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.

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.

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.

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.

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.

Lipoprotein(a) and Cardiovascular Disease: A Missing Link for Premature Atherosclerotic Heart Disease and/or Residual Risk.

ABSTRACT: Lipoprotein(a) or lipoprotein "little a" [Lp(a)] is an under-recognized causal risk factor for cardiovascular (CV) disease (CVD), including coronary atherosclerosis, aortic valvular stenosis, ischemic stroke, heart failure, and peripheral arterial disease. Elevated plasma Lp(a) (≥50 mg/dL or ≥100 nmol/L) is commonly encountered in almost 1 in 5 individuals and confers a higher CV risk compared with those with normal Lp(a) levels, although such normal levels have not been generally agreed upon. Elevated Lp(a) is considered a cause of premature and accelerated atherosclerotic CVD. Thus, in patients with a positive family or personal history of premature coronary artery disease (CAD), Lp(a) should be measured. However, elevated Lp(a) may confer increased risk for incident CAD even in the absence of a family history of CAD, and even in those who have guideline-lowered LDL cholesterol (<70 mg/dL) and continue to have a persisting CV residual risk. Thus, measurement of Lp(a) will have a significant clinical impact on the assessment of atherosclerotic CVD risk, and will assume a more important role in managing patients with CVD with the advent and clinical application of specific Lp(a)-lowering therapies. Conventional therapeutic approaches like lifestyle modification and statin therapy remain ineffective at lowering Lp(a). Newer treatment modalities, such as gene silencing via RNA interference with use of antisense oligonucleotide(s) or small interfering RNA molecules targeting Lp(a), seem very promising. These issues are herein reviewed, accumulated data are scrutinized, meta-analyses and current guidelines are tabulated, and Lp(a)-related CVDs and newer therapeutic modalities are pictorially illustrated.

Mitochondrial dysfunction in cardiovascular disease: Current status of translational research/clinical and therapeutic implications.

Mitochondria provide energy to the cell during aerobic respiration by supplying ~95% of the adenosine triphosphate (ATP) molecules via oxidative phosphorylation. These organelles have various other functions, all carried out by numerous proteins, with the majority of them being encoded by nuclear DNA (nDNA). Mitochondria occupy ~1/3 of the volume of myocardial cells in adults, and function at levels of high-efficiency to promptly meet the energy requirements of the myocardial contractile units. Mitochondria have their own DNA (mtDNA), which contains 37 genes and is maternally inherited. Over the last several years, a variety of functions of these organelles have been discovered and this has led to a growing interest in their involvement in various diseases, including cardiovascular (CV) diseases. Mitochondrial dysfunction relates to the status where mitochondria cannot meet the demands of a cell for ATP and there is an enhanced formation of reactive-oxygen species. This dysfunction may occur as a result of mtDNA and/or nDNA mutations, but also as a response to aging and various disease and environmental stresses, leading to the development of cardiomyopathies and other CV diseases. Designing mitochondria-targeted therapeutic strategies aiming to maintain or restore mitochondrial function has been a great challenge as a result of variable responses according to the etiology of the disorder. There have been several preclinical data on such therapies, but clinical studies are scarce. A major challenge relates to the techniques needed to eclectically deliver the therapeutic agents to cardiac tissues and to damaged mitochondria for successful clinical outcomes. All these issues and progress made over the last several years are herein reviewed.

Electrocardiography of cardiac resynchronization therapy: Pitfalls and practical tips.

Cardiac resynchronization therapy (CRT) has been established as an effective mode of therapy in patients with heart failure and concurrent cardiac dyssynchrony, principally in the form of left bundle branch block (LBBB). The widespread use of CRT has ushered in a new landscape in 12-lead electrocardiography (ECG). ECG readings in these patients are most important to guide troubleshooting and also appropriate device programming, as well as discerning and managing nonresponders. A set of four ECG recordings need to accompany each patient with a CRT device, including a baseline ECG and recordings from monochamber (right and left ventricular) and biventricular pacing, which can be compared against a new recording to facilitate the evaluation of proper versus problematic biventricular pacing. Precordial ECG leads V1/2 acquired at the fourth intercostal space and limb leads, I and III, together with a quick assessment of perpendicular leads I and aVF to determine the quadrant of the QRS axis in the hexaxial diagram, may provide the framework for proper ECG interpretation in these patients. This important issue of 12-lead ECG in CRT patients is herein reviewed, pitfalls are pointed out and practical tips are provided for ECG reading to help recognize and manage problems with CRT device function. Furthermore, several pertinent ECG recordings and tabulated data are provided, and an algorithm is suggested that integrates prior algorithms and relevant information from current literature.

Cardiovascular implications and complications of the coronavirus disease-2019 pandemic: a world upside down.

