A Descriptive Review of the Action Mechanisms of Berberine, Quercetin and Silymarin on Insulin Resistance/Hyperinsulinemia and Cardiovascular Prevention.

Insulin resistance (IR) and the associated hyperinsulinemia are early pathophysiological changes which, if not well treated, can lead to type 2 diabetes, endothelial dysfunction and cardiovascular disease. While diabetes care is fairly well standardized, the prevention and treatment of IR lacks a single pharmaceutical approach and many lifestyle and dietary interventions have been proposed, including a wide range of food supplements. Among the most interesting and well-known natural remedies, alkaloid berberine and the flavonol quercetin have particular relevance in the literature, while silymarin-the active principle of the Silybum marianum thistle-was traditionally used for lipid metabolism disorders and to sustain liver function. This review describes the major defects of insulin signaling leading to IR and the main properties of the three mentioned natural substances, their molecular targets and synergistic action mechanisms. The actions of berberine, quercetin and silymarin are partially superimposable as remedies against reactive oxygen intermediates generated by a high-lipid diet and by NADPH oxidase, which is triggered by phagocyte activation. Furthermore, these compounds inhibit the secretion of a battery of pro-inflammatory cytokines, modulate intestinal microbiota and are especially able to control the various disorders of the insulin receptor and post-receptor signaling systems. Although most of the evidence on the effects of berberine, quercetin and silymarin in modulating insulin resistance and preventing cardiovascular disease derive from experimental studies on animals, the amount of pre-clinical knowledge strongly suggests the need to investigate the therapeutic potential of these substances in human pathology.

A Review of the Potential Roles of Antioxidant and Anti-Inflammatory Pharmacological Approaches for the Management of Mild-to-Moderate Symptomatic COVID-19.

In the past 2 years, the coronavirus disease 2019 (COVID-19) pandemic has driven investigational studies and controlled clinical trials on antiviral treatments and vaccines that have undergone regulatory approval. Now that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants may become endemic over time, there remains a need to identify drugs that treat the symptoms of COVID-19 and prevent progression toward severe cases, hospitalization, and death. Understanding the molecular mechanisms of SARS-CoV-2 infection is extremely important for the development of effective therapies against COVID-19. This review outlines the key pathways involved in the host response to SARS-CoV-2 infection and discusses the potential role of antioxidant and anti-inflammatory pharmacological approaches for the management of early mild-to-moderate COVID-19, using the examples of combined indomethacin, low-dose aspirin, omeprazole, hesperidin, quercetin, and vitamin C. The pharmacological targets of these substances are described here for their possible synergism in counteracting SARS-CoV-2 replication and progression of the infection from the upper respiratory airways to the blood, avoiding vascular complications and cytokine and bradykinin storms.

Retrospective Study of Outcomes and Hospitalization Rates of Patients in Italy with a Confirmed Diagnosis of Early COVID-19 and Treated at Home Within 3 Days or After 3 Days of Symptom Onset with Prescribed and Non-Prescribed Treatments Between November 2020 and August 2021.

BACKGROUND This retrospective study aimed to investigate outcomes and hospitalization rates in patients with a confirmed diagnosis of early COVID-19 treated at home with prescribed and non-prescribed treatments. MATERIAL AND METHODS The medical records of a cohort of 158 Italian patients with early COVID-19 treated at home were analyzed. Treatments consisted of indomethacin, low-dose aspirin, omeprazole, and a flavonoid-based food supplement, plus azithromycin, low-molecular-weight heparin, and betamethasone as needed. The association of treatment timeliness and of clinical variables with the duration of symptoms and with the risk of hospitalization was evaluated by logistic regression. RESULTS Patients were divided into 2 groups: group 1 (n=85) was treated at the earliest possible time (<72 h from onset of symptoms), and group 2 (n=73) was treated >72 h after the onset of symptoms. Clinical severity at the beginning of treatment was similar in the 2 groups. In group 1, symptom duration was shorter than in group 2 (median 6.0 days vs 13.0 days, P<0.001) and no hospitalizations occurred, compared with 19.18% hospitalizations in group 2. One patient in group 1 developed chest X-ray alterations and 2 patients experienced an increase in D-dimer levels, compared with 30 and 22 patients, respectively, in group 2. The main factor determining the duration of symptoms and the risk of hospitalization was the delay in starting therapy (P<0.001). CONCLUSIONS This real-world study of patients in the community showed that early diagnosis and early supportive patient management reduced the severity of COVID-19 and reduced the rate of hospitalization.

