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.

Impaired Right and Left Ventricular Longitudinal Function in Patients with Fibrotic Interstitial Lung Diseases.

Background: Left ventricular (LV) and right ventricular (RV) dysfunction is recognized in idiopathic pulmonary fibrosis (IPF). Little is known about cardiac involvement in non-idiopathic pulmonary fibrosis (no-IPF). This issue can be explored by advanced echocardiography. Methods: Thirty-three clinically stable and therapy-naive fibrotic IPF and 28 no-IPF patients, and 30 healthy controls were enrolled. Exclusion criteria were autoimmune systemic diseases, coronary disease, heart failure, primary cardiomyopathies, chronic obstructive lung diseases, pulmonary embolism, primary pulmonary hypertension. Lung damage was evaluated by diffusion capacity for carbon monoxide (DLCOsb). All participants underwent an echo-Doppler exam including 2D global longitudinal strain (GLS) of both ventricles and 3D echocardiographic RV ejection fraction (RVEF). Results: We observed LV diastolic dysfunction in IPF and no-IPF, and LV GLS but not LV EF reduction only in IPF. RV diastolic and RV GLS abnormalities were observed in IPF versus both controls and no-IPF. RV EF did not differ significantly between IPF and no-IPF. DLCOsb and RV GLS were associated in the pooled pulmonary fibrosis population and in the IPF subgroup (ß = 0.708, p < 0.001), independently of confounders including pulmonary arterial systolic pressure. Conclusion: Our data highlight the unique diagnostic capabilities of GLS in distinguishing early cardiac damage of IPF from no-IPF patients.

Prominent basal and middle strain longitudinal involvement in newly-diagnosed and never treated hypertensive patients without clear-cut hypertrophy.

BACKGROUND: Left ventricular (LV) global longitudinal strain (GLS) can detect an early dysfunction in arterial hypertension. We investigated regional LV patterns of longitudinal strain (LS) and base-to-apex behaviour in newly diagnosed, never-treated hypertensive patients (HTN) without LV hypertrophy. METHODS: 180 HTN and 115 healthy controls underwent standard echocardiography, including regional LS and GLS assessment (in absolute values). The average LS of six basal (BLS), six middle (MLS), and six apical (ALS) segments and relative regional strain ratio = [ALS/(BLS + MLS)] were also computed. RESULTS: The two groups were comparable for sex, age and heart rate. Body mass index (BMI), systolic, diastolic and mean blood pressure (BP) (all p < 0.0001) were higher in HTN. Despite LV ejection fraction (EF) was comparable, GLS, BLS and MLS resulted lower in HTN (all p < 0.0001), without difference in ALS. Relative regional strain ratio resulted higher in HTN (p < 0.001). Dividing HTN group according to lower normal values derived from the controls, BLS was able to identify a higher rate of LV dysfunction than GLS. By a multiple linear regression analysis performed in the pooled population after adjusting for age, sex, BMI, end-systolic stress, relative wall thickness and LV mass index, the association between BLS and mean BP remained significant (ß coefficient = -0.42, p < 0.0001), despite the significant impact of male sex. In a similar model, MLS and mean BP resulted also independently associated (ß = -0.21, p < 0.002). CONCLUSIONS: Despite normal LV EF, LS dysfunction is detectable in HTN, mainly involving basal and middle segments, resulting in higher relative regional strain ratio.

A nutraceutical combination reduces left ventricular mass in subjects with metabolic syndrome and left ventricular hypertrophy: A multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: Increased left ventricular mass (LVM) is often present in metabolic syndrome (MS), also in the setting of well-controlled blood pressure (BP). Aim of the present study was to evaluate the efficacy of a nutraceutical combination of berberine, red yeast rice extract and policosanol (Armolipid Plus™, AP) in reducing LVM in patients with MS and left ventricular hypertrophy (LVH). METHODS: In this multicenter, randomized, double-blind, placebo-controlled trial, 158 patients with MS (IDF criteria) and LVH (LVM > 48 g/m2.7 in men and > 44 g/m2.7 in women), were randomized 1:1 to receive AP or placebo for 24 weeks. Reduction of LVM, regression of LVH, and changes in lipids were analysed. RESULTS: One-hundred-and-forty-five patients (AP n = 74, placebo n = 71) completed the study. A significant percentage reduction in LVM was observed in AP group vs baseline (-2.7%, p < 0.0001), and compared to placebo (-4.1%, p < 0.0001), and remained significant after adjustment for age, sex, baseline systolic BP and BMI and their changes during the study period. The proportion of subjects showing LVM reduction was higher in AP group than in the placebo group (57% vs 28%, adjusted p = 0.007). Treatment with AP was associated with improvement of lipid profile. CONCLUSIONS: 24-week of treatment with AP is associated with a significant reduction in LVM in subjects with MS and LVH, in addition to favourable effects on lipid profile, and could represent an effective strategy aiming at reducing the associated cardiovascular risk. The trial was registered at clinicaltrials.gov with ID NCT02295176.

