Are We Using Ezetimibe As Much As We Should?

Lipid-lowering therapies, particularly non-statin regimens, are underutilized as ~2/3 of patients with atherosclerotic cardiovascular (CV) disease (CVD) are not optimally managed, and do not attain target low-density lipoprotein cholesterol (LDL-C) concentrations, despite statin treatment. Statins have been the mainstay of hypolipidemic therapies; however, they are plagued by adverse effects, which have partly hindered their more widespread use. Ezetimibe is often the first added mode of treatment to attain LDL-C goals as it is efficacious and also allows the use of a smaller dose of statin, while the need for more expensive therapies is obviated. We herein provide a comprehensive review of the effects of ezetimibe in lipid lowering and reducing CV events and improving outcomes. Of the hypolipidemic therapies, oral ezetimibe, in contrast to newer agents, is the most convenient and/or affordable regimen to be utilized as mono- or combined therapy supported by data from CV outcomes studies attesting to its efficacy in reducing CVD risk and events. When combined with a statin, the statin dose could be lower, thus curtailing side-effects, while the hypolipidemic effect is enhanced (by ~20%) as the percentage of patients with target level LDL-C (<70 mg/dL) is higher with combined treatment versus a high-intensity statin. Ezetimibe could also serve as an alternative treatment in cases of statin intolerance. In conclusion, ezetimibe has an excellent safety/tolerability profile; it is the first added treatment to a statin that can attain LDL-C targets. In the combined therapy, the hypolipidemic effect is enhanced while the dose of statin could be lower, thus limiting the occurrence of side-effects. Ezetimibe could also serve as an alternative mode of treatment in cases of statin intolerance.

Early-Onset or Premature Coronary Artery Disease.

The aim of this review was to examine the literature regarding younger individuals without classical risk factors for atherosclerosis who develop coronary artery disease (CAD) prematurely at an early age. An extensive literature review was undertaken in Pubmed, Scopus, and Google Scholar regarding early-onset or premature atherosclerosis, CAD, its diagnosis, management, and prophylaxis. There are individuals of both genders, particularly in the younger age group of 20-40 years of age, who lack the traditional/ classical risk factors and still develop CAD and other manifestations of atherosclerosis. Even the 10-year age gap in manifesting CAD that is noted between women and men ascribable to a cardioprotective effect of sex hormones may not be noted under these circumstances. This indicates that the risk profile differs in young patients with non-- classical atherosclerotic risk factors, and factors such as genetics, inflammation, thrombosis, psychosocial, environmental, and other parameters play an important role in atherosclerosis and other mechanisms that lead to CAD in younger individuals. These patients are at risk of major adverse cardiac events, which determine their prognosis. Unfortunately, current major guidelines do not acknowledge that many patients who manifest premature CAD are at high risk, and as a consequence, many of these patients may not be receiving guideline-directed hypolipidemic and other therapies before they present with symptoms of CAD. Caretakers need to be more vigilant in offering efficacious screening and strategies of prevention for early-onset or premature CAD to younger individuals.

Managing chronic coronary syndrome: how do we achieve optimal patient outcomes?

INTRODUCTION: Chronic coronary syndrome (CCS) remains the leading cause of death worldwide with high admission/re-admission rates. Medical databases were searched on CCS & its management. AREAS COVERED: This review discusses phenotypes per stress-echocardiography, noninvasive/invasive testing (coronary computed-tomography angiography-CCTA; coronary artery calcium - CAC score; echocardiography assessing wall-motion, LV function, valvular disease; biomarkers), multidisciplinary management (risk factors/anti-inflammatory/anti-ischemic/antithrombotic therapies and revascularization), newer treatments (colchicine/ivabradine/ranolazine/melatonin), cardiac rehabilitation/exercise improving physical activity and quality-of-life, use of the implantable-defibrillator, and treatment with extracorporeal shockwave-revascularization for refractory symptoms. EXPERT OPINION: CCS is age-dependent, leading cause of death worldwide with high hospitalization rates. Stress-echocardiography defines phenotypes and guides prophylaxis and management. CAC is a surrogate for atherosclerosis burden, best for patients of intermediate/borderline risk. Higher CAC-scores indicate more severe coronary abnormalities. CCTA is preferred for noninvasive detection of CAC and atherosclerosis burden, determining stenosis' functional significance, and guiding management. Combining CAC score with CCTA improves diagnostic yield and assists prognosis. Echocardiography assesses LV wall-motion and function and valvular disease. Biomarkers guide diagnosis/prognosis. CCS management is multidisciplinary: risk-factor management, anti-inflammatory/anti-ischemic/antithrombotic therapies, and revascularization. Newer therapies comprise colchicine, ivabradine, ranolazine, melatonin, glucagon-like peptide-1-receptor antagonists. Cardiac rehabilitation/exercise improves physical activity and quality-of-life. An ICD protects from sudden death. Extracorporeal shockwave-revascularization treats refractory symptoms.

