Beta-blockers in Hypertensive Left Ventricular Hypertrophy and Atrial Fibrillation Prevention.

BACKGROUND: Hypertensive left ventricular hypertrophy (HTN LVH) is a key risk factor for atrial fibrillation (AF). OBJECTIVE: To evaluate the possible role of beta-blockers (BBs) in addition to a renin-angiotensinaldosterone system (RAAS) blocker in AF prevention in patients with HTN LVH. METHODS: We performed a PubMed, Elsevier, SAGE, Oxford, and Google Scholar search with the search items 'beta blocker hypertension left ventricular hypertrophy patient' from 2013-2023. In the end, a 'snowball search', based on the references of relevant papers as well as from papers that cited them was performed. RESULTS: HTN LVH is a risk factor for AF. In turn, AF substantially complicates HTN LVH and contributes to the genesis of heart failure (HF) with preserved ejection fraction (HFpEF). The prognosis of HFpEF is comparable with that of HF with reduced EF (HFrEF), and, regardless of the type, HF is associated with five-year mortality of 50-75%. The antiarrhythmic properties of BBs are wellrecognized, and BBs as a class of drugs are - in general - recommended to decrease the incidence of AF in HTN. CONCLUSION: BBs are recommended (as a class) for AF prevention in several contemporary guidelines for HTN. LVH regression in HTN - used as a single criterion for the choice of antihypertensive medication - does not capture this protective effect. Consequently, it is worth studying how meaningful this antiarrhythmic action (to prevent AF) of BBs is in patients with HTN LVH in addition to a RAAS blocker.

The role of melatonin in preventing amiodarone-induced rat liver damage.

Long-term exposure to amiodarone, an antiarrhythmic drug, can induce different organ damage, including liver. Cell damage included by amiodarone is a consequence of mitochondrial damage, reactive oxygen species production, and cell energy depletion leading to programmed cell death. In the present study, hepatoprotective potential of neurohormone melatonin (50 mg/kg/day) was evaluated in a chronic experimental model of liver damage induced by a 4-week application of amiodarone (70 mg/kg/day). The obtained results indicate that amiodarone induces an increase in xanthine oxidase activity, as well as the content of the lipid and protein oxidatively modified products and p53 levels. Microscopic analysis further corroborated the biochemical findings revealing hepatocyte degeneration, apoptosis, and occasional necrosis, with the activation of Kupffer cells. Coadministration of melatonin and amiodaron prevented an increase in certain damage associated parameters, due to its multiple targets. In conclusion, the application of melatonin together with amiodarone prevented an increase in tissue oxidative damage parameters and moderately prevented liver cell apoptosis, indicating that the damage of hepatocytes provoked by amiodarone supersedes the protective properties of melatonin in a given dose.

Theoretical investigation of tautomerism of 2- and 4-pyridones: origin, substituent and solvent effects.

Computational investigation at the BHandHLYP/6-311+G(d,p) level of theory of the gas-phase tautomerism of 2- and 4-pyridones confirmed the slight prevalence of lactim in the case of the former, but its dominance in the case of the latter, as shown previously. Examination of aromaticity by using HOMA, EDDB, NBOdel, NICS and AICD led to the conclusion that tautomerization of 4-pyridone results in greater aromaticity gain. It is also driven by the Pauli repulsion relief, which was revealed by the tautomerization energy decomposition analysis. By contrast, in the case of 2-pyridone, lactim is favoured by orbital and electrostatic interactions and disfavoured by the Pauli repulsion. Aromaticity gain in this case is smaller. The position of the tautomeric equilibrium can be modulated by substituent inductive effects (Cl and F), inductive and resonance effects (NH2 and NO2), hydrogen bonding (NO2), and medium polarity, the increase of which increases lactam population.

A Need for Improvement in the Definition of Resistant Arterial Hypertension.

