Beyond Quadruple Therapy and Current Therapeutic Strategies in Heart Failure with Reduced Ejection Fraction: Medical Therapies with Potential to Become Part of the Therapeutic Armamentarium.

Heart failure with reduced ejection fraction (HFrEF) is a complex clinical syndrome with significant morbidity and mortality and seems to be responsible for approximately 50% of heart failure cases and hospitalizations worldwide. First-line treatments of patients with HFrEF, according to the ESC and AHA guidelines, include ß-blockers, angiotensin receptor/neprilysin inhibitors, sodium-glucose cotransporter 2 inhibitors, and mineralocorticoid receptor antagonists. This quadruple therapy should be initiated during hospital stay and uptitrated to maximum doses within 6 weeks after discharge according to large multicenter controlled trials. Quadruple therapy improves survival by approximately 8 years for a 55-year-old heart failure patient. Additional therapeutic strategies targeting other signaling pathways such as ivabradine, digoxin, and isosorbide dinitrate and hydralazine combination for African Americans, as well as adjunctive symptomatic therapies, seem to be necessary in the management of HFrEF. Although second-line medications have not achieved improvements in mortality, they seem to decrease heart failure hospitalizations. There are novel medical therapies including vericiguat, omecamtiv mecarbil, genetic and cellular therapies, and mitochondria-targeted therapies. Moreover, mitraclip for significant mitral valve regurgitation, ablation in specific atrial fibrillation cases, omecamtiv mecarbil are options under evaluation in clinical trials. Finally, the HeartMate 3 magnetically levitated centrifugal left ventricular assist device (LVAD) has extended 5-year survival for stage D HF patients who are candidates for an LVAD.

Oral Cardiac Drug-Gut Microbiota Interaction in Chronic Heart Failure Patients: An Emerging Association.

Regardless of the currently proposed best medical treatment for heart failure patients, the morbidity and mortality rates remain high. This is due to several reasons, including the interaction between oral cardiac drug administration and gut microbiota. The relation between drugs (especially antibiotics) and gut microbiota is well established, but it is also known that more than 24% of non-antibiotic drugs affect gut microbiota, altering the microbe's environment and its metabolic products. Heart failure treatment lies mainly in the blockage of neuro-humoral hyper-activation. There is debate as to whether the administration of heart-failure-specific drugs can totally block this hyper-activation, or whether the so-called intestinal dysbiosis that is commonly observed in this group of patients can affect their action. Although there are several reports indicating a strong relation between drug-gut microbiota interplay, little is known about this relation to oral cardiac drugs in chronic heart failure. In this review, we review the contemporary data on a topic that is in its infancy. We aim to produce scientific thoughts and questions and provide reasoning for further clinical investigation.

Human Gut Microbiota in Heart Failure: Trying to Unmask an Emerging Organ.

There is a bidirectional relationship between the heart and the gut. The gut microbiota, the community of gut micro-organisms themselves, is an excellent gut-homeostasis keeper since it controls the growth of potentially harmful bacteria and protects the microbiota environment. There is evidence suggesting that a diet rich in fatty acids can be metabolized and converted by gut microbiota and hepatic enzymes to trimethyl-amine N-oxide (TMAO), a product that is associated with atherogenesis, platelet dysfunction, thrombotic events, coronary artery disease, stroke, heart failure (HF), and, ultimately, death. HF, by inducing gut ischemia, congestion, and, consequently, gut barrier dysfunction, promotes the intestinal leaking of micro-organisms and their products, facilitating their entrance into circulation and thus stimulating a low-grade inflammation associated with an immune response. Drugs used for HF may alter the gut microbiota, and, conversely, gut microbiota may modify the pharmacokinetic properties of the drugs. The modification of lifestyle based mainly on exercise and a Mediterranean diet, along with the use of pre- or probiotics, may be beneficial for the gut microbiota environment. The potential role of gut microbiota in HF development and progression is the subject of this review.

Arrhythmias in Patients with Cardiac Amyloidosis: A Comprehensive Review on Clinical Management and Devices.

