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Background/Objectives : While post-acute COVID-19 syndrome is well known and extensively studied, the post-acute COVID vaccination syndrome (PACVS) is a more recent nosological entity that is poorly defined at the immunopathological level, although it shares many symptoms with the sequelae of viral infections. Methods : This single-center retrospective study reports a case series of 17 subjects vaccinated with mRNA or adenoviral vector vaccines who were healthy before vaccination and had never been infected with SARS-CoV-2 but who presented with symptoms similar to PACVS for a median time of 20 months (min 4, max 32). The medical records of all patients referred to our outpatient clinic over a one-year period were retrospectively analyzed. Results : In this group, serological tests showed that, in addition to positivity for anti-spike protein antibodies, a high percentage of subjects were positive for antibodies against G protein-coupled receptors and molecules involved in the response to SARS-CoV-2. In a panel of 16 autoantibodies tested, a few were positively associated with some of the symptoms reported by patients: anti-ATR1 with lymphadenopathy and/or tonsillitis; anti-ACE2 with skin symptoms such as ecchymosis, skin oedema, and rash; anti-MAS1 with widespread burning sensation; and anti-STAB1 with skin oedema and rash. Anti-ADRA2A were negatively associated with memory loss and/or mental fog. ACE2 correlated with the serum levels of anti-S antibodies, supporting the hypothesis of an anti-idiotype mechanism in the immunopathogenesis of PACVS. Conclusions : This exploratory analysis suggests that the levels of autoantibodies directed against ACE2, and probably also MAS1 and STAB1, may serve as biomarkers for PACVS.

Despite all the progress made by science in the prevention and treatment of cardiovascular diseases and cancers, these are still the main reasons for hospitalizations and death in the Western world. Among the possible causes of this situation, disorders related to hyperinsulinemia and insulin resistance (Hyperin/IR) are still little-known topics. An analysis of the literature shows that this condition is a multiple risk factor for type 2 diabetes, cardiovascular diseases, cellular senescence and cancer, and neurodegenerative diseases. Hyperin/IR is progressively increasing worldwide, and its prevalence has now exceeded 50% of the general population and in overweight children. Asymptomatic or poorly symptomatic, it can last for many years before manifesting itself as diabetes, cardiovascular disease, neoplasm, cognitive deficit, or dementia, therefore leading to enormous social and healthcare costs. For these reasons, a screening plan for this pathology should be implemented for the purpose of identifying people with Hyperin/IR and promptly starting them on preventive treatment.

Peripheral insulin resistance (IR) is a well-documented, independent risk factor for the development of type 2 diabetes, cardiovascular disease, cancer and cellular senescence. Recently, the brain has also been identified as an insulin-responsive region, where insulin acts as regulator of the brain metabolism. Despite the clear link between IR and the brain, the exact mechanisms underlying this relationship remain unclear. Therapeutic intervention in patients showing symptoms of neurodegenerative diseases has produced little or no results. It has been demonstrated that insulin resistance plays a significant role in the pathogenesis of neurodegenerative diseases, particularly cognitive decline. Peripheral and brain IR may represent a modifiable state that could be used to prevent major brain disorders. In this review, we will analyse the scientific literature supporting IR as a risk factor for Alzheimer's disease and suggest some therapeutic strategies to provide a new proposal for the prevention of brain IR and its consequences.

Unfortunately, cardiovascular diseases and cancers are still the leading causes of death in developed and developing countries despite the considerable progress made in the prevention and treatment of diseases. Maybe we missed something? Insulin resistance (IR) with associated hyperinsulinemia (Hypein) is a silent pandemic whose prevalence is continually growing in developed and developing countries, now exceeding 51% of the general population. IR/Hypein, despite the vast scientific literature supporting its adverse action on the development of type 2 diabetes, cardiovascular alterations, tumors, neurological disorders, and cellular senescence, is not yet considered an independent risk factor and, therefore, is not screened in the general population and adequately treated. There are now numerous substances, drugs, and natural substances that, in association with the correction of a wrong lifestyle, can help to reduce IR/Hypein. We are convinced that the time has come to implement a prevention plan against this critical risk factor. Therefore, this manuscript aims to highlight IR/Hypein as an independent risk factor for type 2 diabetes, cardiovascular diseases, cancers, cellular senescence, and neuropsychiatric disorders, supporting our conviction with the available scientific literature on the topic.