Interrelation between midwall mechanics and longitudinal strain in newly diagnosed and never-treated hypertensive patients without clinically defined hypertrophy.

BACKGROUND: In hypertensive patients, an impairment of midwall myocardial mechanics was described in presence of left ventricular (LV) concentric geometry. Under these circumstances, also LV longitudinal dysfunction was found. PURPOSE: Our aim was to evaluate longitudinal and circumferential systolic function and correlations between these two functional components in newly diagnosed hypertensive patients without clinically defined LV hypertrophy (LVH). One hundred and thirty-eight newly diagnosed, never-treated hypertensive patients without LVH and a control group of 105 healthy normotensive individuals underwent two-dimensional and speckle tracking echocardiography. Global longitudinal strain (GLS) was derived (in absolute value) and midwall fractional shortening (MFS) computed. In addition, the hypertensive population was divided into two groups according to GLS: normal GLS (≥20%, n = 94) and reduced GLS (<20%, n = 44). RESULTS: Hypertensive patients had lower MFS (P < 0.001) and GLS (P < 0.0001) than healthy controls. By dividing hypertensive patients according to GLS thresholds of normalcy, MFS was lower in patients with GLS less than 20% (P < 0.0001) while no significant difference was found in LV geometry, ejection fraction and diastolic parameters in comparison with patients with GLS at least 20%. In the pooled hypertensive population, GLS resulted positively related to MFS (r = 0.33, P < 0.0001). By a multiple linear regression analysis, after adjusting for female sex, age, BMI, circumferential end-systolic stress, average e', ejection fraction and relative wall thickness, MFS remained independently associated with GLS (ß = 0.222, P < 0.005). CONCLUSION: In newly diagnosed and never-treated hypertensive patients without LVH, an early LV systolic dysfunction is testified by the reduction of both MFS and GLS. These two parameters resulted independently associated after adjusting for several confounders.

Efficacy of a nutraceutical combination on lipid metabolism in patients with metabolic syndrome: a multicenter, double blind, randomized, placebo controlled trial.

BACKGROUND: Nutraceuticals represent a new therapeutic frontier in the treatment of metabolic syndrom (MetS) and related cardiovascular risk factors. The aim of this study was to evaluate the potential beneficial effects of Armolipid Plus (AP) (berberine 500 mg, red yest rice, monacolin K 3 mg and policosanol 10 mg) on insulin resistance, lipid profile, particularly on small and dense LDL cholesterol (sdLDL-C), representing the most atherogenic components, as well as its effects on high sensitivity C-reactive protein, a notable marker of cardiovascular risk, blood pressure and cardiac remodeling in subjects affected by MetS, with left ventricular hypertrophy. METHODS: The study was a prospective, multi-center, randomized, double blind, placebo-controlled trial. One hundred and fifty eight patients, aged between 28 and 76 years old, were enrolled and randomized to receive either one tablet of AP or placebo (PL) once daily for 24 weeks. Anthropometric and vital parameters, total cholesterol (tot-C), low-density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglyceridemia (TG), non-HDL cholesterol (NHDL-C) and sdLDL-C were evaluated. RESULTS: After 24 weeks of treatment, the analysis performed on 141 subjects (71 in AP arm and 70 in PL arm), showed a significant improvement of lipid profile in the AP group, with reduction in tot-C (- 13.2 mg/dl), LDL-C (- 13.9 mg/dl) and NHDL-C (- 15.3 mg/dl) and increase in HDL-C (+ 2.0 mg/dl). These changes were equally significant compared with placebo (tot-C: AP - 13.2 mg/dL vs PL + 2.7 mg/dL, p < 0.01; LDL-C: AP -13.9 mg/dl vs PL + 1.5 mg/dl, p < 0.01; NHDL-C: AP -15.3 mg/dl vs PL + 2.8 mg/dl, p < 0.01), Although no significant difference was observed between the two arms in the reduction of HDL-C nevertheless it increased significantly in the AP group (AP + 2 mg/dL p < 0.05, PL 0.13 mg/dL). CONCLUSION: The results of this study, applicable to a specific local population show that, in a population of subjects affected by MetS, treatment with AP improves the lipid profile and the most atherogenic factors, thus suggesting a reduction in the risk of development and progression of atherosclerosis, particularly in subjects with high atherogenic risk, due to the presence of sdLDL-C.

