Programmed death of cardiomyocytes in cardiovascular disease and new therapeutic approaches.

Cardiovascular diseases (CVDs) have a complex pathogenesis and pose a major threat to human health. Cardiomyocytes have a low regenerative capacity, and their death is a key factor in the morbidity and mortality of many CVDs. Cardiomyocyte death can be regulated by specific signaling pathways known as programmed cell death (PCD), including apoptosis, necroptosis, autophagy, pyroptosis, and ferroptosis, etc. Abnormalities in PCD can lead to the development of a variety of cardiovascular diseases, and there are also molecular-level interconnections between different PCD pathways under the same cardiovascular disease model. Currently, the link between programmed cell death in cardiomyocytes and cardiovascular disease is not fully understood. This review describes the molecular mechanisms of programmed death and the impact of cardiomyocyte death on cardiovascular disease development. Emphasis is placed on a summary of drugs and potential therapeutic approaches that can be used to treat cardiovascular disease by targeting and blocking programmed cell death in cardiomyocytes.

Effect of ivabradine on structural and functional changes of myocardium and NT-proBNP levels in patients with stable coronary heart disease after coronary stenting.

OBJECTIVE: Aim: To investigate the effect of ivabradine on the hemodynamics and contractility of the myocardium and the features of NT-pro-BNP production in patients with stable ischemic heart disease after endovascular revascularization of the myocardium depending on the number of affected coronary arteries during 12 months of therapy. PATIENTS AND METHODS: Materials and Methods: The object of the study was 120 patients with stable coronary artery disease: angina pectoris of functional class III with heart failure IIA FC III with preserved and moderately reduced ejection fraction of the left ventricle, who underwent coronary artery stenting. The examined patients were randomized according to the number of affected coronary vessels and the method of treatment. RESULTS: Results: Ivabradine in patients with stable ischemic heart disease after 12 months of therapy had a significant beneficial effect on the structural and functional parameters of the myocardium (contributed to the reverse remodeling of the left ventricle), which did not depend on the number of stented coronary arteries (p<0.05). In patients with stented one coronary artery, all structural and functional indicators of the heart after 12 months of treatment reached the values of practically healthy individuals from the control group. The use of ivabradine in patients with stable ischemic heart disease with heart failure with preserved and intermediate ejection fraction of the left ventricle after coronary stenting made it possible to ensure the correction of a number of clinical and pathogenetic links of the disease, which generally contributed to the improvement of metric and volumetric parameters of the heart. CONCLUSION: Conclusions: Ivabradine made it possible to significantly increase the effectiveness of standard therapy, which was manifested by a faster recovery of the geometry and contractility of the left ventricle. Therefore, the use of ivabradine along with standard therapy was appropriate for such a contingent of patients. The management of patients with stable coronary heart disease should combine adequate (surgical and pharmacological) treatment of the underlying disease, further individual medication correction of symptoms and circulatory disorders inherent in coronary heart disease and heart failure.

Ivabradine effects on heart rate and quality of life among chronic heart failure patients.

OBJECTIVE: To determine the effect of Ivabradine in lowering heart rate and quality of life in chronic heart failure patients. METHODS: The observational study was conducted in the out-patient department of the National Institute of Cardiovascular Disease, Karachi, from December 2016 to June 2017, and comprised chronic heart failure patients aged 30-70 years who were on 5mg Ivabradine for 8-weeks. Heart rate was evaluated through electrocardiogram, and health-related quality of life was measured using the validated questionnaire. Baseline demographics and clinical characteristics were recorded, with follow-ups at week-4 and week-8. Safety and tolerability were assessed by adverse drug reactions monitoring. Data was analysed using SPSS 21. RESULTS: Of the 50 patients, 34(68%) were males. The overall mean age was 54.8±9.17 years. Baseline mean heart rate significantly reduced at first and second follow-up visit (p< 0.001). Mobility problems declined significantly as well (p<0.05). Health-related quality of life significantly improved on follow-up visits (p<0.001). CONCLUSIONS: There was significant control of heart rate in chronic heart failure patients with improvement in all parameters of quality of life.