Neurohumoral Activation in Heart Failure.

In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased systemic vascular resistance. Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms. There are biomarkers of activation of these neurohormonal pathways, such as the natriuretic peptides, catecholamine levels and neprilysin and various newer ones, which may be employed to better understand the mechanisms of HF drugs and also aid in defining the subgroups of patients who might benefit from specific therapies, irrespective of the degree of left ventricular dysfunction. These therapies are directed against these neurohumoral systems (neurohumoral antagonists) and classically comprise beta blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers and vaptans. Recently, the RAAS blockade has been refined by the introduction of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, which combines the RAAS inhibition and neprilysin blocking, enhancing the actions of natriuretic peptides. All these issues relating to the neurohumoral activation in HF are herein reviewed, and the underlying mechanisms are pictorially illustrated.

Role of Vitamins in Cardiovascular Health: Know Your Facts - Part 1.

Cardiovascular (CV) disease (CVD) is a major cause of morbidity and mortality world-wide, thus it is important to adopt preventive interventions. Observational data demonstrating CV benefits of vitamin supplements, advanced by self-proclaimed experts have resulted in ~50% of Americans reporting the use of multivitamins for health promotion; this practice has led to a multi-billion-dollar business of the multivitamin-industry. However, the data on the extensive use of multivitamins show no consistent benefit for CVD prevention or all-cause mortality, while the use of certain vitamins might prove harmful. Thus, the focus of this two-part review is on the attributes or concerns about specific vitamins on CVD. In Part 1, the CV effects of specific vitamins are discussed, indicating the need for further supportive evidence of potential benefits. Vitamin A preserves CV homeostasis as it participates in many biologic functions, including atherosclerosis. However, supplementation could potentially be harmful. Betacarotene, a pro-vitamin A, conveys pro-oxidant actions that may mitigate any other benefits. Folic acid alone and certain B-vitamins (e.g., B1/B2/B6/B12) may reduce CVD, heart failure, and/or stroke, while niacin might increase mortality. Vitamin C has antioxidant and cardioprotective effects. Vitamin D may confer CV protection, but all the data are not in agreement. Combined vitamin E and C have antiatherogenic effects but clinical evidence is inconsistent. Vitamin K seems neutral. Thus, there are individual vitamin actions with favorable CV impact (certain B-vitamins and vitamins C and D), but other vitamins (ß-carotene, niacin) may potentially have deleterious effects, which also holds true for high doses of fat-soluble vitamins (A/D/E/K).

Role of Vitamins in Cardiovascular Health: Know Your Facts-Part 2.

Cardiovascular disease (CVD) is a major cause of morbidity/mortality world-wide, hence preventive interventions are crucial. Observational data showing beneficial CV effects of vitamin supplements, promoted by self-proclaimed experts, have led to ~50% of Americans using multivitamins; this practice has culminated into a multi-billion-dollar business. However, robust evidence is lacking, and certain vitamins might incur harm. This two-part review focuses on the attributes or concerns about specific vitamin consumption on CVD. The evidence for indiscriminate use of multivitamins indicates no consistent CVD benefit. Specific vitamins and/or combinations are suggested, but further supportive evidence is needed. Data presented in Part 1 indicated that folic acid and certain B-vitamins may decrease stroke, whereas niacin might raise mortality; beta-carotene mediates pro-oxidant effects, which may abate the benefits from other vitamins. In Part 2, data favor the anti-oxidant effects of vitamin C and the anti-atherogenic effects of vitamins C and E, but clinical evidence is inconsistent. Vitamin D may provide CV protection, but data are conflicting. Vitamin K appears neutral. Thus, there are favorable CV effects of individual vitamins (C/D), but randomized/controlled data are lacking. An important caveat regards the potential toxicity of increased doses of fat-soluble vitamins (A/D/E/K). As emphasized in Part 1, vitamins might benefit subjects who are antioxidant-deficient or exposed to high levels of oxidative-stress (e.g., diabetics, smokers, and elderly), stressing the importance of targeting certain subgroups for optimal results. Finally, by promoting CV-healthy balanced-diets, we could acquire essential vitamins and nutrients and use supplements only for specific indications.