Three-dimensional echocardiographic ventricular mass/end-diastolic volume ratio in native hypertensive patients: relation between stroke volume and geometry.

BACKGROUND: Elevated left ventricular (LV) mass/end-diastolic volume ratio (LVM/EDV) has been associated with higher evidence of myocardial fibrosis and dysfunction in hypertensive patients by cardiac magnetic resonance, a technique with limited availability. OBJECTIVES: We investigated the ability of three-dimensional (3D) echocardiography in identifying a phenotype of LV concentric geometry according to LVM/EDV ratio, possibly detecting early myocardial damage in native-hypertensive patients. METHODS: One hundred and twenty-eight native-hypertensive patients underwent 2D and 3D-echocardiography. The population was divided into two groups, according to cut-off point values of 3D-LVM/EDV ratio corresponding to its upper 95% confidence interval in a population of 90 healthy normotensive individuals: LVM/EDV ratio cut-off was 1.22 in men and 1.23 in women. RESULTS: An increased 3D-LVM/EDV ratio identified a higher rate of LV concentric geometry in comparison with 2D-derived relative wall thickness (37 versus 24%, P = 0.03). Patients with LVM/EDV ratio of 1.22 or more in men and 1.23 or more in women were significantly older, had smaller 3D-LV end-diastolic and end-systolic volumes and higher LV mass index, without difference in ejection fraction. 3D-stroke volume (P < 0.0001) was lower in patients with elevated LVM/EDV ratio. By a multilinear regression analysis, after adjusting for sex, age, heart rate, mean blood pressure and BMI, stroke volume was independently and negatively associated to LVM/EDV ratio (ß = -0.55, P < 0.0001). CONCLUSION: In native hypertensive patients, 3D-echo-derived LVM/EDV ratio identifies a higher prevalence of LV concentric geometry than 2D-relative wall thickness. Stroke volume is independently and negatively associated with LVM/EDV ratio and its reduction represents an early marker of myocardial dysfunction in hypertensives with LV concentric geometry.

Not smoking is associated with lower risk of hypertension: results of the Olivetti Heart Study.

BACKGROUND: Few epidemiological investigations evaluated the role of smoking cessation on blood pressure (BP), and the results are not univocal. Therefore, the aim of this study was to assess the effect of smoking cessation on the risk to develop hypertension (HPT) and on BP values. METHODS: This longitudinal study, with a follow-up period of 8 years, included the participants of the Olivetti Heart Study. Participants were 430 untreated normotensive non-diabetic men with normal renal function, examined twice in 1994-95 and in 2002-04. The sample included current smokers (S, n = 212), former smokers (ES, n = 145) and never smokers (NS, n = 73) at baseline. RESULTS: Basal body mass index (BMI), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were significantly higher in ES than in S (ES vs. S; BMI: 27.0 ± 2.5 vs. 26.1 ± 2.9 kg/m2; P < 0.01; SBP/DBP: 121.2 ± 9.3/80.0 ± 5.8 vs. 19.1 ± 9.9/77.4 ± 6.7 mm Hg; P < 0.05; M ± SD). After 8 years of follow-up, BP changes (Δ) were significantly lower in ES than in S (ΔSBP/DBP: 12.6 ± 13.4/7.9 ± 8.1 vs. 16.0 ± 14.9/10.3 ± 10.1 mm Hg; P < 0.05; M ± SD), also after adjustment for potential confounders. Moreover, at the last examination, the overall HPT prevalence was 33%, with lower values in ES than in S (25 vs. 38%, P = 0.01). After accounting for age, BP and BMI at baseline, and changes in smoking habit over the 8-year period, ES still had significant lower risk of HPT than S (odds ratio 0.30, 95% confidence interval 0.15-0.58; P < 0.01). CONCLUSIONS: In this sample of healthy men, smoking cessation was associated with lower BP increment and minor HPT risk, independently of potential confounders.

Insulin resistance: Is it time for primary prevention?

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.

Endocrine alterations are the main determinants of cardiac remodelling in restrictive anorexia nervosa.

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.

Cardiovascular and metabolic effects of Berberine.

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.

Efficacy and safety of valsartan plus hydroclorothiazide for high blood pressure.

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.