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Owing to its ease of application, noninvasive nature, and safety, echocardiography is an essential imaging modality to assess cardiac function in patients affected by ischemic heart disease (IHD). Over the past few decades, we have witnessed a continuous series of evolutions in the ultrasound field that have led to the introduction of innovative echocardiographic modalities which allowed to better understand the morphofunctional abnormalities occurring in cardiovascular diseases. This article offers an overview of some of the newest echocardiographic modalities and their promising application in IHD diagnosis, risk stratification, management, and monitoring after cardiac rehabilitation.

Background: atherosclerotic process inexorably advances in patients reaching low-density lipoprotein cholesterol (LDL-C) targets. An attractive hypothesis is that lipoprotein particles (very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL)), could contribute to residual risk. The present study aims to investigate the relationship between carotid intima-media thickness (IMT) and different lipoprotein subfractions in a cohort of healthy postmenopausal women. Methods: 75 postmenopausal women, at LDL-C target levels without overt cardiovascular disease, underwent biochemical analyses (including subfraction assay of plasma lipoproteins) and carotid ultrasound examination. Results: a statistically significant correlation between VLDL and carotid IMT (p < 0.001) was found. No significant correlation was found between carotid IMT and LDL-C (p = 0.179), IDL-C (p = 0.815), high-density lipoprotein (HDL) (p = 0.855), and LDL score (p = 0.240). Moreover, IMT is significantly correlated to LDL particle diameter (p = 0.044). After adjusting for age, systolic blood pressure, body mass index, smoking habits, glucose plasma concentration, and Lipoprotein(a) (Lpa) levels, multivariate analysis showed that women in the third tertile of VLDL-C, compared with those in the first tertile, were significantly associated to the highest IMT (p = 0.04). Conclusions: in this cohort of postmenopausal women, VLDL-C was significantly associated to carotid IMT, independent of main cardiovascular risk factors. These findings pave the way for targeting circulating concentrations of VLDL-C to reduce cardiovascular events in patients with target LDL-C levels.

Inflammation plays a key role in the initiation and progression of atherosclerosis but also in the pathophysiology of atheromatous plaque disruption and the development of acute coronary syndromes. Neopterin is a marker of inflammation and of immune system activation, it is synthesized by macrophages, that, once activated, release this substance. Indeed, in clinical evaluation of patients, measurements of plasma levels of neopterin are usually used to evaluate progression of viral infections, renal transplant rejection, severe systemic inflammatory diseases, nephritic syndrome and several autoimmune diseases. This mediator is able to induce a pro-atherothrombotic phenotype in cells of the coronary circulation. Recent data indicate that serum levels of neopterin are elevated in patients with coronary and peripheral artery disease and seem to be a prognostic marker for major adverse cardiovascular events. In particular, neopterin levels predict future major cardiac and vascular adverse events in patients presenting with chronic coronary artery disease, with acute coronary syndromes, and in those with critical limb ischemia. This renders this molecule a useful marker of atherosclerotic plaque activity, permitting the identification of the subjects at highest risk for major adverse cardiovascular events. In line with the above mentioned evidences, patients with high neopterin levels may require aggressive risk factor modification and intensive medical treatment irrespective of the severity of their coronary artery disease. This data suggest a potential clinical use of neopterin as a marker for disease activity in patients with cardiovascular disease.

Inflammation plays a pivotal role in atherothrombosis. Recent data indicate that serum levels of neopterin, a marker of inflammation and immune modulator secreted by monocytes/macrophages, are elevated in patients with acute coronary syndromes and seem to be a prognostic marker for major cardiovascular events. The aim of the present study was to determine whether neopterin might affect the thrombotic and atherosclerotic characteristics of human coronary endothelial cells (HCAECs). Methods and Results: In HCAECs, neopterin induced TF-mRNA transcription as demonstrated by real time PCR and expression of functionally active tissue factor (TF) as demonstrated by procoagulant activity assay, and of Cellular Adhesion Molecules (CAMs) as demonstrated by FACS analysis, in a dose-dependent fashion. These neopterin effects were prevented by lovastatin, a HMG-CoA reductase inhibitor. Neopterin-induced TF and CAMs expression was mediated by oxygen free radicals through the activation of the transcription factor, NF-B, as demonstrated by electrophoretic mobility shift assay and by suppression of CAMs and TF expression by Superoxide Dismutase and by NF-kB inhibitor, pyrrolidine-dithio-carbamate ammonium. Conclusions: These data indicate that neopterin exerts direct effects on human coronary endothelial cells by promoting CAMs and TF expression and support the hypothesis that neopterin, besides representing a marker of inflammation, might be an effector molecule able to induce a pro-atherothrombotic phenotype in cells of the coronary circulation.