Depression and atrial fibrillation in a reciprocal liaison: a neuro-cardiac link.

OBJECTIVE: To explore the reciprocal relationship of depression and atrial fibrillation (AF). METHODS: A literature search was conducted in Pub Med, Scopus, and Google Scholar using relevant terms for depression and AF and respective therapies. RESULTS: There is evidence that depression is involved in the aetiology and prognosis of AF. AF, independently of its type, incurs a risk of depression in 20-40% of patients. Also, depression significantly increases cumulative incidence of AF (from 1.92% to 4.44% at 10 years); 25% increased risk of new-onset AF is reported in patients with depression, reaching 32% in recurrent depression. Hence, emphasis is put on the importance of assessing depression in the evaluation of AF and vice versa. Persistent vs paroxysmal AF patients may suffer from more severe depression. Furthermore, depression can impact the effectiveness of AF treatments, including pharmacotherapy, anticoagulation, cardioversion and catheter ablation. CONCLUSIONS: A reciprocal association of depression and AF, a neurocardiac link, has been suggested. Thus, strategies which can reduce depression may improve AF patients' course and treatment outcomes. Also, AF has a significant impact on risk of depression and quality of life. Hence, effective antiarrhythmic therapies may alleviate patients' depressive symptoms. KEY POINTSAF, independently of its type of paroxysmal, permanent or chronic, appears to have mental besides physical consequences, including depression and anxietyA reciprocal influence or bidirectional association of depression and AF, a neurocardiac link, has been suggestedAF has considerable impact on the risk of depression occurrence with 20-40% of patients with AF found to have high levels of depressionAlso, depression significantly increases 10-year cumulative incidence and risk of AF from 1.92% to 4.44% in people without depression, and the risk of new-onset AF by 25-32%Emphasis should be placed on the importance of assessing depression in the evaluation of AF and vice versaPersistent/chronic AF patients may suffer from more severe depressed mood than paroxysmal AF patients with similar symptom burdenDepression and anxiety can impact the effectiveness of certain AF treatments, including pharmacotherapy, anticoagulation treatment, cardioversion and catheter ablationThus, strategies which can reduce anxiety and depression may improve AF patients' course and treatment outcomesAlso, effective antiarrhythmic therapies to control AF may alleviate patients' depressive mood.

Features of a Balanced Healthy Diet with Cardiovascular and Other Benefits.

BACKGROUND: Cardiovascular (CV) disease (CVD) remains the leading cause of death globally. Besides lack of exercise, obesity, smoking, and other risk factors, poor nutrition and unhealthy/ unbalanced diets play an important role in CVD. OBJECTIVE: This review examined data on all issues of the CV-health benefits of a balanced diet, with tabulation of nutritional data and health-authority recommendations and pictorial illustration of the main features of a CV-healthy diet. METHODS: PubMed and Google Scholar were searched for relevant studies and reviews on diet and CV health. RESULTS: For a long time, there has been evidence, corroborated by recent findings, that pro-vegetarian diets have a beneficial influence on serum lipid levels, markers of inflammation and endothelial function, prooxidant-antioxidant balance, and gut microbiome, all probably contributing to reduced CV risk. Worries about the nutritional adequacy of vegetarian diets are circumvented by obtaining certain nutrients lacking or found in lower amounts in plants than in animal foods, by consuming a wide variety of healthy plant foods and through intake of oral supplements or fortified foods. Well-balanced diets, such as the Mediterranean or the Dietary-Approaches-to-Stop-Hypertension diets, provide CV-health benefits. Nevertheless, a broad variety of plant-based diets with low/minimal animal food intake may allow for a personalized and culturally adjusted application of dietary recommendations contributing to the maintenance of CV health. CONCLUSION: Universal adoption of a balanced CV-healthy diet can reduce global, CV and other mortality by ~20%. This requires world-wide programs of information for and education of the public, starting with school children and expanding to all groups, sectors, and levels.