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.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (© 2024 Fazio, Mercurio, Tibullo, Fazio and Affuso.)

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.

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.

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., Competing Interests: Potential Conflicts of interest: P.B. has a consultancy agreement with Vanda s.r.l. (Frascati, Rome). The other authors have no competing interests to declare.

(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.

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.

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., (© 2021 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

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.

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.

We describe a 76-year-old former smoker with a diagnosis of combined pulmonary fibrosis and emphysema associated with pulmonary hypertension and rapidly progressive right heart failure, in whom combined treatment with sitaxsentan and sildenafil resulted in sustained improvement of his clinical condition and exercise performance, without any relevant adverse events. Combined pulmonary fibrosis and emphysema comprises a recently identified syndrome, probably related to tobacco use, and characterized by the coexistence of upper-lobe emphysema and fibrotic changes of the lower lobes, preserved lung volumes, significant hypoxemia, and a high prevalence of pulmonary hypertension, resulting in severe dyspnea. To date, no prospective series, to the best of our knowledge, has reported on the effects of pulmonary vasodilator therapy in such patients., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Aim: To test the efficacy of a proprietary nutraceutical combination in reducing insulin resistance associated with the metabolic syndrome (MetS)., Methods: Sixty-four patients with MetS followed at a tertiary outpatient clinic were randomly assigned to receive either placebo or a proprietary nutraceutical combination (AP) consisting of berberine, policosanol and red yeast rice, in a prospective, double-blind, placebo-controlled study. Evaluations were performed at baseline and after 18 wk of treatment. The homeostasis model assessment of insulin resistance (HOMA-IR) index was the primary outcome measure. Secondary endpoints included lipid panel, blood glucose and insulin fasting, after a standard mixed meal and after an oral glucose tolerance test (OGTT), flow-mediated dilation (FMD), and waist circumference., Results: Fifty nine patients completed the study, 2 withdrew because of adverse effects. After 18 wk there was a significant reduction in the HOMA-IR index in the AP group compared with placebo (ΔHOMA respectively -0.6 ± 1.2 vs 0.4 ± 1.9; P < 0.05). Total and low density lipoprotein cholesterol also significantly decreased in the treatment arm compared with placebo (Δlow density lipoprotein cholesterol -0.82 ± 0.68 vs -0.13 ± 0.55 mmol/L; P < 0.001), while triglycerides, high density lipoprotein cholesterol, and the OGTT were not affected. In addition, there were significant reductions in blood glucose and insulin after the standard mixed meal, as well as an increase in FMD (ΔFMD 1.9 ± 4.2 vs 0 ± 1.9 %; P < 0.05) and a significant reduction in arterial systolic blood pressure in the AP arm., Conclusion: This short-term study shows that AP has relevant beneficial effects on insulin resistance and many other components of MetS.

Insulin resistance is a clinical condition characterized by a decrease in sensitivity and responsiveness to the metabolic actions of insulin, so that a given concentration of insulin produces a less-than-expected biological effect. As a result, higher levels of insulin are needed to maintain normal glucose tolerance. Hyperinsulinemia, indeed, is one of the principal characteristics of insulin resistance states. This feature is common in several pathologic conditions, such as type 2 diabetes, obesity, and dyslipidemia, and it is also a prominent component of hypertension, coronary heart disease, and atherosclerosis. The presence of endothelial dysfunction, related to insulin resistance, plays a key role in the development and progression of atherosclerosis in all of these disorders. Insulin resistance represents the earliest detectable abnormality in type 2 diabetes, and is one of the major underlying mechanisms of hypertension and cardiovascular diseases. Its early detection could be of great importance, in order to set a therapeutic attack and to counteract the higher risk of diabetes and cardiovascular diseases.

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. , (©2011, The Authors. Journal compilation ©2011 Wiley Periodicals, Inc.)