Insulin Resistance/Hyperinsulinemia, Neglected Risk Factor for the Development and Worsening of Heart Failure with Preserved Ejection Fraction.

Heart failure (HF) has become a subject of continuous interest since it was declared a new pandemic in 1997 because of the exponential increase in hospitalizations for HF in the latest years. HF is the final state to which all heart diseases of different etiologies lead if not adequately treated. It is highly prevalent worldwide, with a progressive increase with age, reaching a prevalence of 10% in subjects over the age of 65 years. During the last two decades, it was possible to see that the prevalence of heart failure with preserved ejection fraction (HFpEF) was increasing while that of heart failure with reduced ejection fraction (HFrEF) was decreasing. HFpEF is typically characterized by concentric remodeling of the left ventricle (LV) with impaired diastolic function and increased filling pressures. Over the years, also the prevalence of insulin resistance (IR)/hyperinsulinemia (Hyperins) in the general adult population has progressively increased, primarily due to lifestyle changes, particularly in developed and developing countries, with a range that globally ranges between 15.5% and 46.5%. Notably, over 50% of patients with HF also have IR/Hyperins, and the percentage is even higher in those with HFpEF. In the scientific literature, it has been well highlighted that the increased circulating levels of insulin, associated with conditions of insulin resistance, are responsible for progressive cardiovascular alterations over the years that could stimulate the development and/or the worsening of HFpEF. The aim of this manuscript was to review the scientific literature that supports a pathophysiologic connection between IR/Hyperins and HFpEF to stimulate the scientific community toward the identification of hyperinsulinemia associated with insulin resistance as an independent cardiovascular risk factor in the development and worsening of HF, believing that its adequate screening in the general population and an appropriate treatment could reduce the prevalence of HFpEF and improve its progression.

Insulin resistance/hyperinsulinemia: an important cardiovascular risk factor that has long been underestimated.

Cardiovascular mortality is still excessively high, despite the considerable progress made in the prevention and treatment of cardiovascular diseases. Although many cardiovascular risk factors (such as arterial hypertension, hypercholesterolemia, diabetes, etc.), identified in the general population, are being promptly treated, to date little consideration is given to a cardiovascular risk factor which we believe has largely demonstrated in the scientific literature of the last three decades that, if neglected, can produce a series of relevant negative effects on the cardiovascular system: insulin resistance (IR)/hyperinsulinemia (Hyperins). This risk factor is still not sufficently sought in the general population and, consequently, is not treated promptly, as it should be, to avoid its negative impact on the cardiovascular system. IR's prevalence is constantly growing worldwide, and it is estimated to have reached a prevalence of 51% of the general population in developed and developing countries, and Hyperins is a constant and strong feature of IR. This article aims to stimulate the scientific community towards IR/Hyperins as relevant cardiovascular risk factor, since it is still neglected. The scientific literature analyzed and used to for this article was found on PubMed, Scopus, Science Direct, etc, using the following keywords: insulin, insulin signaling, insulin resistance, hyperinsulinemia, cardiovascular risk factors, cardiovascular system, cardiovascular diseases. We selected studies that explored the association between IR/Hyperins and the cardiovascular system, and those that discussed the possibilities of screening and treatment of IR/Hyperins.

The Negative Impact of Insulin Resistance/Hyperinsulinemia on Chronic Heart Failure and the Potential Benefits of Its Screening and Treatment.