Resveratrol isoforms and conjugates: A review from biosynthesis in plants to elimination from the human body.

The natural isomers of resveratrol, cis- and trans-resveratrol, are natural phenolic substances synthetized via the shikimate pathway and found in many sources, including grapes, peanuts, blackberries, pistachios, cacao, cranberries, and jackfruits. They have functional and pharmacological properties such as anticarcinogenic, antidiabetic, anti-inflammatory, and cardioprotective activities. The aim of this article is to review the data published on resveratrol and its isomers, and their biosynthesis in plants, food sources, health and toxic effects, and the excretion of their metabolites. Due to its contribution to the promotion of human health, it is convenient to gather more knowledge about its functional properties, food sources, and the interactions with the human body during the processes of eating, digestion, absorption, biotransformation, and excretion, to combine this information to improve the understanding of these substances.

Heart Rate As a Biomarker in Heart Failure: Role of Heart Rate Lowering Agents.

Heart failure (HF) is a common clinical condition affecting more than 5.8 million people in the United States, it remains the leading cause of death in the United States and worldwide. Ongoing challenges for biomarker identification include the need for objective assessment, measurement precision, and meaningful replication. Biomarkers not only serve as traditional predictors of prognosis, they can also help to identify high-risk patients who need closer monitoring and more aggressive therapy; therefore, we reviewed the use of heart rate (HR) as a biomarker in HF both of diagnostic and prognostic values, in addition, to being easily detected. HR is a determinant of myocardial oxygen demand, coronary blood flow, and myocardial performance and is central to the adaptation of cardiac output to metabolic needs. Increased HR is known to predict adverse outcome in the general population and in patients with chronic HF. Part of the ability of HR to predict risk is related to the forces driving it, namely, neurohormonal activation. We reviewed therapies, which slow the HR like ß-blockers and ivabradine (a drug that is a pure HR-reducing agent), and all the clinical studies suggest the benefit of these drugs in the management of HF, and increasing evidence suggests HR as a biomarker of both diagnostic and prognostic values in HF.

Special Issue "Saffron (Crocus sativus, L.): Omics and Other Techniques in Authenticity, Quality, and Bioactivity Studies".

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Ivabradine reduces myocardial stunning in patients with exercise-inducible ischaemia.

Ivabradine is an effective treatment for angina in patients with stable coronary artery disease (CAD) and for heart failure. Experiments in a canine model have shown that ivabradine reduces both acute left ventricular (LV) dysfunction and post-ischaemic stunning. Aim of this study was to investigate the effect of ivabradine on LV dysfunction and stunning in patients with CAD and exercise-inducible ischaemia. Fifteen patients with ejection fraction >40 % and heart rate >70 bpm were enrolled. After pharmacologic washout, echocardiography was performed at rest, at peak treadmill exercise and during recovery until return to baseline. After 2 weeks of ivabradine (7.5 mg bid) stress echocardiography was repeated at the same workload achieved during washout. Peak global and segmental (ischaemic vs. remote normal segments) LV longitudinal strain (LS) was assessed by 2D speckle tracking analysis. At washout, LS was significantly impaired in ischaemic compared to remote segments at peak stress and for several minutes during recovery. After ivabradine a smaller, albeit still significant, impairment of LS in ischaemic segments was observed at peak whilst no difference with remote segments was present during recovery. Furthermore, the average global LS value improved significantly after treatment. In conclusion, ivabradine reduces both acute LV dysfunction and stunning in patients with CAD and exercise-inducible ischaemia. We hypothesise that this mechanism might contribute to reduce chronic LV dysfunction in patients with CAD. In this setting the drug might limit the development of hibernating myocardium which is believed to result from repeated episodes of ischaemia and stunning.

Effects of Angiotensin II Receptor Blockers on Metabolism of Arachidonic Acid via CYP2C8.