Objective. Anorexia nervosa is a condition of reduced hemodynamic load, characterized by varying degrees of cardiac remodelling, only in part related to reduced body mass; the mechanism for such variability, as well as its clinical significance, remains unknown. Aim of the study was to assess the possible influence of a great number of clinical, biochemical, and endocrine factors on cardiovascular parameters in restrictive anorexia nervosa. Method. Twenty-five female patients hospitalized for restrictive anorexia nervosa underwent extensive cardiovascular, clinical, and biochemical evaluation. Results. Height-adjusted and cardiac workload-matched left ventricular mass was significantly related to several endocrine parameters, blood pressure, and vasoreactivity. On multivariate analysis, IGF/GH ratio and systolic blood pressure were the only independent predictors of height-adjusted ventricular mass (adj-R(2) = 0.585; P = 0.001); when matching for cardiac workload, left ventricular mass was independently predicted only by GH and FT3 levels. All effects were independent of patient's weight and BMI. Conclusions. Indices of endocrine impairment seem to be the most relevant determinants of left ventricular hypotrophy in anorectic patients, apparently independent of reduced hemodynamic load and BMI. In particular, IGF/GH ratio and FT3 seem to particularly affect left ventricular mass in this population.

Aim: To evaluate efficacy and tolerability of the combination valsartan plus hydrochlorothiazide (160 mg and 25 mg daily, respectively) in young-middle aged males with high-normal blood pressure (BP) or first-degree arterial hypertension with evidence of target organ damage., Methods: Twenty males with high-normal BP or first-degree hypertension associated with left ventricular concentric remodeling and/or increased aortic stiffness were enrolled. BP at rest and during exercise, and echocardiographic parameters of the left ventricle (LV), were evaluated at baseline and after 3 mo of treatment. The effects of treatment on aortic stiffness, metabolic parameters, renal and erectile function were also assessed., Results: BP was significantly reduced by treatment both at rest (P < 0.001) and during exercise (P < 0.001), and 85% of patients achieved BP normalization (< 130/85 mmHg). Doppler echocardiography showed a significant reduction of LV mass (P < 0.005). LV hypertrophy was identified in 70% of subjects at baseline and in 5% after 3 mo of treatment. The ratio of early (E) to late (A) trans-mitral diastolic flow velocity increased, (P < 0.05), the relative wall thickness decreased (P < 0.05) and the left ventricular relaxation time shortened (P < 0.005). The left atrial diameter (P < 0.05) and the aortic diameter (P < 0.05) and stiffness (P < 0.005) also decreased., Conclusion: The full-dose combination of valsartan plus hydrochlorothiazide produced optimal BP control with regression of target organ damage, already after 3 mo, without relevant side effects.

Berberine (BBR) is a natural alkaloid isolated from the Coptis Chinensis. While this plant has been used in Ayurvedic and Chinese medicine for more than 2500 years, interest in its effects in metabolic and cardiovascular disease has been growing in the Western world in the last decade. Many papers have been published in these years reporting beneficial effects in carbohydrate and lipid metabolism, endothelial function and the cardiovascular system. In this review, we report a detailed analysis of the scientific literature regarding this topic, describing the effects and the underlying mechanisms of BBR on carbohydrate and lipid metabolism, endothelial function and the cardiovascular system.

Background: Recent application of brain natriuretic peptide and N-terminal prohormone brain natriuretic peptide (NT-proBNP) in cardiac valvular disease is very promising., Aims: To test the usefulness of NT-proBNP in the assessment of patients with aortic or mitral regurgitation., Patients and Methods: Sixty-seven patients - 23 with aortic and 12 with mitral regurgitation vs. 32 controls - were examined by color Doppler echocardiography, cardiopulmonary exercise testing, Minnesota Living with Heart Failure Questionnaire (MLWHFQ) and plasma NT-proBNP assay at rest (T0) and after maximal physical exercise (T1)., Results: NT-proBNP was significantly higher in patients than in controls, both at T0 (298 +/- 85 vs. 46 +/- 11 pg/ml; P < 0.01) and at T1 (366 +/- 106 vs. 50 +/- 12 pg/ml; P < 0.01). MLWHFQ score was significantly higher in patients (19 +/- 3 vs. 1 +/- 0.6; P < 0.001) with a significant inverse correlation with VO2max (r = -0.538, P < 0.001) and a direct correlation with NT-proBNP (T0: r = 0.415, P < 0.01; T1: r = 0.458, P < 0.01). NT-proBNP was inversely correlated with VO2max (T0: r = -0.444, P < 0.001; T1:r = -0.428, P < 0.001) and directly correlated with left atrial diameter (T0: r = 0.370, P < 0.01; T1: r = 0.409, P = 0.001), and left ventricular mass index (r = 0.279, P < 0.01, and r = 0.272, P < 0.01). No correlations were found between echocardiographic parameters of valvular disease severity and VO2max, NT-proBNP and MLWHFQ., Conclusions: NT-proBNP is useful in the assessment of the cardiac functional damage secondary to mitral and aortic regurgitation.