With the medical and social importance of resistant arterial hypertension (HTN) in mind, we had three goals in this paper: to study the definitions of resistant HTN in the guidelines on the topic, to analyze them, and to suggest some improvements. We found (at least) eleven insufficiencies in the definition of resistant HTN: (1) different blood pressure (BP) values are used for diagnoses; (2) the number of BP measurements is not specified; (3) the time-frame for the definition is not obtained; (4) it fails to provide normal or target or controlled BP values; (5) secondary HTN is not currently defined as true resistant HTN, but as apparently treatment-resistant HTN; (6) the definition usually directly incorporates BP cut-offs for systolic BP (sBP) and diastolic BP (dBP) making the diagnosis temporary; (7) stress is not included in the exclusion strategy for resistant HTN; (8) there is potentially a need to introduce a category of recovered resistant HTN; (9) to what degree do healthy lifestyle measures have to be fulfilled to consider it as sufficient to change the diagnosis from "apparent treatment-resistant HTN" to the "resistant HTN"; (10) sBP values normal-for-the-age for 61 and 81 year old patients in some guidelines fulfill the criterion for resistant HTN; (11) it probably ought to read "In the absence of contraindications and compelling indications…" in the others. We believe that it is better to use the phrase "above the target BP" for the definition of (treatment) resistant HTN, because the whole story of resistant HTN is related to non-responders to antihypertensive treatment. Therefore, as we treat to target and not to normal values, it is appropriate to define resistant HTN as an insufficiency to reach the target BP values. Moreover, the definition of (treatment) resistant HTN should not be universal for every patient with HTN, but it should be age-related: (treatment) resistant HTN is elevated BP over the target/normal BP values. Using this modification, there will be no need to automatically change the definition of resistant HTN when we change the BP targets in the future.

Significance of Beta-Blocker in Patients with Hypertensive Left Ventricular Hypertrophy and Myocardial Ischemia.

BACKGROUND: Arterial Hypertension (HTN) is a key risk factor for left ventricular hypertrophy (LVH) and a cause of ischemic heart disease (IHD). The association between myocardial ischemia and HTN LVH is strong because myocardial ischemia can occur in HTN LVH even in the absence of significant stenoses of epicardial coronary arteries. OBJECTIVE: To analyze pathophysiological characteristics/co-morbidities precipitating myocardial ischemia in patients with HTN LVH and provide a rationale for recommending beta-blockers (BBs) to prevent/treat ischemia in LVH. METHODS: We searched PubMed, SCOPUS, PubMed, Elsevier, Springer Verlag, and Google Scholar for review articles and guidelines on hypertension from 01/01/2000 until 01/05/2022. The search was limited to publications written in English. RESULTS: HTN LVH worsens ischemia in coronary artery disease (CAD) patients. Even without obstructive CAD, several pathophysiological mechanisms in HTN LVH can lead to myocardial ischemia. In the same guidelines that recommend BBs for patients with HTN and CAD, we could not find a single recommendation for BBs in patients with HTN LVH but without proven CAD. There are several reasons for the proposal of using some BBs to control ischemia in patients with HTN and LVH (even in the absence of obstructive CAD). CONCLUSION: Some BBs ought to be considered to prevent/treat ischemia in patients with HTN LVH (even in the absence of obstructive CAD). Furthermore, LVH and ischemic events are important causes of ventricular tachycardia, ventricular fibrillation, and sudden cardiac death; these events are another reason for recommending certain BBs for HTN LVH.

Solid-state silica gel-catalyzed synthesis of fluorescent polysubstituted 1,4- and 1,2-dihydropyridines.

We present the green, highly atom-economical, solid-state silica gel-catalyzed synthesis of polysubstituted 1,4- and 1,2-dihydropyridines (DHPs) from commercially available materials, amines and ethyl propiolate. The DHP skeleton was assembled by heating the reactants and silica gel in a closed vessel. Aliphatic amines provided 1,4-isomers as the main or only DHP products, but the reactions of aromatic amines yielded a mixture of 1,4- and 1,2-isomers. To the best of our knowledge, this is the first example of the formation of a 1,2-DHP structure by the reaction of an amine with propiolic ester. Addition of 1 mass percent of H2SO4 to silica gel shifted the product distribution to 1,4-DHP as the main or the only isomer obtained. Experimental and theoretical analyses led to the identification of two key intermediates en route to DHPs and the explanation of the observed regioisomeric ratios. 1,2-DHPs show blue-cyan fluorescence in MeOH with the quantum yield Φ = 0.10-0.22 relative to quinine sulfate Φ = 0.58 and 1,4-DHPs show blue-violet fluorescence with Φ = 0.09-0.81.

Blood pressure cut-offs to diagnose impending hypertensive emergency depend on previous hypertension-mediated organ damage and comorbid conditions.