Arachidonic acid (AA) is metabolized to epoxyeicosatrienoic acids (EETs) via cytochrome enzymes such as CYP 2C9, 2C8 and 2J2. EETs play a role in cardioprotection and regulation of blood pressure. Recently, adverse reactions such as sudden heart attack and fatal myocardial infarction were reported among patients taking angiotensin II receptor blockers (ARBs). As some ARBs have affinity for these CYP enzymes, metabolic inhibition of AA by ARBs is a possible cause for the increase in cardiovascular events. In this study, we quantitatively investigated the inhibitory effects of ARBs on the formation of EETs and further metabolites, dihydroxyeicosatrienoic acids (DHETs), from AA via CYP2C8. In incubations with recombinant CYP2C8 in vitro, the inhibitory effects were compared by measuring EETs and DHETs by HPLC-MS/MS. Inhibition of AA metabolism by ARBs was detected in a concentration-dependent manner with IC50 values of losartan (42.7 µM), telmisartan (49.5 µM), irbesartan (55.6 µM), olmesartan (66.2 µM), candesartan (108 µM), and valsartan (279 µM). Losartan, telmisartan and irbesartan, which reportedly accumulate in the liver and kidneys, have stronger inhibitory effects than other ARBs. The lower concentration of EETs leads to less protective action on the cardiovascular system and a higher incidence of adverse effects such as sudden heart attack and myocardial infarction in patients taking ARBs.

[Effect of sanatorium treatment on endothelial function in children with primary arterial hypertension].

To study the effect of sanatorium treatment (ST) using sodium chloride baths and metabolic drug mildronat on the dynamics of the ambulatory blood pressure monitoring (ABPM), markers of endothelial function in children with primary arterial hypertension (PAH). ABPM and held defined level of asymmetric dimethylarginine (ADMA), endothelin-1 (ET-1) and nitric oxide (NO) in the serum of 114 children with PAH aged 12-17. The positive dynamics of ABPM in all groups, but significantly (P < 0.05) decrease in mean BP was noted in the group with combined ST using sodium chloride baths. When analyzing the level of NO a positive trend (P < 0.01) in the group was using metabolic therapy, but significantly (P < 0.001) pronounced effect was observed when it is combined balneotherapy and metabolic therapy. Analysis of ET-1 and ADMA at ST in conjunction with therapy and metabolic rate of sodium chloride baths there was a significant (P < 0.01) decrease in these parameters in comparison with those before treatment. In children with PAH have been identified violations of the functional activity of the endothelium, which is reflected in increased levels of ET-1, ADMA and reducing NO. Conducting rehabilitation inclusion complex balneotherapy and metabolic therapy helps to reduce average daily blood pressure, normalization of functional activity of the endothelium as a normalization of the synthesis of NO (P < 0.,001), a significant decrease of ET-1 (P < 0.01) and ADMA (P < 0.01).

Time to benefit of heart rate reduction with ivabradine in patients with heart failure and reduced ejection fraction.

AIMS: In the SHIFT (Systolic Heart failure treatment with the If inhibitor ivabradine Trial, ISRCTN70429960) study, ivabradine reduced cardiovascular death or heart failure (HF) hospitalizations in patients with HF and reduced ejection fraction (HFrEF) in sinus rhythm and with a heart rate (HR) ≥70 bpm. In this study, we sought to determine the clinical significance of the time durations of HR reduction and the significant treatment effect on outcomes among patients with HFrEF. METHODS AND RESULTS: The time to statistically significant reduction of the primary outcome (HF hospitalization and cardiovascular death) and its components, all-cause death, and HF death, were assessed in a post-hoc analysis of the SHIFT trial in the overall population (HR ≥70 bpm) and at HR ≥75 bpm, representing the approved label in many countries. Compared to placebo, the primary outcome and HF hospitalizations were significantly reduced at 102 days, while there was no effect on cardiovascular death, all-cause death, and HF death at HR ≥70 bpm. In the population with a baseline HR ≥75 bpm, a reduction of the primary outcome occurred after 67 days, HF hospitalization after 78 days, cardiovascular death after 169 days, death from HF after 157 days and all-cause death after 169 days. CONCLUSION: Treatment with ivabradine should not be deferred in patients in sinus rhythm with a HR of ≥70 bpm to reduce the primary outcome and HF hospitalizations, in particular in patients with HR ≥75 bpm. At HR ≥75 bpm, the time to risk reduction was shorter for reduction of hospitalization and mortality outcomes in patients with HFrEF after initiation of guideline-directed medication, including beta-blockers at maximally tolerated doses.