Context: A reduced activity of the GH/IGF-I axis in chronic heart failure (CHF) has been described by several independent groups and is associated with poor clinical status and outcome., Objective: The aim of the current study was to investigate the prevalence of GH deficiency in a patient population with CHF and evaluate the cardiovascular effects of GH replacement therapy., Design and Setting: The randomized, single-blind, controlled trial was conducted at the Federico II University., Participants: One hundred fifty-eight patients with CHF, New York Heart Association class II-IV, underwent a GH stimulation test. Sixty-three patients satisfied the criteria for GH deficiency, and 56 of them were enrolled in the trial., Intervention: The treated group (n = 28) received GH at a replacement dose of 0.012 mg/kg every second day (approximately 2.5 IU)., Main Outcomes Measures: Changes in physical performance and various cardiovascular indexes were measured., Results: GH replacement therapy improved quality of life score (from 46 +/- 5 to 38 +/- 4; P < 0.01), increased peak oxygen uptake and exercise duration (from 12.9 +/- .9 to 14.5 +/- 1 ml/kg x min and from 520 +/- 36 to 586 +/- 43 sec, respectively; P < 0.01), and flow-mediated vasodilation (from 8.8 +/- 1.3 to 12.7 +/- 1.2%; P < 0.01). GH increased left ventricular ejection fraction (from 34 +/- 2 to 36 +/- 2%; P < 0.01) and reduced circulating N-terminal pro-brain natriuretic peptide levels (from 3201 +/- 900 to 2177 +/- 720 pg/ml; P = 0.006). No significant changes from baseline were observed in controls., Conclusions: As many as 40% of patients with CHF are GH deficient. GH replacement therapy in these patients improves exercise capacity, vascular reactivity, left ventricular function, and indices of quality of life.

The growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis regulates cardiac growth, stimulates myocardial contractility and influences the vascular system. The GH/IGF-1 axis controls intrinsic cardiac contractility by enhancing the intracellular calcium availability and regulating expression of contractile proteins; stimulates cardiac growth, by increasing protein synthesis; modifies systemic vascular resistance, by activating the nitric oxide system and regulating non-endothelial-dependent actions. The relationship between the GH/IGF-1 axis and the cardiovascular system has been extensively demonstrated in numerous experimental studies and confirmed by the cardiac derangements secondary to both GH excess and deficiency. Several years ago, a clinical non-blinded study showed, in seven patients with idiopathic dilated cardiomyopathy and chronic heart failure (CHF), a significant improvement in cardiac function and structure after three months of treatment with recombinant GH plus standard therapy for heart failure. More recent studies, including a small double-blind placebo-controlled study on GH effects on exercise tolerance and cardiopulmonary performance, have shown that GH benefits patients with CHF secondary to both ischemic and idiopathic dilated cardiomyopathy. However, conflicting results emerge from other placebo-controlled trials. These discordant findings may be explained by the degree of CHF-associated GH resistance. In conclusion, we believe that more clinical and experimental studies are necessary to exactly understand the mechanisms that determine the variable sensitivity to GH and its positive effects in the failing heart.

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.

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.

Echocardiography can be used to estimate myocardial contractility by the assessment of the circumferential end-systolic stress-corrected left ventricular (LV) fractional shortening measured at midwall level (stress-corrected MWS). Whether stress-corrected MWS at rest predicts exercise peak oxygen uptake (peak VO(2)) is unknown. Also, it is not known whether the propagation rate of the early LV filling wave (E wave propagation rate, V(p)), a new pre-load insensitive index of LV diastolic function, and echocardiographically assessed indices of arterial stiffness correlate to peak VO(2). Accordingly, we performed echocardiographic studies and exercise tests with respiratory gas analysis in 15 young healthy male subjects (mean age 27 years, range 18-36). Neither stress-corrected-MWS ( r=0.20, P=NS) nor ejection fraction ( r=-0.05, P=NS) correlated significantly with peak VO(2). Adjustment for age and resting heart rate had no effect on the results. In separate multiple regression models adjusting for standard covariates (age, LV size and heart rate), peak VO(2) correlated with V(p) (beta=0.98, P<0.01), as well as with E/A (beta=0.85, P<0.01), and with the isovolumic relaxation time (indicator of LV relaxation) (beta=-0.59, P<0.05). Arterial stiffness indices showed no significant relation to peak VO(2). We conclude that in young healthy male subjects, resting myocardial contractility and arterial stiffness are not significant correlates of peak VO(2), whereas LV diastolic function, and in particular V(p), influences the variability of peak VO(2).

