinicians in this phenomenon has been spurred by the potential to target vessel wall neovascularization with angiogenesis inhibitors, a therapeutic approach that has been associated with impressive reductions in plaque progression in animal models of vascular disease. The rationale for pursuing an "antiangiogenic" strategy in the treatment of patients with vascular disease, and a framework for further preclinical evaluation of such therapy, is presented here.     

Atrial fibrillation and Brugada syndrome

Brugada syndrome is characterized by right bundle branch block pattern with ST-segment elevation in leads V(1) to V(3) and a propensity for sudden cardiac death due to ventricular arrhythmias. The arrhythmogenic substrate in Brugada syndrome may not be restricted to the ventricles, and atrial arrhythmias are being increasingly reported. Incidences of spontaneous atrial arrhythmias vary from 6% to 38% and those of inducible atrial arrhythmias from 3% to 100%. Atrial fibrillation (AF) is the most common atrial arrhythmia found in Brugada syndrome. Enhanced duration of atrial action potential and increased intra-atrial conduction time may contribute to the genesis of atrial arrhythmias in Brugada syndrome. Atrial arrhythmias are an important cause of inappropriate discharge of implantable defibrillators in patients with Brugada syndrome. Hence, implantation of dual-chamber defibrillators and careful programming of single-chamber devices have been recommended. Atrial fibrillation has been associated with mutations in both the sodium and calcium channels of the heart, as well as with cases of Brugada syndrome that could not genotyped to any of the known genes associated with the disease. This observation suggests that the substrate responsible for the development of ventricular arrhythmias also may contribute to arrhythmogenesis in the atria of the heart. The presence of a prominent transient outward current in atria and the observation that episodes of AF are triggered by closely coupled atrial extrasystoles point to the possibility that a substrate similar to that responsible for ventricular arrhythmogenesis underlies the development of AF in patients with Brugada syndrome.     

Atherosclerosis in the back yard

The phenomenon of neovascularization in atherosclerosis has been widely recognized through "the eyes of novel imaging techniques" in recent years. Oxidative stress, inflammation, and hypoxia have been implied as the underlying mechanisms. The pathophysiologic consequences and therapeutic implications of this neovascularization process for atherosclerosis have, however, remained challenging and controversial. In the current focus issue of the Journal, 4 articles and this commentary are devoted to this topic.     

Mechanisms, prevention, and treatment of atrial fibrillation after cardiac surgery

Post-operative atrial fibrillation (POAF) is a frequent complication occurring in 30% to 50% of patients after cardiac surgery. It is associated with an increased risk of mortality and morbidity, predisposes patients to a higher risk of stroke, requires additional treatment, and increases the costs of the post-operative care. The aim of this review is to present the current state of knowledge about the risk factors, mechanisms, prevention, and treatment of this complication. In addition to the well known risk factors for the development of POAF such as age, left atrial enlargement, and valvular surgery, new metabolic risk factors related to visceral obesity have been identified. With regard to the prevention of POAF, beta-blocker drugs are effective and safe and can be used in most patients, whereas amiodarone can be added in high-risk patients. Biatrial pacing was shown to be effective; however, its complexity might limit its application. Although there are only few data regarding the usefulness of magnesium, statins, N-3 polyunsaturated fatty acids, and corticosteroids, their addition to beta-blocker drugs might be of benefit for further reducing POAF. Treatment includes the use of an AV nodal blocking agent to achieve the rate control. If AF does not spontaneously convert to sinus rhythm within 24 h, anticoagulation should be initiated and a rhythm control strategy should be attempted. More investigations are warranted to explore mechanisms by which POAF occurs. This new knowledge would undoubtedly translate into a more efficient prevention and treatment of this common post-operative complication that is associated with a major health and economic burden.     

Progression of Device-Detected Subclinical Atrial Fibrillation and the Risk of Heart Failure

Background

Long-term continuous monitoring detects short-lasting, subclinical atrial fibrillation (SCAF) in approximately one-third of older individuals with cardiovascular conditions. The relationship between SCAF, its progression, and the development of heart failure (HF) is unclear.

The Compelling Need for a Cardiology and Oncology Partnership and the Birth of the International CardiOncology Society

Cardiac disease in patients with cancer is common and influences the longevity and quality of life both of patients in active treatment and of survivors of cancer. The disciplines of cardiology and oncology have increasingly recognized the benefits to patients of collaborating in the care of cancer patients with cardiac disease. This increased recognition arises from several factors: the aging population in which both cardiac and cancer diagnoses are common; the cellular and molecular therapeutic targets of newer medical treatments, and, in particular, the specific patient treatment choices and decisions that require careful, effective clinical interactions between these 2 disciplines. Responding to this need for an effective partnership between cardiology and oncology, the International CardiOncology Society was created and has set goals to develop and enhance our understanding and management of these clinical difficulties.     

Digoxin and Mortality in Patients With Atrial Fibrillation

Background

Digoxin is widely used in patients with atrial fibrillation (AF).