Ketone Bodies and Cardiovascular Disease: An Alternate Fuel Source to the Rescue.

The increased metabolic activity of the heart as a pump involves a high demand of mitochondrial adenosine triphosphate (ATP) production for its mechanical and electrical activities accomplished mainly via oxidative phosphorylation, supplying up to 95% of the necessary ATP production, with the rest attained by substrate-level phosphorylation in glycolysis. In the normal human heart, fatty acids provide the principal fuel (40-70%) for ATP generation, followed mainly by glucose (20-30%), and to a lesser degree (<5%) by other substrates (lactate, ketones, pyruvate and amino acids). Although ketones contribute 4-15% under normal situations, the rate of glucose use is drastically diminished in the hypertrophied and failing heart which switches to ketone bodies as an alternate fuel which are oxidized in lieu of glucose, and if adequately abundant, they reduce myocardial fat delivery and usage. Increasing cardiac ketone body oxidation appears beneficial in the context of heart failure (HF) and other pathological cardiovascular (CV) conditions. Also, an enhanced expression of genes crucial for ketone break down facilitates fat or ketone usage which averts or slows down HF, potentially by avoiding the use of glucose-derived carbon needed for anabolic processes. These issues of ketone body utilization in HF and other CV diseases are herein reviewed and pictorially illustrated.

Neuropsychiatric disorders in patients with heart failure: not to be ignored.

Among various neuropsychiatric disorders, depression and anxiety are commonly encountered in patients with heart failure (HF), reported in ≥ 50% of patients attending a HF clinic, but may frequently elude clinician's attention. Both disorders are associated with the development and progression of HF, incurring higher rates of morbidity/mortality, probably via physiologic and behavioral mechanisms. Patients with devices and/or advanced HF are more severely affected, especially early following device receipt. In addition, various other neuropsychiatric and neuropsychological disorders and symptoms of these and other disorders occur in and impact HF patients, including sleep disorders and cognitive impairment, which further interact with and amplify depression and anxiety. Mechanisms involved in the link between neuropsychiatric/neuropsychological disorders and HF may relate to pathophysiological processes, lifestyle factors, and behavioral patterns. Among the pathophysiological factors, inflammation, autonomic dysfunction, endothelial dysfunction, thrombotic mechanisms, and dysregulation of the hypothalamic-pituitary-adrenal axis may play a significant role as they are implicated in the pathogenesis, progression, and prognosis of HF. Multimodal psychiatric management strategies with flexible approaches, using antidepressants/anxiolytics/atypical antipsychotics and various psychotherapies such as cognitive behavioral therapy combined with exercise adjusted to patients' care and needs, appear promising in this patient group. Choosing agents with a higher efficacy/safety profile is a prudent strategy. Although depression and anxiety are risk factors for mortality in HF patients, indiscriminate use of psychiatric medications may not improve or even worsen survival when one neglects to closely monitor for potential proarrhythmic and other side effects. Newer meta-analytic data in HF patients indicate no increase in mortality for newer antidepressants, while secondary analyses show improved survival in patients who achieved remission of depressive symptoms.

Sodium-glucose cotransporter type 2 inhibitors and cardiac arrhythmias.

The introduction of sodium-glucose cotransporter 2 (SGLT2) inhibitors as a new and effective class of therapeutic agents for type 2 diabetes (T2D) preventing the reabsorption of glucose in the kidneys and thus facilitating glucose excretion in the urine, but also as agents with cardiovascular benefits, particularly in patients with heart failure (HF), regardless of the diabetic status, has ushered in a new era in treating patients with T2D and/or HF. In addition, data have recently emerged indicating an antiarrhythmic effect of the SGLT2 inhibitors in patients with and without diabetes. Prospective studies, randomized controlled trials and meta-analyses have provided robust evidence for a protective and beneficial effect of these agents against atrial fibrillation, ventricular arrhythmias and sudden cardiac death. The antiarrhythmic mechanisms involved include reverse atrial and ventricular remodeling, amelioration of mitochondrial function, reduction of hypoglycemic episodes with their attendant arrhythmogenic effects, attenuated sympathetic nervous system activity, regulation of sodium and calcium homeostasis, and suppression of prolonged ventricular repolarization. These new data on antiarrhythmic actions of SGLT2 inhibitors are herein reviewed, potential mechanisms involved are discussed and pictorially illustrated, and treatment results on specific arrhythmias are described and tabulated.