Subclinical hypothyroidism (SH), defined by elevated serum levels of thyroid stimulating hormone (TSH) with normal levels of free thyroid hormones, is common in adults, especially in women over 60 years of age. Among individuals with this condition, up to two-thirds have serum TSH levels between 5-10 mU/L and thyroid autoantibodies; almost half of them may progress to overt thyroid failure, the annual percent risk increasing with serum TSH level. There is evidence that elevated TSH levels in patients with SH do not reflect pituitary compensation to maintain euthyroidism, but a mild tissue hypothyroidism sensu strictu. When lasting more than 6-12 months, SH may be associated with an atherogenic lipid profile, a hypercoagulable state, a subtle cardiac defect with mainly diastolic dysfunction, impaired vascular function, and reduced submaximal exercise capacity. The deviation from normality usually increases with serum TSH level ('dosage effect' phenomenon). Restoration of euthyroidism by levothyroxine (LT4) treatment may correct the lipid profile and cardiac abnormalities, especially in patients with an initially higher deviation from normality and higher serum TSH levels. Importantly, a strong association between SH and atherosclerotic cardiovascular disease, independent of the traditional risk factors, has been recently reported in a large cross-sectional survey (the Rotterdam Study). However, whether SH confers a high risk for cardiovascular disease, and whether LT4 therapy has a long-term benefit that clearly outweighs the risks of overzealous treatment in these individuals, remain topics of controversy. Therefore, until randomized, controlled, prospective, and adequately powered trials provide unequivocal answers to these critical questions, it is advisable to prescribe LT4 therapy on a case-by-case basis, taking into account the risk of progressive thyroid failure and the risk of cardiovascular events.

Increased or reduced action of thyroid hormone on certain molecular pathways in the heart and vasculature causes relevant cardiovascular derangements. It is well established that overt hyperthyroidism induces a hyperdynamic cardiovascular state (high cardiac output with low systemic vascular resistance), which is associated with a faster heart rate, enhanced left ventricular (LV) systolic and diastolic function, and increased prevalence of supraventricular tachyarrhythmias - namely, atrial fibrillation - whereas overt hypothyroidism is characterized by the opposite changes. However, whether changes in cardiac performance associated with overt thyroid dysfunction are due mainly to alterations of myocardial contractility or to loading conditions remains unclear. Extensive evidence indicates that the cardiovascular system responds to the minimal but persistent changes in circulating thyroid hormone levels, which are typical of individuals with subclinical thyroid dysfunction. Subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased LV mass, impaired ventricular relaxation, reduced exercise performance, and increased risk of cardiovascular mortality. Subclinical hypothyroidism is associated with impaired LV diastolic function and subtle systolic dysfunction and an enhanced risk for atherosclerosis and myocardial infarction. Because all cardiovascular abnormalities are reversed by restoration of euthyroidism ("subclinical hypothyroidism") or blunted by beta-blockade and L-thyroxine (L-T4) dose tailoring ("subclinical hyperthyroidism"), timely treatment is advisable in an attempt to avoid adverse cardiovascular effects. Interestingly, some data indicate that patients with acute and chronic cardiovascular disorders and those undergoing cardiac surgery may have altered peripheral thyroid hormone metabolism that, in turn, may contribute to altered cardiac function. Preliminary clinical investigations suggest that administration of thyroid hormone or its analogue 3,5-diiodothyropropionic acid greatly benefits these patients, highlighting the potential role of thyroid hormone treatment in patients with acute and chronic cardiovascular disease.