Cardiac amyloidosis (CA) is a rare but potentially life-threatening disease in which misfolded proteins accumulate in the cardiac wall tissue. Heart rhythm disorders in CA, including supraventricular arrhythmias, conduction system disturbances, or ventricular arrhythmias, play a major role in CA morbidity and mortality, and thus require supplementary management. Among them, AF is the most frequent arrhythmia during CA hospitalizations and is associated with significantly higher mortality, while ventricular arrhythmias are also common and are usually associated with poor prognosis. Early diagnosis of potential arrythmias could be performed through ECG, Holter monitoring, and/or electrophysiology study. Clinical management of these patients is quite significant, and it usually includes initiation of amiodarone and/or digoxin in patients with AF, potential electrical cardioversion, or ablation in specific patients with indication, as well as initiation of anticoagulants in all patients, independent of AF and CHADS-VASc score, for potential intracardiac thrombus. Moreover, identification of patients with conduction disorders that could benefit from prophylactic pacemaker implantation and/or CRT as well as identification of patients with life-threatening ventricular arrythmias that could benefit from ICD could both increase the survival rates of these patients and improve their quality of life.

Medical Treatment in Heart Failure with Reduced Ejection Fraction: A Proposed Algorithm Based on the Patient's Electrolytes and Congestion Status.

In heart failure (HF) with reduced ejection fraction (HFrEF), four classes of drugs (ß-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor neprilysin inhibitors, mineralocorticoid receptor antagonists, and the most recent Sodium-Glucose Co-Transporters 2 Inhibitors) have demonstrated positive results in randomized controlled trials (RCTs). Nevertheless, the latest RCTs are not proper for comparison since they were carried out at various times with dissimilar background therapies and the patients enrolled did not have the same characteristics. The difficulty of extrapolating from these trials and proposing a common framework appropriate for all cases is thus obvious. Despite the fact that these four agents are now the fundamental pillars of HFrEF treatment, the built-up algorithm of initiation and titration is a matter of debate. Electrolyte disturbances are common in HFrEF patients and can be attributed to several factors, such as the use of diuretics, renal impairment, and neurohormonal activation. We have identified several HFrEF phenotypes according to their sodium (Na+) and potassium (K+) status in a "real world" setting and suggest an algorithm on how to introduce the most appropriate drug and set up therapy based on the patients' electrolytes and the existence of congestion.

Inflammation and Heart Failure: Searching for the Enemy-Reaching the Entelechy.

The pivotal role of inflammation in the pathophysiology of heart-failure (HF) development and progression has long been recognized. High blood levels of pro-inflammatory and inflammatory markers are present and associated with adverse outcomes in patients with HF. In addition, there seems to be an interrelation between inflammation and neurohormonal activation, the cornerstone of HF pathophysiology and management. However, clinical trials involving anti-inflammatory agents have shown inconclusive or even contradictory results in improving HF outcomes. In the present review, we try to shed some light on the reciprocal relationship between inflammation and HF in an attempt to identify the central regulating factors, such as inflammatory cells and soluble mediators and the related inflammatory pathways as potential therapeutic targets.

Targeting Key Inflammatory Mechanisms Underlying Heart Failure: A Comprehensive Review.

Inflammation is a major component of heart failure (HF), causing peripheral vasculopathy and cardiac remodeling. High levels of circulating inflammatory cytokines in HF patients have been well recognized. The hallmark of the inflammatory imbalance is the insufficient production of anti-inflammatory mediators, a condition that leads to dysregulated cytokine activity. The condition progresses because of the pathogenic consequences of the cytokine imbalance, including the impact of endothelial dysfunction and adrenergic responsiveness deterioration, and unfavorable inotropic effects on the myocardium. Hence, to develop possible anti-inflammatory treatment options that will enhance the outcomes of HF patients, it is essential to identify the potential pathophysiological mechanisms of inflammation in HF. Inflammatory mediators, such as cytokines, adhesion molecules, and acute-phase proteins, are elevated during this process, highlighting the complex association between inflammation and HF. Therefore, these inflammatory markers can be used in predicting prognosis of the syndrome. Various immune cells impact on myocardial remodeling and recovery. They lead to stimulation, release of alarmins and risk-related molecule patterns. Targeting key inflammatory mechanisms seems a quite promising therapy strategy in HF. Cytokine modulation is only one of several possible targets in the fight against inflammation, as the potential molecular targets for therapy in HF include immune activation, inflammation, oxidative stress, alterations in mitochondrial bioenergetics, and autophagy.