This opinion article highlights the potential alterations caused by insulin resistance and hyperinsulinemia on the cardiovascular system and their negative impact on heart failure (HF), and describes the potential benefits of an early screening with consequent prompt treatment. HF is the final event of several different cardiovascular diseases. Its incidence has been increasing over the last decades because of increased survival from ischemic heart disease thanks to improvements in its treatment (including myocardial revascularization interventions) and the increase in life span. In particular, incidence of HF with preserved ejection fraction (HFpEF) is significantly increasing, and patients with HFpEF often are also affected by diabetes mellitus and insulin resistance (IR), with a prevalence > 45%. Concentric left ventricular (LV) remodeling and diastolic dysfunction are the main structural abnormalities that characterize HFpEF. It is well documented in the literature that IR with chronic hyperinsulinemia, besides causing type 2 diabetes mellitus, can cause numerous cardiovascular alterations, including endothelial dysfunction and increased wall thicknesses of the left ventricle with concentric remodeling and diastolic dysfunction. Therefore, it is conceivable that IR might play a major role in the pathophysiology and the progressive worsening of HF. To date, several substances have been shown to reduce IR/hyperinsulinemia and have beneficial clinical effects in patients with HF, including SGLT2 inhibitors, metformin, and berberine. For this reason, an early screening of IR could be advisable in subjects at risk and in patients with heart failure, to promptly intervene with appropriate therapy. Future studies aimed at comparing the efficacy of the substances used both alone and in association are needed.

The Problem of Home Therapy during COVID-19 Pandemic in Italy: Government Guidelines versus Freedom of Cure?

After starting in late 2019, COVID-19 spread worldwide, and Italy was one of the first Western nations to be seriously affected. At that time, both the virus and the disease were little known and there were no Evidence-Based Medicine indications for treatment. The Italian Health Ministry guidelines claimed that, unless oxygen saturation fell to <92%, no pharmacological treatment was necessary during the first 72 hours, other than on a purely symptomatic basis, preferably with paracetamol. As later confirmed, that delay in therapeutic intervention may have been responsible for numerous hospital admissions and a very high lethality (3.5 %). To try to remedy this situation, several volunteer groups were formed, managing to promptlycure thousands of patients at home with non-steroidal anti-inflammatory drugs and a variety of re-purposed drugs (principally hydroxychloroquine, ivermectin) and supplements (such as antioxidants, polyphenols and vitamin D). Although not documented by any randomized controlled studies, these approaches were nonetheless based on the best available evidence, were aimed at addressing otherwise unmet major needs and produced a significant reduction of hospitalizations, of symptom duration, and a complete recovery from the disease compared with late treatment, according to some retrospective observational studies and the clinical experience of many physicians. A prompt discussion, with a clear and open exchange between healthcare Institutions and the said groups of voluntary physicians, could clarify the most effective approaches to reduce the number of hospitalizations and the lethality of this disease.

COVID-19 Medical and Pharmacological Management in the European Countries Compared to Italy: An Overview.

(1) Background: Italy accounts for more than 150,000 deaths due to the COVID-19 pandemic, leading the top rank in SARS-CoV-2-caused deceases in Europe. A survey on the different ways by which the COVID-19 pandemic emergency was managed in the foreign European countries compared to Italy is the purpose of this paper. (2) Methods: A literature search and various mathematical algorithms to approach a rank scoring scale were used to describe in detail the different approaches used by European countries to manage the COVID-19 pandemic emergency. (3) Results: The study showed that Italy stands at the bottom ranking for COVID-19 management due to its high mortality rate. Possible causes of the observed huge numbers of hospitalization and deaths were (a) the demographic composition of the European country; (b) its decentralized healthcare system organization; (c) the role of correct pharmacology in the early stages before hospitalization. Post-mortem examinations were of paramount importance to elucidate the etiopathogenesis of COVID-19 and to tailor a suitable and proper therapy in the early symptomatic stages of COVID-19, preventing hospitalization. (4) Conclusions: Factors such as the significant impact on elderly people, the public health organization prevalently state-owned and represented mainly by hospitals, and criticism of the home therapy approach toward SARS-CoV-2-infected people, may have concurred in increasing the number of COVID-19 deaths in Italy.

Home pharmacological therapy in early COVID-19 to prevent hospitalization and reduce mortality: Time for a suitable proposal.