Cardiovascular medications in angiogenesis--how to avoid the sting in the tail.

Cancer and cardiovascular disease are the leading causes of death worldwide. Cardiovascular medications have recently been found to have favorable effects also for the treatment of noncardiovascular diseases, including cancer. In this review, we use a reverse bedside-to-bench approach to investigate the effects of common cardiovascular medications on tumor angiogenesis and vascular angiogenesis. Aspirin seems to reduce the risk of developing cancer, particularly colon cancer. However, whether the protective influence of aspirin is due to antiangiogenesis effect is still unclear. ß-Blockers, which are normally used to reduce heart rate and prolong diastole, trigger an increase in stretch-associated release of proangiogenic growth factors thereby inducing angiogenesis. However, according to other studies ß-blockers are able to inhibit angiogenesis via multiplicate mechanisms. Similarly, angiotensin converting enzyme inhibitor and angiotensin II type 1 receptor blocker have controversial effects for the regulation of cell proliferation and angiogenesis. Statins can augment collateral vascular growth in ischemic tissues and restrict the development of cancer. So this topical anti-inflammatory drug seems to be of high value for further therapy. Finally, suggestions on how this pilot experience may guide the conduct of future preclinical investigations, and clinical trials are discussed.

Efficacy of treatments for orthostatic hypotension: a systematic review.

BACKGROUND: orthostatic hypotension (OH) affects up to 30% of adults over 65 and frequently contributes to falls and syncopal episodes. Current guidelines suggest a wide range of treatments, but systematic reviews of the evidence base for such recommendations are lacking. METHODS: we performed a systematic review to assess the evidence for all non-pharmacological and pharmacological interventions for OH. Our search included the following databases: MEDLINE; EMBASE; CINAHL; and the Cochrane library. We searched grey literature and references from included studies and other reviews. We included randomised, placebo-controlled trials, which measured postural drop as an outcome. Study quality was assessed using pre-specified measures of bias. RESULTS: overall, 36 trials (21 interventions) were included. We identified a heterogeneous population and a wide variety of study methods, precluding meta-analysis. Most trials were of poor quality with high risk of bias. Changes in postural drop and symptoms were frequently inconsistent. Compression bandages, indomethacin, oxilofrine, potassium chloride and yohimbine improved the postural drop. Several vasoactive drugs-including midodrine and pyridostigmine-improved the standing blood pressure, but overall worsened the postural drop. CONCLUSIONS: many commonly recommended interventions for OH have a limited evidence base supporting their use. High quality, randomised, controlled trials are needed to underpin clinical practice for this condition.

A meta-analysis of optimal medical therapy with or without percutaneous coronary intervention in patients with stable coronary artery disease.

BACKGROUND: Whether percutaneous coronary intervention (PCI) improves clinical outcomes in patients with chronic angina and stable coronary artery disease (CAD) has been a continuing area of investigation for more than two decades. The recently reported results of the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches, the largest prospective trial of optimal medical therapy (OMT) with or without myocardial revascularization, provides a unique opportunity to determine whether there is an incremental benefit of revascularization in stable CAD patients. METHODS: Scientific databases and websites were searched to find randomized clinical trials (RCTs). Pooled risk ratios were calculated using the random-effects model. RESULTS: Data from 10 RCTs comprising 12 125 patients showed that PCI, when added to OMT, were not associated with lower all-cause mortality (risk ratios, 0.96; 95% CI, 0.87-1.08), cardiovascular mortality (risk ratios, 0.91; 95% CI, 0.79-1.05) or myocardial infarction (MI) (risk ratios, 0.90; 95% CI, 0.78-1.04) as compared with OMT alone. However, OMT+PCI was associated with improved anginal symptoms and a lower risk for revascularization (risk ratios, 0.52; 95% CI, 0.37-0.75). CONCLUSIONS: In patient with chronic stable CAD (without left main disease or reduced ejection fraction), PCI in addition to OMT did not improve mortality or MI compared to OMT alone. However, this strategy is associated with a lower rate of revascularization and improved anginal symptoms.