A New Hope: Sodium-Glucose Cotransporter-2 Inhibition to Prevent Atrial Fibrillation.

Atrial arrhythmias are common in patients with diabetes mellitus (DM), and despite recent advances in pharmaceutical and invasive treatments, atrial fibrillation (AF) and atrial flutter (AFl) are still associated with substantial mortality and morbidity. Clinical trial data imply a protective effect of sodium-glucose cotransporter-2 inhibitors (SGLT2is) on the occurrence of AF and AFl. This review summarizes the state of knowledge regarding DM-mediated mechanisms responsible for AF genesis and recurrence but also discusses the recent data from experimental studies, published trials and metanalyses.

Reshaping Treatment of Heart Failure with Preserved Ejection Fraction.

Current data indicate that in the community, approximately 50% of patients with heart failure (HF) have preserved left ventricular (LV) ejection fraction (LVEF)­the so-called HFpEF. Treatment of HFpEF has been considered an unmet need for decades. We believe that the main underlying reasons have been (a) the ever-changing LVEF cut-offs used for HF classification; (b) controversies regarding the definition of the LVEF normal range; (c) the fact that HFpEF does not represent a phenotype, but a category of diseases with entirely different characteristics (hypertensive heart disease, valvular heart disease (VHD), hypertrophic cardiomyopathy (HCM) etc.); (d) the lack of recognition that hypertensive HFpEF is the most common and important HFpEF phenotype; (e) the assumption that neurohormonal overactivity is absent in HF patients with a LVEF > 45−50% which has been proven to be wrong. Current HFpEF trials, in which the vast majority of the participants suffered from hypertension (HTN), whereas VHD and HCM were absent, demonstrated that neurohormonal and sodium-glucose cotransporter 2 (SGLT2) inhibitors are effective in HF patients over a wide LVEF range. Thus, restricting these lifesaving treatments to HF patients with reduced LVEF is not justified anymore and it should be additionally considered for HFpEF patients suffering from HTN.

Practical Approaches to Build and Sustain a Cardio-Oncology Clinic.

The therapeutical advances in recent years in the field of oncology treatment have increased survival rates and improved the quality of life of oncology patients, thus turning cancer into a chronic disease. However, most of the new cancer treatments come at the expense of serious cardiovascular adverse events threatening the success story of these patients. The establishment of multidisciplinary medical teams to prevent, monitor, and treat cardiovascular diseases in cancer-treated patients is needed now more than ever. The aim of this narrative review is to demonstrate the existing knowledge and practical approaches on how to establish and maintain a cardio-oncology program for the rising number of patients who need it.

The Effects of Different Hormones on Supraventricular and Ventricular Premature Contractions in Healthy Premenopausal Women.

Background and Objectives: The effects of gender differences on cardiac parameters have been well-established. In this study, we aimed to evaluate the possible associations of plasma levels of different sex hormones with premature atrial or ventricular contractions in premenopausal women. Materials and Methods: We conducted a prospective study which included women in late reproductive age who presented with palpitations during an eight-month period. A 12-lead electrocardiography, a transthoracic echocardiogram, blood samples, and 24-hour rhythm Holter were conducted on the third day of the menstrual cycle. Results Overall, 93 healthy premenopausal women with a median age of 42 years were enrolled. QTc interval was within normal limits in all patients. The 24 h range of premature atrial contractions (PACs) and premature ventricular contractions (PVCs) was 0-6450 and was 0-21,230, respectively. The median number of PVCs was 540 and the median number of PACs was 212, respectively. In total, 51 patients (54.8%) had a frequency of PVCs > 500/24 h and 37 patients (39.8%) had a frequency of PACs > 500/24 h, respectively. No statistically significant association was shown between any hormone and the frequency of PACs. Regarding PVCs, patients with a PVCs frequency > 500/24 h had higher estradiol levels compared to patients with PVCs less than 500/24 h (median 60 pg/mL versus 42 pg/mL, p = 0.02, OR: 1.01). No association was found between PVCs and other hormones. Conclusions: In premenopausal healthy women, higher estradiol levels are independently associated with increased PVCs. This suggests that estradiol in late reproductive stages may exert proarrhythmic effects.