The COVID-19 pandemic is a highly dramatic concern for mankind. In Italy, the pandemic exerted its major impact throughout the period of February to June 2020. To date, the awkward amount of more than 134,000 deaths has been reported. Yet, post-mortem autopsy was performed on a very modest number of patients who died from COVID-19 infection, leading to a first confirmation of an immune-thrombosis of the lungs as the major COVID-19 pathogenesis, likewise for SARS. Since then (June-August 2020), no targeted early therapy considering this pathogenetic issue was approached. The patients treated with early anti-inflammatory, anti-platelet, anticoagulant and antibiotic therapy confirmed that COVID-19 was an endothelial inflammation with immuno-thrombosis. Patients not treated or scarcely treated with the most proper and appropriate therapy and in the earliest, increased the hospitalization rate in the intensive care units and also mortality, due to immune-thrombosis from the pulmonary capillary district and alveoli. The disease causes widespread endothelial inflammation, which can induce damage to various organs and systems. Therapy must be targeted in this consideration, and in this review, we demonstrate how early anti-inflammatory therapy may treat endothelia inflammation and immune-thrombosis caused by COVID-19, by using drugs we are going to recommend in this paper.

The importance of tricuspid regurgitation and right ventricular overload in ICD/CRT recipients: beside the left, beyond the left.

Device therapy for advanced heart failure has become increasingly employed in the last 10 years. Several retrospective studies have postulated a harmful effect of implantable cardioverter-defibrillator (ICD) lead placement on tricuspid valve function and right heart hemodynamics, in particular among patients with preexisting pulmonary vascular overload and both left and right ventricular remodeling/dysfunction. This functional hypothesis is also supported by long-term clinical follow-up analyses of ICD and cardiac resynchronization therapy recipients. In this viewpoint, we propose that the possibility of worsening tricuspid regurgitation and consequent hemodynamic deterioration following device implantation should be considered in future studies, as well as in the preimplant evaluation of individual candidates among other clinical factors.

Effects of growth hormone on exercise capacity and cardiopulmonary performance in patients with chronic heart failure.

BACKGROUND: Because GH exerted beneficial effects in various experimental models of heart failure, we investigated the effects of GH on physical exercise capacity and cardiopulmonary performance in patients with dilated cardiomyopathy and chronic heart failure (CHF). METHODS: Twenty-two patients with CHF (New York Heart Association functional class II-III) underwent spirometry and a symptom-limited, cardiopulmonary exercise testing before and after 3 months of GH (n = 11; seven males; seven idiopathic; 57 +/- 11 yr; 4 IU sc every other day) or placebo (n = 11; eight males; six idiopathic; 54 +/- 10 yr) administration, in a randomized, double-blind trial. Background CHF therapy remained unchanged. RESULTS: GH, but not placebo, increased IGF-I serum concentration (from 144 +/- 35 to 293 +/- 58 ng/ml; P < 0.005) and improved New York Heart Association functional class (from 2.4 +/- 0.5 to 1.8 +/- 0.4; P < 0.005), exercise duration (from 831 +/- 273 to 925 +/- 266 sec; P < 0.005), peak power output (from 245 +/- 127 to 280 +/- 132 W; P < 0.05), peak minute ventilation (from 52.5 +/- 16.1 to 61.3 +/- 17.3 liters/min; P < 0.05), peak oxygen consumption (from 19.8 +/- 5.6 to 25.1 +/- 5.6 ml/kg.min; P < 0.005), and anaerobic threshold (from 14.9 +/- 4.8 to 20.0 +/- 4.5 ml/kg.min; P < 0.005) without affecting lung function parameters. Furthermore, the slope of the relationship between minute ventilation and pulmonary carbon dioxide production (ventilatory efficiency) decreased from 34.7 +/- 5.1 to 31.7 +/- 5.3 (P < 0.005), whereas the slope of the relation between percent predicted heart rate reserve used and percent observed metabolic reserve used (chronotropic index) rose from 0.57 +/- 0.20 to 0.69 +/- 0.18 (P < 0.005). CONCLUSION: Given the predictive value of physical exercise capacity and cardiopulmonary performance in CHF progression, these data provide additional insights into the mechanisms by which GH may potentially benefit CHF patients.

Tadalafil improves quality of life and exercise tolerance in idiopathic pulmonary arterial hypertension.