Background Hypertensive emergencies (HTN-E) are important due to a high risk of mortality. However, a sudden increase in blood pressure (BP) can damage target organs before the BP reaches cut-offs to diagnose HTN-E. We (i) analyse HTN guidelines for recommendations of treatment individualization, such as adjusting BP cut-offs for hypertensive urgency or impending HTN-E according to patient's susceptibility to complications (because of previous hypertension-mediated organ damage [HMOD], cardiovascular events and comorbid conditions), and (ii) provide a rationale for the inclusion of patient's susceptibility in protocols for treatment of acute HTN-E. Methods We searched PubMed, SCOPUS, Science Direct, Springer, Oxford Press, Wiley, SAGE and Google Scholar for the following terms: arterial hypertension, impending, emergency, target organ damage, hypertension-mediated organ damage, and comorbidity. Results The available guidelines do not recommend that when we estimate the probability of HTN-E in a patient with very high BP, we take into account not only the 'aggressive factor' (i.e. history of HTN, absolute BP values and rate of its increase), but also the 'vulnerability of the patient' due to previous major adverse cardio-vascular events, HMOD and comorbid conditions. Conclusion The risk does not depend only on the aggressiveness of the health threat but also on the strength of the host's defence. It is, therefore, surprising that one side of the natural interaction (i.e. susceptibility of a patient) is overlooked in almost all available guidelines on HTN.

Less Known but Clinically Relevant Comorbidities of Atrial Fibrillation: A Narrative Review.

BACKGROUND: The important risk factors for atrial fibrillation (AF) in the general population are not always equally important in specific and relatively prevalent diseases. OBJECTIVE: The main goal of this narrative review is to focus attention on the presence and the relationship of AF with several important diseases, such as cancer or sepsis, in order to: 1) stimulate further research in the field, and 2) draw attention to this relationship and search for AF in clinical practice. METHODS: We searched PubMed, SCOPUS, Elsevier, Wiley, Springer, Oxford Journals, Cambridge, SAGE, and Google Scholar for less-known comorbidities of AF. The search was limited to publications in English. No time limits were applied. RESULTS: AF is widely represented in cardiovascular and other important diseases, even in those in which AF is rarely mentioned. In some specific clinical subsets of AF patients (e.g., patients with sepsis or cancer), the general risk factors for AF may not be so important. Patients with new-onset AF have a several-fold increase in relative risk of cancer, deep vein thrombosis, and pulmonary thromboembolism (PTE) during the follow-up. CONCLUSION: AF presence, prognosis, and optimal therapeutic approach are insufficiently recognised in several prevalent diseases, including life-threatening ones. There is a need for a better search for AF in PTE, pulmonary oedema, aortic dissection, sepsis, cancer and several gastrointestinal diseases. Improved AF detection would influence treatment and improve outcomes.

A Discrepancy: Calcium Channel Blockers Are Effective for the Treatment of Hypertensive Left Ventricular Hypertrophy but Not as Effective for Prevention of Heart Failure.

Arterial hypertension (HTN) is important due to its high prevalence, morbidity, and mortality rates. Calcium channel blockers (CCBs) are the first-line antihypertensive drugs. HTN can lead to heart failure (HF) by causing hypertensive left ventricular hypertrophy (HTN LVH). CCBs are recommended for the treatment of HTN LVH. The aim of this study was to analyze the status of CCBs regarding (1) HTN LVH treatment and (2) capability to prevent HTN-induced HF in the guidelines. For this narrative review, the following databases were searched: Medline, Scopus, Science Direct, Springer, SAGE, Wiley, Oxford Journals, Cambridge, and Google Scholar. CCBs are effective antihypertensive drugs and a very good therapeutic option for HTN LVH as they can cause reverse LVH remodeling. Consequently, we may expect that CCBs would prevent HF. However, evidence suggests that CCBs confer less protection from HF than other first-line antihypertensive drugs. A negative inotropic action of nondihydropyridine CCBs may contribute to suboptimal protection against HF. This discrepancy is clinically relevant because CCBs are in one of the two recommended (single pill) combinations for the initial treatment of HTN. LVH is a strong risk factor for HF in HTN patients. When LVH arises, the risk of HF increases dramatically. CCBs are inferior to renin-angiotensin-aldosterone system blockers but still very effective in bringing about regression of HTN LVH; consequently, CCBs are expected to protect from HF. On the contrary, CCBs protect from HF less effectively than other first-line antihypertensive drugs. This discrepancy needs to be investigated further to improve clinical practice.

Beta Blockers can Mask not only Hypoglycemia but also Hypotension.