Takotsubo Syndrome and Sudden Cardiac Death.

Takotsubo syndrome (TTS), triggered by intense emotional or physical stress, occurring most commonly in post-menopausal women, presents as an ST-elevation myocardial infarction (MI). Cardiovascular complications occur in almost half the patients with TTS, and the inpatient mortality is comparable to MI (4-5%) owing to cardiogenic shock, myocardial rupture, or life-threatening arrhythmias. Thus, its prognosis is not as benign as previously thought, as it may cause mechanical complications (cardiac rupture) and potentially lethal arrhythmias and sudden cardiac death (SCD). Similar to MI, some patients may perish before reaching the hospital due to out-of-hospital cardiac arrest; this may lead to underestimation of the actual SCD risk. Furthermore, after discharge, some patients may develop late SCD and/or TTS recurrence that may result in SCD. There are risk factors for SCD in TTS patients, such as severe/persistent QT-interval prolongation inciting torsade-de-pointes, other ECG abnormalities (diffuse giant negative T-waves, widened QRS-complex), bradyarrhythmias, comorbidities, concurrent obstructive coronary artery disease or vasospasm, male gender, older age, severe left ventricular dysfunction, and use of sympathomimetic drugs. All these issues are herein reviewed, case reports/series and data from large cohort studies and meta-analyses are analyzed, risk factors are tabulated, and proarrhythmic effects and management strategies are discussed and pictorially illustrated.

Patients with Polyvascular Disease: A Very High-risk Group.

Polyvascular disease (PolyvascDis) with atherosclerosis occurring in >2 vascular beds (coronary, carotid, aortic, visceral and/or peripheral arteries) is encountered in 15-30% of patients who experience greater rates of major adverse cardiovascular (CV) events. Every patient with multiple CV risk factors or presenting with CV disease in one arterial bed should be assessed for PolyvascDis clinically and noninvasively prior to invasive angiography. Peripheral arterial disease (PAD) can be readily diagnosed in routine practice by measuring the ankle-brachial index. Carotid disease can be diagnosed by duplex ultrasound showing % stenosis and/or presence of plaques. Coronary artery disease (CAD) can be screened by determining coronary artery calcium score using coronary computed tomography angiography; further, non-invasive testing includes exercise stress and/or myocardial perfusion imaging or dobutamine stress test, prior to coronary angiography. Abdominal ultrasound can reveal an abdominal aortic aneurysm. Computed tomography angiography will be needed in patients with suspected mesenteric ischemia to assess the mesenteric arteries. Patients with the acute coronary syndrome and concomitant other arterial diseases have more extensive CAD and poorer CV outcomes. Similarly, PolyvascDis in patients with carotid disease and/or other PAD is independently associated with an increased risk for all-cause and CV mortality during long-term follow-up. Treatment of patients with PolyvascDis should include aggressive management of all modifiable risk factors by lifestyle changes and drug therapy, with particular attention to patients who are commonly undertreated, such as those with PAD. Revascularization should be reserved for symptomatic vascular beds, using the least aggressive strategy in a multidisciplinary vascular team approach.

Diet and Sudden Death: How to Reduce the Risk.