Pulmonary arterial hypertension has a poor prognosis quoad vitam et valitudinem. Herein, we report on a middle-aged woman affected by idiopathic pulmonary arterial hypertension whose quality of life and exercise tolerance improved remarkably after a six-month course of treatment with the long-acting phosphodiesterase-5 inhibitor tadalafil.

Association between post-ischemic forearm blood flow and blood pressure response to maximal exercise in well trained healthy young men.

BACKGROUND: The relationship between peripheral circulation and blood pressure (BP) response to maximal exercise is an intriguing and not yet well defined topic. AIMS: Aims of the present study were to investigate in well trained young healthy males the possible relationships between the endothelial or the smooth muscle component of the peripheral circulation and 1) the BP response to physical exercise on treadmill 2) the body mass composition. SUBJECTS AND METHODS: Fifteen subjects (18-36 years), regularly performing physical activity 3 times weekly underwent the following examinations: body composition by bioelectrical impedance analysis; measurement of the forearm blood flow (FBF) at rest and during post-ischemic hyperemia by strain-gauge plethysmography at the upper arm; measurement of brachial artery diameter (BAD) at rest and after 4-min ischemia by echography; BP response to maximal exercise on treadmill with the determination of maximal oxygen consumption and the measurement of lactic acid serum concentration. RESULTS: BAD was significantly increased during post-ischemic hyperemia up to the 4th minute of observation with a peak at 60 s (+8.5%); FBF increased at 30 s after ischemia (+210%) and returned to baseline levels at the 2nd minute. In the linear correlation analysis, systolic BP increase at the end of the maximal exercise was significantly and inversely related to the increase in FBF (r=-0.663, p<0.01) and to the early FMD (r=0.503, p<0.05). In the multiple regression analysis, however, only FBF independently affected SBP increase during exercise (t=-3.268, p<0.02). Systolic BP increase at the end of the maximal exercise was significantly related to the increase in FBF but not to that of BAD. Among parameters of body composition, fat-free mass was closely related to changes only in BAD. CONCLUSIONS: These data indicate that FBF, which depends on the smooth muscle component of the peripheral circulation, is closely related to BP response to exercise while the endothelial function, which has been determined as changes in BAD, is related to the fat-free mass of the body, possibly through the peripheral insulin sensitivity.

Growth hormone corrects vascular dysfunction in patients with chronic heart failure.

OBJECTIVES: The goal of this study was to test the hypothesis that growth hormone (GH) administration to patients with chronic heart failure (CHF) corrects their vascular dysfunction. BACKGROUND: Endothelial dysfunction is a prominent feature of CHF. Recent evidence indicates that GH plays a role in vascular reactivity. METHODS: We studied vascular reactivity in 16 patients with CHF (New York Heart Association class II to III) before and after three months of GH (4 IU subcutaneously every other day) or placebo administration in a randomized, double-blind trial. We measured forearm blood flow (FBF) by strain-gauge plethysmography during intrabrachial, graded infusion of acetylcholine (ACh) and sodium nitroprusside (NP). We also measured the forearm balance of nitrite and cyclic guanosine monophosphate (cGMP) before and during ACh infusion. Maximal oxygen uptake (VO2max) was measured by breath-to-breath respiratory gas analysis. RESULTS: Before treatment, the response of FBF to ACh was flat (p = NS). Growth hormone, but not placebo, greatly improved this response (p = 0.03) and, concomitantly, increased the forearm release of nitrite and cGMP (p < 0.05). Growth hormone also potentiated the FBF response to NP (p = 0.013). Growth hormone interacted with ACh response (p = 0.01) but not with the response to NP (p = NS). Accordingly, GH enhanced the slope of the dose-response curve to ACh (p < 0.05) but not to NP. The VO2max increased significantly after GH treatment (20 +/- 2 and 26 +/- 2 ml x Kg(-1) x min(-1) before and after GH treatment, respectively, p < 0.05) but not after placebo. CONCLUSIONS: A three-month treatment with GH corrected endothelial dysfunction and improved non-endothelium-dependent vasodilation in patients with CHF. The data highlight the potential role of GH in the progression of congestive heart failure.