Cardioactive agents from plants.

This review presents 201 compounds isolated and identified from plants that present cardioactive activity. These substances have been classified by chemical groups and each provides the most relevant information of its pharmacological activity, action mechanism, chemical structure, spectroscopic date and other properties. Chemical structures have been drawn to indicate the stereochemistry. In this review the summary of the scientific information of plants that present biological activity and the compounds responsible for this activity is presented, which introduces the reader to the study of medicinal plants and also provide bibliographic references, where a detailed study of pharmacology can be found.

Neurohormonal regulation of cardiac ion channels in chronic heart failure.

Alteration of neurohormonal homeostasis is a hallmark of the pathophysiology of chronic heart failure (CHF). In particular, overactivation of the renin-angiotensin-aldosterone system and the sympathetic catecholaminergic system is consistently observed. Chronic overactivation of these hormonal pathways leads to a detrimental arrhythmogenic remodeling of cardiac tissue due to dysregulation of cardiac ion channels. Sudden cardiac death resulting from ventricular arrhythmias is a major cause of mortality in patients with CHF. All the drug classes known to reduce mortality in patients with CHF are neurohormonal blockers. The aim of this review was to provide an overview of how cardiac ion channels are regulated by hormones known to play a central role in the pathogenesis of CHF.

Which strategy is more effective for the treatment of cardiovascular disease: high-dose angiotensin II type 1 receptor antagonist monotherapy or combination therapy?

Angiotensin II type 1 (AT(1)) receptor antagonists (blockers) [ARBs] are highly selective for the AT(1) receptor and block the diverse effects of angiotensin II. When high BP is not controlled by low-dose ARB monotherapy, physicians need to employ another strategy, either high-dose ARB monotherapy or combination therapy with calcium channel antagonists (blockers) [CCBs], diuretics, or other agents. High-dose ARB monotherapy is more effective for decreasing proteinuria than low-dose ARB monotherapy or CCBs. Although the ARB valsartan has been shown to prevent coronary restenosis in a clinical study (Val-PREST [Valsartan for prevention of restenosis after stenting of type B2/C lesions]), it is still unclear whether ARBs help to prevent restenosis. The results reported by Peters in this issue highlight the relative efficacies of low- (80 mg/day) and high-dose valsartan (160-320 mg/day) for the prevention of in-stent restenosis after the implantation of bare-metal stents, and suggest that high-dose valsartan can reduce the in-stent restenosis rate, target lesion revascularization and target vessel revascularization rates, late lumen loss, and major adverse cardiac events rate more effectively than low-dose valsartan. A better understanding of the differences in the efficacies of high- and low-dose ARBs could be useful in the treatment of patients with cardiovascular disease and may resolve the issue of whether ARBs prevent coronary restenosis. Clinical benefits may be induced by complete blockade of the renin-angiotensin system using high-dose ARB monotherapy. Therefore, physicians need to select a strategy carefully; i.e. either high-dose ARB monotherapy or combination therapy.

Magnesium Sulfate Treatment Correlates With Improved Neurological Function in Posterior Reversible Encephalopathy Syndrome (PRES): Report of a Case.

Posterior reversible encephalopathy syndrome (PRES) is a potentially reversible failure of cerebral autoregulation managed by correction of hypertension or underlying medical condition. Nonresponding cases progress to irreversible brain damage. There is some evidence of association of hypomagnesemia with PRES. We describe a case of nonresolving PRES where use of magnesium sulfate led to improvement in neurological function and eventual recovery. Our case highlights the need for a randomized controlled trial to test the efficacy of magnesium in PRES.