PURPOSE OF REVIEW: The new pandemic of coronavirus disease-2019 (COVID-19) has produced a global tumult and has overburdened national health systems. We herein discuss the cardiovascular implications and complications of this pandemic analyzing the most recent data clustered over the last several months. RECENT FINDINGS: COVID-19 afflicts the cardiovascular system producing acute cardiac injury in 10-20% of cases with mild disease but in greater than 50-60% in severe cases, contributing to patients' demise. Other cardiovascular complications include arrhythmias, heart failure, pulmonary embolism and shock. Off-label therapies are being trialed with their own inherent cardiovascular risks, while supportive therapies currently dominate, until more specific and effective antiviral therapies and vaccinations become available. A controversial issue relates to the safety of drugs blocking the renin--angiotensin system as an angiotensin-converting enzyme (ACE) homologue, ACE2, serves as the receptor for viral entry into host cells. However, to-date, no harm has been proven for these drugs. SUMMARY: In the cardiovascular system, COVID-19 can induce acute cardiac injury, arrhythmias, heart failure, pulmonary embolism, shock and death, whereas anti-COVID therapies also confer serious cardiovascular side-effects. Ongoing extensive efforts focus on specific vaccines and antivirals. Meanwhile, cardiovascular risk factors and diseases should be jointly controlled according to current evidence-based guidelines.

COVID-19 Infection: A Neuropsychiatric Perspective.

As a potentially life-threatening disease with no definitive treatment and without fully implemented population-wide vaccination, COVID-19 has created unprecedented turmoil in socioeconomic life worldwide. In addition to physical signs from the respiratory and many other systems, the SARS-CoV-2 virus produces a broad range of neurological and neuropsychiatric problems, including olfactory and gustatory impairments, encephalopathy and delirium, stroke and neuromuscular complications, stress reactions, and psychoses. Moreover, the psychosocial impact of the pandemic and its indirect effects on neuropsychiatric health in noninfected individuals in the general public and among health care workers are similarly far-ranging. In addition to acute neuropsychiatric manifestations, COVID-19 may also produce late neuropsychiatric sequelae as a function of the psychoneuroimmunological cascade that it provokes. The present article presents a state-of-the-science review of these issues through an integrative review and synthesis of case series, large-cohort studies, and relevant meta-analyses. Heuristics for evaluation and further study of the neuropsychiatric manifestations of SARS-CoV-2 infection are offered.

The Controversy of Renin-Angiotensin-System Blocker Facilitation Versus Countering COVID-19 Infection.

The ongoing COVID-19 pandemic has produced serious turmoil world-wide. Lung injury causing acute respiratory distress syndrome seems to be a most dreaded complication occurring in ∼30%. Older patients with cardiovascular comorbidities and acute respiratory distress syndrome have an increased mortality. Although the precise mechanisms involved in the development of lung injury have not been fully elucidated, the role of the extended renin-angiotensin system seems to be pivotal. In this context, angiotensin-converting enzyme 2 (ACE2), an angiotensin-converting enzyme homologue, has been recognized as a facilitator of viral entry into the host, albeit its involvement in other counter-regulatory effects, such as converting angiotensin (Ang) II into Ang 1-7 with its known protective actions. Thus, concern was raised that the use of renin-angiotensin system inhibitors by increasing ACE2 expression may enhance patient susceptibility to the COVID-19 virus. However, current data have appeased such concerns because there has been no clinical evidence of a harmful effect of these agents as based on observational studies. However, properly designed future studies will be needed to further confirm or refute current evidence. Furthermore, other pathways may also play important roles in COVID-19 transmission and pathogenesis; spike (S) protein proteases facilitate viral transmission by cleaving S protein that promotes viral entry into the host; neprilysin (NEP), a neutral endopeptidase known to cleave natriuretic peptides, degrades Ang I into Ang 1-7; NEP can also catabolize bradykinin and thus mitigate bradykinin's role in inflammation, whereas, in the same context, specific bradykinin inhibitors may also negate bradykinin's harmful effects. Based on these intricate mechanisms, various preventive and therapeutic strategies may be devised, such as upregulating ACE2 and/or using recombinant ACE2, and exploiting the NEP, bradykinin and serine protease pathways, in addition to anti-inflammatory and antiviral therapies. These issues are herein reviewed, available studies are tabulated and pathogenetic mechanisms are pictorially illustrated.

Sudden death in heart failure with preserved ejection fraction and beyond: an elusive target.