BACKGROUND: Beta-adrenergic (ß-AR) receptor blockers (BBs) are an essential class of drugs as they have numerous indications. On the other hand, they have numerous unwanted effects that decrease the compliance, adherence, and persistence of this very useful group of drugs. OBJECTIVE: The paper aims to analyze the possibility that an unnoticed side effect may contribute to a less favorable pharmacologic profile of BBs, e.g., a diminished reaction to a sudden fall in BP. METHODS: We searched two medical databases for abstracts and citations (Medline and SCOPUS). Moreover, we searched the internet for drug prescription leaflets (of the individual BBs). RESULTS: Whichever cause of stress is considered, the somatic manifestations of stress will be (partially) masked if a patient takes BB. Stress-induced hypercatecholaminemia acts on ß-AR of cardiomyocytes; it increases heart rate and contractility, effects suppressed by BBs. The answers of the organism to hypoglycemia and hypotension share the main mechanisms such as sympathetic nervous system activation and hypercatecholaminemia. Thus, there is a striking analogy: BBs can cover up symptoms of both hypoglycemia (which is widely known) and of hypotension (which is not recognized). It is widely known that BBs can cause hypotension. However, they can also complicate recovery by spoiling the defense mechanisms in hypotension as they interfere with the crucial compensatory reflex to increase blood pressure in hypotension. CONCLUSION: Beta blockers can cause hypotension, mask it, and make recovery more difficult. This is clinically important and deserves to be more investigated and probably to be stated as a warning.

Rationale for the Concept of Impending Hypertension-Mediated Organ Damage.

BACKGROUND: The number of patients with hypertension urgencies (HTN-Us) and emergencies (HTN-Es) in the emergency department is relatively constant despite improved detection, awareness and control of arterial hypertension. OBJECTIVE: This study analyses the precision of the often-used definition of HTN-E, particularly the phrase 'with the evidence of impending or progressive hypertension-mediated organ damage (HMOD)'. We then provide a rationale for the concept of impending HMOD. METHODS: The databases PubMed, Science Direct, Springer, Oxford Press, Wiley, SAGE and Google Scholar were searched and the relevant definition has been analyzed. RESULTS: The definition of HTN-E is suboptimal and requires a consensus on whether to include the phrase 'impending hypertensive HMOD' in the definition. CONCLUSION: A consensus on the principles of treating the 'impending hypertensive HMOD' does not exist, making its use inconsistent in emergency departments worldwide. In this paper, we present a rationale for the concept of 'impending HMOD'.

Revival of Hückel Aromatic (Poly)benzenoid Subunits in Triplet State Polycyclic Aromatic Hydrocarbons by Silicon Substitution.

By employing density functional theory (DFT) calculations we show that mono- and disilicon substitution in polycyclic aromatic hydrocarbons, having two to four benzene units, quenches their triplet state antiaromaticity by creating Hückel aromatic (poly)benzenoid subunit(s) and weakly antiaromatic, or almost nonaromatic silacycle. Therefore, such systems are predicted to be globally aromatic in both the ground state and the first excited triplet state. Putting the silicon atom(s) into various positions of a hydrocarbon provides an opportunity to tune the singlet-triplet energy gaps. They depend on the global aromaticity degree which, in turn, depends on the type of aromatic carbocyclic subunit(s) and the extent of their aromaticity. On the basis of the set of studied compounds, some preliminary rules on how to regulate the extent of global, semiglobal and local aromaticity are proposed. The results of this work extend the importance of Hückel aromaticity concept to excited triplet states which are usually characterized by the Baird type of (anti)aromaticity.

Contraindications Differ Widely Among Beta Blockers and Ought to be Cited for an Individual Drug, Not for the Entire Class.

Beta blockers (BBs) have important side effects that contribute to low adherence and persistence. Therefore, the optimal choice of BB is an important mode to prevent BB's side effects, leading to an increase in compliance, which can improve the outcomes in BBs' evidence-based indications, such as acute myocardial infarction, heart failure, etc. The aim of the paper is to suggest an improved method of reporting contraindications for BBs. We used a search of the following indexing databases: SCOPUS and PubMed, and web search engine Google Scholar to identify guidelines on arterial hypertension (HTN). HTN guidelines published during the last 2 decades were analyzed (from 2000 to 2020). Some of the contraindications (e.g., bradycardia, acute heart failure) are true for every BB. However, some contraindications do not belong to the whole BB class. For example, propranolol and carvedilol are contraindicated in chronic obstructive lung disease, but nebivolol and bisoprolol are not. We suggest that contraindications which are specific for some BBs (i.e., not for the whole class) ought to be listed with the exact name(s) of the individual BBs. In this way, we may decrease the number of wrong choices among BBs and consequently increase drug adherence (which is currently worse for the class of BBs than for most of the other antihypertensive drugs). To our knowledge, there is a lack of guidelines citing contraindications for individual BBs, because they vary a lot within-the-class of BBs. This is an approach to improve both basic medical education and guidelines.