The Effect of Antioxidant and Anti-Inflammatory Capacity of Diet on Psoriasis and Psoriatic Arthritis Phenotype: Nutrition as Therapeutic Tool?

Chronic inflammation and increased oxidative stress are contributing factors to many non-communicable diseases. A growing body of evidence indicates that dietary nutrients can activate the immune system and may lead to the overproduction of pro-inflammatory cytokines. Fatty acids as macronutrients are key players for immunomodulation, with n-3 polyunsaturated fatty acids having the most beneficial effect, while polyphenols and carotenoids seem to be the most promising antioxidants. Psoriasis is a chronic, immune-mediated inflammatory disease with multifactorial etiology. Obesity is a major risk factor for psoriasis, which leads to worse clinical outcomes. Weight loss interventions and, generally, dietary regimens such as gluten-free and Mediterranean diet or supplement use may potentially improve psoriasis' natural course and response to therapy. However, data about more sophisticated nutritional patterns, such as ketogenic, very low-carb or specific macro- and micro-nutrient substitution, are scarce. This review aims to present the effect of strictly structured dietary nutrients, that are known to affect glucose/lipid metabolism and insulin responses, on chronic inflammation and immunity, and to discuss the utility of nutritional regimens as possible therapeutic tools for psoriasis and psoriatic arthritis.

Cardiovascular complications of metastatic colorectal cancer treatment.

Colorectal cancer (CRC) is the third most common malignancy in men and the second in women and the fourth cause of cancer death. Survival rates decrease greatly according to the stage of the disease at the time of diagnosis. Approximately 50% of CRC patients will develop metastatic disease (mCRC) with survival and prognosis depending on the timing of metastatic development, and the localization and number of metastatic sites. The overall survival of patients with mCRC has been significantly improved over the last years from approximately 12 to more than 30 months with the integration of multiple cytotoxic agents and targeted therapies. The optimal therapeutic strategy depends on the general condition and performance status of the patient, the resectability or not of metastases and the mutational status of the tumor in terms of BRAF and RAS. Cardiovascular (CV) complications of mCRC treatment may develop peri-operatively and mostly during chemotherapy. During first-line treatment, 90% of patients experience more than one adverse event (AE) and 39% of them are CV. Angina, hypertension, arrhythmias, arterial and venous thrombotic events (VTEs), heart failure (HF) and death are the main CV events resulting from the applied chemotherapy regimens. Cardio-oncology consultation for identification of high-risk patients, proper monitoring during and after therapy and timely intervention would allow the successful prevention and the efficient management of cardiotoxicity, rendering the patient able to receive the indicated cancer therapy and improving the overall outcome.

Myocardial strain may predict exercise tolerance in patients with reduced and mid-range ejection fraction.

BACKGROUND: Conventional echocardiographic parameters, such as rest ejection fraction, perform poorly in the prediction of exercise tolerance in heart failure. The aim of the present study was to evaluate the contribution of hemodynamic instability in the observed lower functional capacity and investigate the role of left ventricular strain for the prediction of stress test duration in obese hypertensive patients with reduced ejection fraction. METHODS: Sixty-one patients with reduced ejection fraction underwent treadmill exercise echocardiography. Systolic and diastolic echocardiographic parameters were recorded. Moreover, the presence of hemodynamic instability was assessed through N-terminal pro B-type natriuretic peptide (NT-proBNP) measurements at baseline and peak exercise. RESULTS: Rest and peak NT-proBNP levels, and their difference, were significantly correlated with mean global strain at peak, which was the only parameter associated with changes in NT-proBNP levels. Rest and peak mean global strain were found to be predictive for the duration of treadmill stress test. In particular, mean global strain, but not left ventricular ejection fraction, was independently correlated with exercise ability. CONCLUSIONS: Stress echocardiography may provide important information regarding exercise tolerance in obese hypertensive patients with reduced ejection fraction, mainly through the evaluation of left ventricular strain. The obtained evidence may also have prognostic value, particularly in the early stages of the syndrome.

Effects of varenicline and nicotine replacement therapy on arterial elasticity, endothelial glycocalyx and oxidative stress during a 3-month smoking cessation program.