Heart failure (HF) with preserved ejection fraction (HFpEF) represents half of HF patients, who are more likely older, women, and hypertensive. Mortality rates in HFpEF are higher compared with age- and comorbidity-matched non-HF controls and lower than in HF with reduced ejection fraction (HFrEF); the majority (50-70%) are cardiovascular (CV) deaths. Among CV deaths, sudden death (SD) (~ 35%) and HF-death (~ 20%) are the leading cardiac modes of death; however, proportionally, CV deaths, SD, and HF-deaths are lower in HFpEF, while non-CV deaths constitute a higher proportion of deaths in HFpEF (30-40%) than in HFrEF (~ 15%). Importantly, the underlying mechanism of SD has not been clearly elucidated and non-arrhythmic SD may be more prominent in HFpEF than in HFrEF. Furthermore, there is no specific strategy for identifying high-risk patients, probably due to wide heterogeneity in presentation and pathophysiology of HFpEF and a plethora of comorbidities in this population. Thus, the management of HFpEF remains problematic due to paucity of data on the clinical benefits of current therapies, which focus on symptom relief and reduction of HF-hospitalization by controlling fluid retention and managing risk-factors and comorbidities. Matching a specific pathophysiology or mode of death with available and novel therapies may improve outcomes in HFpEF. However, this still remains an elusive target, as we need more information on determinants of SD. Implantable cardioverter-defibrillators (ICDs) have changed the landscape of SD prevention in HFrEF; if ICDs are to be applied to HFpEF, there must be a coordinated effort to identify and select high-risk patients.

Eplerenone Versus Spironolactone in Resistant Hypertension: an Efficacy and/or Cost or Just a Men's Issue?

PURPOSE OF REVIEW: To review comparative efficacy and tolerability data between the two main mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, in patients with resistant hypertension (HTN). The focus was whether spironolactone, being the classical non-selective agent that has been used for years, albeit with several anti-androgenic side effects, can be rivaled by eplerenone, an apparently weaker, but better tolerated, more selective MRA. RECENT FINDINGS: Evidence has accumulated that resistant HTN is generally volume-dependent, attributable to varying degrees of aldosterone excess with its attendant renal effects of sodium and fluid retention. Such aldosteronism may be due to an underestimated occurrence of primary aldosteronism; however, it more commonly occurs separately from it and independent from angiotensin II. The aldosterone-induced volume excess placed at the root of the development of resistant HTN in a large number of patients, together with the extrarenal deleterious effects of aldosterone, such as endothelial dysfunction, vascular remodeling and increased arterial stiffness, cardiac hypertrophy, and fibrosis can all be counterbalanced by the administration of MRAs. In the absence of a direct comparison between spironolactone and eplerenone, and in light of compelling evidence provided by the recently reported results of the PATHWAY-2 and ReHOT studies, spironolactone has been established as the most effective add-on anti-aldosterone therapy in resistant HTN. The data on use of eplerenone continue to emerge and are quite encouraging. Despite the lack of direct comparative data, the weight of evidence regarding efficacy is currently in favor of spironolactone. However, the data on the efficacy of eplerenone are promising but still being accumulated suggesting this agent as an alternative to spironolactone and certainly as the preferred choice for those not tolerating spironolactone, especially for patients developing anti-androgenic side effects like breast tenderness, gynecomastia/mastodynia, and/or sexual dysfunction. Both these agents appear to have several other pleiotropic effects that confer cardioprotection and renoprotection beyond their antihypertensive effect. Potassium levels and renal function need to be closely monitored during administration of these therapies. Future comparative studies may shed more light on these issues, while emerging newer agents may offer better and safer therapeutic options.

Winter Swimming: Body Hardening and Cardiorespiratory Protection Via Sustainable Acclimation.

Winter swimming is a stressful condition of whole-body exposure to cold water; however, winter swimmers have achieved variable degrees of adaptation to cold. The question arises whether this extreme sport activity has any health benefits or whether it may confer potentially harmful effects. As a form of aerobic exercise, albeit more strenuous when performed in cold water, winter swimming may increase body tolerance to stressors and achieve body hardening. When practiced by individuals who are in good general health adopting a regular, graded and adaptive mode, winter swimming seems to confer cardiovascular (CV), and other health benefits. On the other hand, unaccustomed individuals are at risk of death either from the initial neurogenic cold-shock response, or from progressive decrease of swimming efficiency or from hypothermia. Furthermore, as it may occur with any intense exercise, individuals with evident or occult underlying CV conditions may be more susceptible to adverse effects with provocation of arrhythmias and CV events that may pose a significant health risk. Hence, a stepwise strategy to initiate and build up this recreational activity is recommended to enhance and sustain acclimation, achieve protection from potential risks of cold-water exposure and possibly avail from its promising health benefits. We need more data from prospective studies to better investigate the short- and long-term health consequences of this important recreational activity.

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.

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.

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.

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.