In addition to the association of dietary patterns, specific foods and nutrients with several diseases, including cardiovascular disease and mortality, there is also strong emerging evidence of an association of dietary patterns with the risk of sudden cardiac death (SCD). In this comprehensive review, data are presented and analyzed about foods and diets that mitigate the risk of ventricular arrhythmias (VAs) and SCD, but also about arrhythmogenic nutritional elements and patterns that seem to enhance or facilitate potentially malignant VAs and SCD. The antiarrhythmic or protective group comprises fish, nuts and other foods enriched in omega-3 polyunsaturated fatty acids, the Mediterranean and other healthy diets, vitamins E, A and D and certain minerals (magnesium, potassium, selenium). The arrhythmogenic-food group includes saturated fat, trans fats, ketogenic and liquid protein diets, the Southern and other unhealthy diets, energy drinks and excessive caffeine intake, as well as heavy alcohol drinking. Relevant antiarrhythmic mechanisms include modification of cell membrane structure by n-3 polyunsaturated fatty acids, their direct effect on calcium channels and cardiomyocytes and their important role in eicosanoid metabolism, enhancing myocyte electric stability, reducing vulnerability to VAs, lowering heart rate, and improving heart rate variability, each of which is a risk factor for SCD. Contrarily, saturated fat causes calcium handling abnormalities and calcium overload in cardiomyocytes, while a high-fat diet causes mitochondrial dysfunction that dysregulates a variety of ion channels promoting VAs and SCD. Free fatty acids have been considered proarrhythmic and implicated in facilitating SCD; thus, diets increasing free fatty acids, e.g., ketogenic diets, should be discouraged and replaced with diets enriched with polyunsaturated fatty acids, which can also reduce free fatty acids. All available relevant data on this important topic are herein reviewed, large studies and meta-analyses and pertinent advisories are tabulated, while protective (antiarrhythmic) and arrhythmogenic specific diet constituents are pictorially illustrated.

Low serum albumin: A neglected predictor in patients with cardiovascular disease.

Albumin, the most abundant circulating protein in blood, is an essential protein which binds and transports various drugs and substances, maintains the oncotic pressure of blood and influences the physiological function of the circulatory system. Albumin also has anti-inflammatory, antioxidant, and antithrombotic properties. Evidence supports albumin's role as a strong predictor of cardiovascular (CV) risk in several patient groups. Its protective role extends to those with coronary artery disease, heart failure, hypertension, atrial fibrillation, peripheral artery disease or ischemic stroke, as well as those undergoing revascularization procedures or with aortic stenosis undergoing transcatheter aortic valve replacement, and patients with congenital heart disease and/or endocarditis. Hypoalbuminemia is a strong prognosticator of increased all-cause and CV mortality according to several cohort studies and meta-analyses in hospitalized and non-hospitalized patients with or without comorbidities. Normalization of albumin levels before discharge lowers mortality risk, compared with hypoalbuminemia before discharge. Modified forms of albumin, such as ischemia modified albumin, also has prognostic value in patients with coronary or peripheral artery disease. When albumin is combined with other risk factors, such as uric acid or C-reactive protein, the prognostic value is enhanced. Although albumin supplementation may be a plausible approach, its efficacy has not been established and in patients with hypoalbuminemia, priority is focused on diagnosing and managing the underlying condition. The CV effects of hypoalbuminemia and relevant issues are considered in this review. Large cohort studies and meta-analyses are tabulated and the physiologic effects of albumin and the deleterious effects of low albumin are pictorially illustrated.

Atrial fibrillation-induced tachycardiomyopathy and heart failure: an underappreciated and elusive condition.

Many patients with persistent, chronic, or frequently recurring paroxysmal atrial fibrillation (AF) may develop a tachycardiomyopathy (TCM) with left ventricular (LV) dysfunction and heart failure (HF), which is reversible upon restoration and maintenance of sinus rhythm, when feasible, or via better and tighter ventricular rate (VR) control. Mechanisms involved in producing this leading cause of TCM (AF-TCM) include loss of atrial contraction, irregular heart rate, fast VR, neurohumoral activation, and structural myocardial changes. The most important of all mechanisms relates to optimal VR control, which seems to be an elusive target. Uncontrolled AF may also worsen preexisting LV dysfunction and exacerbate HF symptoms. Data, albeit less robust, also point to deleterious effects of slow VRs on LV function. Thus, a J-shaped relationship between VR and clinical outcome has been suggested, with the optimal VR control hovering at ~ 65 bpm, ranging between 60 and 80 bpm; VRs above and below this range may confer higher morbidity and mortality rates. A convergence of recent guidelines is noted towards a stricter rather than a more lenient VR control with target heart rate < 80 bpm at rest and < 110 bpm during moderate exercise which seems to prevent TCM or improve LV function and exercise capacity and relieve TCM-related symptoms and signs. Of course, restoring and maintaining sinus rhythm is always a most desirable target, when feasible, either with drugs or more likely with ablation. All these issues are herein reviewed, current guidelines are discussed and relevant data are tabulated and pictorially illustrated.