BACKGROUND AND AIMS: The effects of medically-aided smoking cessation on vascular function and oxidative stress are not fully clarified. METHODS: One hundred eighty-eight current smokers were randomized to varenicline or nicotine replacement treatment (NRT) for a 3-month period. We assessed: (a) augmentation index (Aix) and pulse wave velocity (PWV); (b) perfusion boundary region (PBR) of sublingual microvasculature (range:5-25 µm), an index of the endothelial glycocalyx thickness, using Sideview, Darkfield imaging; (c) the exhaled CO; and (d) the malondialdehyde (MDA) and protein carbonyls (PC) plasma levels, as markers of oxidative stress, at baseline and after 3 and 12 months. RESULTS: After 3 months of treatment, CO, MDA, PC and Aix were decreased in all subjects (median CO: 25 vs. 6 ppm, MDA: 0.81 vs. 0.63 nmol/L, PC: 0.102, vs. 0.093 nmol/mg protein, Aix: 13% vs. 9%, p < 0.05) while PWV remained unchanged. Endothelial glycocalyx integrity showed a greater improvement in the varenicline than the NRT treatment (PBR range 5-9 µm: 1.07 ± 0.02 vs. 1.17 ± 0.02 µm, p = 0.03) in parallel with the greater CO reduction (5 vs. 7 ppm, p = 0.02). At 1-year follow-up, MDA, PC, Aix and PBR at 5-25 µm range were further improved in subjects who abstained from smoking (n = 84 out of 188), while the above markers and PWV deteriorated in relapsed smokers (p < 0.05). CONCLUSIONS: A smoking cessation program using varenicline or NRT for 3 months resulted in a decrease of CO, oxidative stress, arterial stiffness and restored endothelial glycocalyx. These effects were more evident after varenicline treatment, likely because of a greater CO reduction, and were maintained after 1 year only in subjects who abstained from smoking.

Detection of high-burden coronary artery disease by exercise-induced changes of the E/E' ratio.

To investigate whether exercise-induced changes of the E/E' average ratio can detect high-burden coronary artery disease (CAD) in patients with chest pain and normal left ventricular (LV) systolic function. The study population consisted of 359 patients admitted for chest pain (59.8 ± 9.8 years, 75% male). Patients underwent exercise echocardiography, scintigraphy and coronary angiography. The average of the lateral and septal ratios of early diastolic transmitral velocity to early diastolic tissue velocity (E/E') at baseline and immediately after exercise was calculated. Exercise induced wall motion abnormalities were also calculated. Coronary angiography showed flow limiting CAD in 238 patients (66%). The exercise-induced changes of E/E' average ratio had a sensitivity of 87.3% and a specificity of 75.2% for detection of flow limiting CAD, whereas myocardial scintigraphy showed 79.2% sensitivity and 80.1% specificity and exercise induced wall motion abnormalities had a sensitivity of 74.3% and a specificity of 66.9%. Likelihood ratio chi square showed an incremental value of the exercise-induced changes of E/E' average ratio over regional perfusion technique (from 121.37 to 194.15, P < 0.001) and over wall motion abnormalities (from 57.03 to 146.50, P < 0.001). The exercise-induced change of the E/E' average ratio detects flow limiting CAD in patients with chest pain and normal LV systolic function showing an incremental value over regional perfusion technique and wall motion abnormalities.

Catheter ablation for atrial fibrillation in patients with left ventricular systolic dysfunction. A systematic review and meta-analysis.

BACKGROUND: Atrial fibrillation (AF) and heart failure are often coexisting major public health burdens. Although several studies have reported partial restoration of systolic left ventricular (LV) function after catheter ablation for AF, the method is not widely applied in patients with LV dysfunction. We reviewed the results of AF ablation in patients with systolic LV dysfunction. METHODS AND RESULTS: PubMed was searched for studies published after 2000 reporting original data on AF catheter ablation in adult patients with systolic LV dysfunction. Primary end point was the change of LV ejection fraction (LVEF) after catheter ablation; secondary endpoints were the changes of exercise capacity and quality of life after the procedure. We calculated mean difference (MD) of LVEF and 95% confidence interval (95% CI) using random-effects models. Heterogeneity was investigated by I(2) statistic, publication bias with Egger's test. The impact of covariates on LVEF improvement was evaluated with meta-regression analyses. Nine studies with a total of 354 patients with systolic LV dysfunction were analyzed. Study patients were mainly male with mean age 49 to 62 years, LVEF was moderately impaired and ranged in all but 1 study from 35% to 43%. LVEF improved after ablation with a MD of 11.1% (95% CI: 7.1-15.2, P < .001). Heterogeneity among analyzed studies was significant (I(2) = 92.9, P < .001). No potential publication bias was found. In meta-regression analyses, the proportion of patients with coronary artery disease was inversely related with LVEF improvement (P < .0001) whereas there was no association between the LVEF change and the proportion of patients with nonparoxysmal AF or the proportion of patients without AF recurrences during follow-up. CONCLUSIONS: AF ablation in patients with systolic LV dysfunction results in significant improvement of LV function, but the extent of this improvement is heterogeneous. Patients with coronary artery disease seem to benefit less than patients with other underlying diseases. These results may be explained by patient selection.