Effects of subclinical thyroid dysfunction on the heart.

BACKGROUND: Mounting evidence indicates that subclinical thyroid dysfunction has important clinical effects and prognostic implications, supporting the view that it is not a compensated biochemical change sensu strictu. PURPOSE: To review clinical information on the effects of subclinical thyroid dysfunction on the heart. DATA SOURCES: English-language articles identified from files and a MEDLINE search (1970-September 2001), references of relevant articles, textbooks, and meeting abstracts. STUDY SELECTION: Reports on the effects of subclinical hypothyroidism and subclinical hyperthyroidism on the cardiovascular system in humans. DATA EXTRACTION: Data on cardiac structure and performance, arrhythmias, and risk for coronary artery disease were independently assessed by all authors and summarized. DATA SYNTHESIS: Subclinical hypothyroidism is associated with impaired left ventricular diastolic function at rest, systolic dysfunction on effort, and enhanced risk for atherosclerosis and myocardial infarction. Subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased left ventricular mass with marginal concentric remodeling, impaired ventricular relaxation, reduced exercise performance, and increased risk for cardiovascular death. All abnormalities were reversed by restoration of euthyroidism (subclinical hypothyroidism) or were blunted by beta-blockade and tailoring of the l -thyroxine dose (subclinical hyperthyroidism). CONCLUSION: The heart responds to the minimal but persistent changes in circulating thyroid hormone levels typical of subclinical thyroid dysfunction. Thus, the condition is not a compensated biochemical change sensu strictu, and timely treatment should be considered in an attempt to avoid adverse cardiovascular effects.

An exaggerated systolic blood pressure response to exercise is associated with cardiovascular remodeling in subjects with prehypertension.

BACKGROUND: Although many observers consider the cardiovascular risk associated with isolated prehypertension to be low and not worth pharmacological treating, the cardiovascular disease rate is increased among individuals within this blood pressure stratum. METHODS: We performed Doppler echocardiography and submaximal bicycle ergometry in 20 nonsmoking sedentary prehypertensive subjects and 20 age- and sex-matched nonsmoking sedentary normotensive subjects, and investigated the association between the systolic blood pressure response to exercise (SBPRE) and hypertensive target organ damage. An exaggerated SBPRE (E-SBPRE) and a normal SBPRE (N-SBPRE) were diagnosed using the mean +2 standard deviations of systolic blood pressure at 100 W in normotensives. RESULTS: Body mass index was similar in the two groups. Resting blood pressure and systemic vascular resistance were higher in prehypertensives. Almost half the latter had an E-SBPRE. There were no differences in age, gender, and body mass index between normotensives and prehypertensives with an E-SBPRE or a N-SBPRE. Resting blood pressure and systemic vascular resistance were similarly increased in prehypertensives with an E-SBPRE and a N-SBPRE vs normotensives. Compared with normotensives, prehypertensives with an E-SBPRE showed: (a) a significantly greater left ventricular relative wall thickness, mostly due to a smaller cavity, (b) a significantly longer left ventricular isovolumic relaxation time, and (c) a significantly greater global arterial stiffness, as estimated by the pulse pressure/left ventricular stroke volume ratio. CONCLUSIONS: Our findings suggest that an E-SBPRE is frequent among prehypertensive subjects and is associated with cardiovascular remodeling, which may herald cardiovascular disease.

Efficacy of sildenafil in HIV-related pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is one of the long-term complications of HIV infection. The incidence of HIV-PAH is estimated at 0.5% of HIV-infected individuals. The mechanism by which infection leads to full-blown PAH is unknown. We describe a 44-year-old female patient with HIV infection diagnosed in 2004. Pulmonary hypertension was diagnosed in 2006. Seven months after the first cardiovascular clinical signs had started, the patient was referred to hospital because she was in New York Heart Association functional class IV. She commenced treatment with sildenafil. After increasing the sildenafil dose to ensure therapeutic drug levels over 24 h, the PAH and physical performance of the patient improved significantly. Our experience confirms long-term benefits of sildenafil monotherapy in PAH-HIV adult patients with improvements in symptoms and echocardiographic findings.