The aim of this study was to determine the incidence of vascular events during a 7-year follow-up evaluation in a group of 34 hypertensive patients with kinking of the internal carotid artery and 36 well-matched hypertensive control subjects. The carotid intima-media thickness (IMT) was measured at three points of the carotid bifurcation and at three points of carotid kinking on the ultrasonographic posterior wall. The mean IMT measured in the segment of the angular bending was lower than the mean values detected at the bifurcation in normal subjects and in hypertensives without carotid elongation (p < 0.01). At the carotid bifurcation of the same side of the kinking, there was an arterial IMT that was significantly lower as compared to the contralateral axis and to the measurements obtained in other hypertensive subjects. During a 7-year follow-up study, 10 vascular events occurred in the hypertensives with carotid kinking and 14 in the controls, without significant differences between the 2 groups. In hypertensives with carotid kinking, the mean IMT measured on the angular bending and at the ipsilateral carotid bifurcation was significantly lower than the values obtained at the contralateral bifurcation and in the other hypertensive subjects. In the 7-year follow-up study, moreover, the presence of carotid kinking does not impact the incidence of vascular events in the hypertensive population. Thus, the presence of carotid kinking in hypertensive subjects may not be considered a further risk factor for ischemic events.

Eleven patients who had undergone total thyroidectomy for differentiated thyroid cancer and who were on chronic TSH-suppressive therapy with levothyroxine (L-T4), underwent 24-h Holter electrocardiogram and Doppler-echocardiography before and after acute recombinant human TSH (rhTSH) administration for disease staging. The treatment, which was generally well tolerated, did not affect circulating thyroid hormones levels, nor did it have measurable effects on heart rate, rhythm, left ventricular morphology, or systo-diastolic function. Notably, arterial blood pressure tended to be slightly reduced after rhTSH administration, although in no instance did the patients become frankly symptomatic. Our data demonstrate that rhTSH does not alter cardiovascular function acutely. Consequently, it can safely be used in the routine staging of patients affected by differentiated thyroid cancer.

Subclinical Cushing's syndrome (SCS) is increasingly being reported in incidentally discovered adrenal adenomas; its hallmark is mild autonomous cortisol hyperproduction without specific clinical signs of cortisol excess. Increased prevalence of hypertension, obesity, and impaired glucose tolerance have been described in SCS, but there is no specific study of the risk factors for cardiovascular diseases. In this cross-sectional study we assessed the cardiovascular profile in 28 consecutive SCS patients (19 women and 9 men; aged 56 +/- 10.6 yr) compared with 100 controls matched for age, gender, and body mass index. Systolic (P < 0.001) and diastolic (P < 0.005) blood pressures were higher in patients, as were fasting glucose, insulin, total cholesterol, triglycerides (all P < 0.001), and fibrinogen (P < 0.05). Moreover, the insulin resistance index was increased in patients as was the waist to hip ratio and mean carotid artery intima-media thickness (all P < 0.001). Of the patients, 60.7% had arterial hypertension, 71.4% had lipid abnormalities, 28.6% had impaired glucose tolerance, 35.7% type 2 diabetes mellitus, and 53.6% had abnormalities in hemostatic parameters. Atherosclerotic plaques were more frequent in patients (P < 0.0001). Only 4 (14.3%) patients did not have multiple risk factors for cardiovascular events. Six (21.3%) had clinical evidence of cardiovascular disease; another 11 (39.3%) had cardiovascular abnormalities as revealed by ultrasound scanning of carotid arteries and/or electrocardiogram records. These results strongly suggest that an increased cardiovascular risk profile, similar to that described in overt Cushing's syndrome, is present in SCS subjects. This finding supports the concept that chronic mild endogenous cortisol excess may have important systemic effects on the human body.

Mounting evidence suggests that increased circulating aldosterone levels, despite angiotensin-converting-enzyme inhibitors therapy, may exert deleterious cardiovascular effects in heart failure, leading to clinical deterioration and poor prognosis. In the past decades, a number of experimental investigations have provided major insight into the mechanism(s) of action and the biological effects of aldosterone on the cardiovascular system, indicating that aldosterone participates in the structural and functional remodeling of cardiac and vascular tissue. In particular, it has emerged that aldosterone plays a key role in the regulation of myocardial extracellular matrix composition and endothelial function with important pathophysiological implications. Such evidence, coupled with the recent beneficial effects of spironolactone, a competitive aldosterone receptor antagonist, in reducing cardiac mortality and morbidity in patients with severe chronic heart failure treated with angiotensin-converting-enzyme inhibitors and loop diuretics, highlights the importance of aldosterone in the pathophysiology of human heart failure. The purpose of this review is to provide an overview of the regulation of aldosterone production and metabolism in heart failure, the basic mechanism of aldosterone action, and the pathophysiological implications of aldosterone in heart failure, and to discuss recent evidence supporting the efficacy of aldosterone receptor blockade in the treatment of chronic heart failure in humans.