Exercise-induced changes of B-type natriuretic peptide uncover the unknown coronary artery disease in patients with chest pain and normal left ventricular systolic function.

AIM: The diagnostic and prognostic utility of B-type natriuretic peptide (BNP) has been shown in patients either with heart failure or with known coronary artery disease (CAD). We aimed to investigate the utility of the exercise-induced changes of BNP in patients with chest pain, unknown CAD, and normal left ventricular systolic function. METHODS: We evaluated 100 consecutive patients (mean age 58.7 ± 9 years) (80% male) with left ventricular ejection fraction of more than 50%. Blood samples were collected and BNP was measured before exercise stress testing, at peak, and 20 min after it. All patients underwent coronary artery angiography. We used univariate and multivariate logistic regression analysis. RESULTS: An increment in BNP values of 1.3 fold (from before to peak exercise BNP values) have 11 times greater odds of having CAD [odds ratio (OR): 11.45 with 95% confidence interval (CI): 3.48­37.66, P < 0.001]. Receiver operating curve analysis revealed a sensitivity of 81.8% and a specificity of 71.8%. Multivariate analysis revealed that BNP increment from before to peak exercise remained statistically significant regardless of the presence of other risk factors for atherosclerosis (OR: 18.59 with 95% CI: 4.14­83.45, P < 0.001). Interestingly, patients showing 1.79 times increment of before to peak exercise BNP values have 19 times greater odds of having multivessel disease (OR: 19.28 with 95% CI: 4.95­75.17, P < 0.001) with a sensitivity of 81% and specificity of 81.8%. CONCLUSION: The exercise-induced changes of BNP in patients with chest pain, normal left ventricular systolic function, and unknown CAD may uncover patients with CAD and discriminate those with angiographically severe one.

Diastolic stress echocardiography detects coronary artery disease in patients with asymptomatic type II diabetes.

OBJECTIVES: Diabetes mellitus is considered as an equivalent of coronary artery disease (CAD). Aim of the study was to investigate whether in asymptomatic patients with type II diabetes, diastolic stress echocardiography may represent an alternative tool for the detection of CAD. METHODS: The study population consisted of 105 patients with diabetes mellitus (age 61+/-9 years, 26% female, duration of diabetes 37+/-14 months). We performed an exercise stress test, followed by an echo-study and a single-positron emission tomography. Coronary angiography was performed within 1 month. RESULTS: Coronary angiography revealed a coronary artery stenosis of at least 70% in 72 patients (69%, CAD group), while the remaining formed the non-CAD group. Exercise induced an increase of both E/E' lateral and septal ratios as well as their average in the CAD group and on the contrary a decrease of these ratios in the non-CAD group. Receiver operating curve analysis for discrimination between patients with and without obstructive CAD showed an optimal cut-off value of -0.0708 for the exercise-induced change of E/E' average (area under curve 0.892, P<0.001). Sensitivities of scintigraphy and of diastolic stress echocardiography for detection of CAD were 75.0 and 93.1%, respectively; specificity was 78.8% for both methods. In asymptomatic patients, sensitivities of scintigraphy and diastolic stress echocardiography were 76.9 and 92.3%; specificity of both was 80%. CONCLUSION: In patients with type II diabetes, diastolic stress echocardiography, by means of E/E' ratio exercise-induced changes, can be used for the diagnosis and severity of CAD and for the detection of occult myocardial ischemia.