Certain beta blockers (e.g., bisoprolol) may be reevaluated in hypertension guidelines for patients with left ventricular hypertrophy to diminish the ventricular arrhythmic risk.

Hypertensive left ventricular hypertrophy (HTN LVH) is associated with almost threefold increased risk of ventricular tachycardia (VT)/ventricular fibrillation (VF). Furthermore, HTN LVH increases the risk of sudden cardiac death (SCD). The reverse LV remodeling due to efficient antihypertensive therapy lowers the incidence rates of cardiovascular events and SCD and the vast majority of available arterial hypertension (HTN) guidelines recommend renin angiotensin system (RAS) blockers and calcium channel blockers (CCBs) for HTN LVH aiming for LVH regression. On the other hand, beta blockers (BBs) as a class are not recommended in HTN LVH due to their insufficient capacity to reverse LVH remodeling even though they are recommended as the first-line drugs for prevention/treatment of VT/VF (in general, unrelated to HTN LVH). Moreover, BBs are the best antiarrhythmic (against VT/VF) among antihypertensive drugs. Despite that, BBs are currently not recommended for LVH treatment in HTN Guidelines. It is important to prevent VT/VF in patients at high risk, such as those with HTN LVH. Therefore, certain BBs (such as Bisoprolol) may be reevaluated in guidelines for HTN (in the section of HTN LVH).

By Discontinuing Beta-Blockers Before an Exercise Test, We may Precipitate a Rebound Phenomenon.

BACKGROUND: There is a need to analyse the current approach to beta-blocker (BB) use in relation to exercise-based stress tests. OBJECTIVE: We compared various guidelines regarding recommending abrupt vs. gradual discontinuation of BB prior to exercise tests. We also analyse the shortcomings of the currently recommended approach and suggest a new approach to avoid BB rebound. METHODS: A narrative review is used to analyse this topic due to the lack of valid randomized clinical trials. RESULTS: Omitting the BB therapy prior to exercise-based test has been recommended in guidelines for many years. Although reasonable, this approach has potential disadvantages since sudden BB withdrawal may induce a rebound phenomenon, which is also acknowledged in several guidelines. CONCLUSION: We observed inconsistency among relevant guidelines; there is no homogenous approach regarding BB use before exercise tests. Most guidelines recommend BB withdrawal for a couple of days before the test; they do not advise BB dose tapering. This approach is not standardised and raises the risk of BB rebound phenomenon before and during the test. Therefore, we suggest using half the prescribed BB dose at the usual time of administration (in the morning, prior to the exercise test).

Does HAS-BLED risk score underestimate the risk of bleeding in patients with triple antithrombotic therapy?

stroke or other thromboembolic complications in patients with atrial fibrillation (AF). On the other hand, dual antiplatelet therapy (aspirin plus P2Y12 inhibitor) represents a cornerstone in the treatment of acute coronary syndrome. Atrial fibrillation is relatively common in patients with coronary artery disease and patients who undergo primary percutaneous coronary interventions (PCI) with stent implantation. They should be on triple antithrombotic therapy (TAT): preferably direct oral anticoagulants (DOAC) plus aspirin plus clopidogrel as it prevents ischemic as well as thromboembolic events. Before introducing OAT in patients with AF we must assess the risk of future bleeding episodes as OAT can lead to some life-threatening bleeding events. The most common risk score used for that purpose is HASBLED score. HAS-BLED score is valuable, proven tool in assessing future bleeding events in patients with AF. Nevertheless, it does not make the difference between dual and triple antithrombotic therapy which can be of great importance in preventing bleeding events.

Synthesis of 2,3-Dihydro-4-pyridones and 4-Pyridones by the Cyclization Reaction of Ester-Tethered Enaminones.

2,3-Dihydro-4-pyridone skeleton is an important building block in organic synthesis because it features several reaction sites with nucleophilic or electrophilic properties. Herein, we disclose a method for its formation by intramolecular cyclization of ester-tethered enaminones, which can easily be synthesized from readily available materials, such as amines, activated alkynes, and activated alkenes. 2,3-Dihydro-4-pyridones have been isolated in 41-90% yields. We also demonstrate the transformation of these heterocycles into another important class of compounds, 4-pyridones, by utilizing 2,3,5,6-tetrachloro-p-benzoquinone (chloranil) as an oxidizing agent. The latter products were isolated in 65-94% yields.