Leptin–VEGF crosstalk in excess body mass and related disorders: A systematic review

By 2030, it is expected that a billion people will have suffer from obesity. Adipose tissue synthesizes leptin, an adipokine that affects cardiovascular risk. Leptin intensifies the synthesis of vascular endothelial growth factor (VEGF). Our study reviews recent reports on leptin–VEGF crosstalk in obesity and related disorders. PubMed, Web of Science, Scopus, and Google Scholar were searched. One hundred and one articles involving human, animal, and in vitro research were included. In vitro studies show the crucial role of interaction between endothelial cells and adipocytes and hypoxia as a factor that intensifies leptin's effects on VEGF. Leptin–VEGF crosstalk promotes the progression of cancer. The animal research reveal that a high-fat diet enhances leptin and VEGF crosstalk. Genetic and epigenetic mechanisms and procreator-offspring programming may be involved in leptin–VEGF crosstalk. Some female-specific characteristics of leptin–VEGF relation in obesity were observed. The human studies have shown that increased leptin and VEGF synthesis and leptin–VEGF crosstalk are factors linking obesity with elevated cardiovascular risk. The studies of the last 10 years documented a range of significant aspects of leptin–VEGF crosstalk specific for obesity and related disorders, shedding new light on the link between obesity and increased cardiovascular risk.     

Role of genetic analysis in the management of patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a recognized cause of sudden cardiac death, which may be prevented by timely detection and intervention. Clinical diagnosis of ARVC is fraught with difficulties in both index cases and relatives owing to the nonspecific nature of associated features, diverse phenotypic manifestations, and a lack of conspicuous abnormalities in the early, "concealed" phase. During the past 7 years, researchers have isolated causative mutations in several components of the desmosome, shedding light on the molecular mechanisms underlying the disease and offering the promise of genetic testing as a diagnostic tool. Sequence analysis is likely to be the mainstay of genotyping in ARVC because of marked allelic heterogeneity, frequent "private" mutations, and digenicity in a minority, highlighting the importance of comprehensive genetic screening. The main technical obstacle to implementation of genotyping in clinical practice will be the prohibitive costs of performing sequence analysis of a genomic region exceeding 40 kb. Nevertheless, the success rate of genotyping in ARVC is of the order of 40%, and key clinical applications include confirmatory testing of index cases to facilitate interpretation of borderline investigations and cascade screening of families. The latter is particularly attractive in ARVC, because age-related penetrance otherwise demands lifelong clinical reassessment of extended families. A role for genetic analysis in prognostication is more tenuous at present, but increasing identification of individuals with early and familial disease underscores the need for a definitive risk stratification algorithm in this population.     

Survival and cause-specific mortality in ulcerative colitis: follow-up of a population-based cohort in Copenhagen County

BACKGROUND & AIMS: A population-based cohort from Copenhagen County comprising 1160 patients diagnosed with ulcerative colitis between 1962 and 1987 was followed-up until 1997 to describe survival and cause-specific mortality. METHODS: Observed vs. expected deaths were presented as standardized mortality ratio (SMR) with exact 95% confidence intervals (CI) calculated by using individually registered person-years at risk and Danish 1995 mortality rates. Cumulative survival curves were calculated. RESULTS: A total of 261 deaths occurred, not significantly different from the expected number of 249 (SMR, 1.05; 95% CI, 0.92-1.19). The median age at death among men was 70 years (range, 6-96 years) and among women 74 years (range, 25-96 years). Twenty-five deaths (9.6%) were caused by complications to ulcerative colitis, mostly infectious and cardiovascular postoperative complications. Patients older than 50 years of age at diagnosis and with extensive colitis showed an increased mortality within the first 2 years because of ulcerative colitis-associated causes. The mortality from colorectal cancer was not increased and that of cancer in general was significantly lower than expected: 50 vs. 71 (SMR, 0.70; 95% CI, 0.52-0.93). A significantly increased mortality from pulmonary embolism and pneumonia was found. Among women only, death from genitourinary tract diseases and suicide was significantly increased. CONCLUSIONS: Despite an overall normal life expectancy for patients with ulcerative colitis, patients >50 years of age and with extensive colitis at diagnosis had increased mortality within the first 2 years after diagnosis, owing to colitis-associated postoperative complications and comorbidity.     

Platelets and Granulocytes, in Particular the Neutrophils, Form Important Compartments for Circulating Vascular Endothelial Growth Factor

The measurement of circulating vascular endothelial growth factor (VEGF) levels as a prognostic factor will gain increasing relevance in the diagnosis and evaluation of treatment in cancer patients. Angiogenesis is an absolute requirement in tumour growth and metastatic disease. In the present study data are presented which indicate that circulating VEGF mainly resides in peripheral blood cells. In 15 healthy volunteers we demonstrated that approximately 34% of the circulating VEGF resides in platelets and approximately 11% in patients with cancer ( n = 4). An important part namely 58% in healthy volunteers and 69% in patients with cancer of the total circulating VEGF is contained in granulocytes, particular in the neutrophils, as confirmed by fluorescence-activated cell sorting (FACS). Also an increased VEGF level per granulocyte is found in patients with cancer (77 microg VEGF/l) compared with the healthy volunteers (164 microg VEGF/l). In contrast only 2% was present in plasma. The biological significance of platelet- or granulocyte-derived VEGF is not yet known. Liberation of VEGF from these compartments could well be of importance for tumour angiogenesis. Therefore, future studies on the clinical value of circulating VEGF as a prognostic factor in cancer patients should include measurements of VEGF in peripheral blood cells.