Background—Tissue factor (TF) is the main initiator of coagulation in vivo. Recently, however, a role for TF as a cell receptor involved in signal transduction has been suggested. The aim of the present study was to assess whether activated factor VII (FVIIa) binding to TF could induce smooth muscle cell (SMC) proliferation and to clarify the possible intracellular mechanism(s) responsible for this proliferation. Methods and Results—Cell proliferation was induced by FVIIa in a dose-dependent manner, as assessed by [3H]thymidine incorporation and direct cell counting, whereas no response was observed with active site–inhibited FVIIa (FVIIai), which is identical to FVIIa but is devoid of enzymatic activity. Similarly, no proliferation was observed when binding of FVIIa to TF was prevented by the monoclonal anti-TF antibody AP-1. Activation of the p44/42 mitogen-activated protein (MAP) kinase (extracellular signal–regulated kinases 1 and 2 [ERK 1/2]) pathway on binding of FVIIa to TF was demonstrated by transient ERK phosphorylation in Western blots and by suppression of proliferation with the specific MEK (MAP kinase/ERK kinase) inhibitor UO126. ERK phosphorylation was not observed with FVIIai or when cells were pretreated with AP-1. Conclusions—These data indicate a specific effect by which binding of FVIIa to TF on the surface of SMCs induces proliferation via a coagulation-independent mechanism and possibly indicate a new link between coagulation, inflammation, and atherosclerosis.

Iron deficiency anemia (IDA) is frequent after cardiac surgery and is associated with increased morbidity and mortality. In a retrospective study, we analyzed 106 patients with IDA (hemoglobin [Hb] ≤ 12 g/dl in women and ≤ 13 g/dl in men, transferrin saturation [TSAT] ≤ 20%) on admission to a Cardiac Rehabilitation Unit after cardiac surgery. The patients were divided into two groups, one was treated with oral sucrosomial iron (SI) and the other with intravenous ferric carboxymaltose (FCM). Patients received a single 1000 mg dose of FCM from the day after admission to rehabilitation (T1), or a 120 mg/day dose of SI from T1 until discharge (T2); after discharge, SI was reduced to 30 mg/day until the end of follow-up (T3). Hb was evaluated at T1, T2 and T3; the other hematological parameters at T1 and T3; natriuretic peptides at T1, T2 and T3; 6-minute walk test (6MWT) at T1 and T2. Folate, vitamin B12 and reticulocytes were sampled on admission. Folate deficiency was documented in 60.4% of patients. Hb increased in both groups with no significant differences between the two treatments (p = 0.397). The other iron metabolism parameters (sideremia, transferrin, TSAT) displayed similar behavior, showing a significant increase at T3 (p < 0.001) with both therapies, although the increase was faster with FCM. Ferritin - high on admission - decreased at T3 in the SI group and rose significantly in the FCM group (SI 219.5 vs. FCM 689 ng/ml p < 0.0001). The 6MWT increased significantly at T2, with an overlap between SI and FCM. In conclusion, the results of this study show that SI and FCM exhibit the same effectiveness on IDA; the response time to therapy of both treatments is also equally fast. SI and FCM induce a similar increase in functional capacity. The study shows that SI can be a viable alternative to FCM after cardiac surgery in terms of effectiveness and tolerability.

Background andObjectives: Current guidelines on cardiac rehabilitation (CR) suggest moderate-intensity physical activity after acute coronary syndrome (ACS). Recent report have shown that high-intensity interval training (HIIT) could be more effective than moderate-intensity continuous training (MCT) in improving cardiac performance. Our aim was to analyze the effects of HIIT protocol after ACS on advanced echocardiographic parameters of myocardial function. Materials and Methods: In total, 75 patients with recent ACS, with or without ST segment elevation, were enrolled and compared with a control group of 50 age- and sex-comparable healthy subjects. Patients were randomized to perform a MCT training or HIIT-based rehabilitation program. A complete echocardiographic evaluation, including left ventricular (LV) and left atrial (LA) global longitudinal strain (GLS) and myocardial work (MW) through speckle-tracking analysis, was performed for all patients, before and after cardiac rehabilitation training. A cardiopulmonary exercise testing (CPET) was also performed at the end of the rehabilitation program. Results: Patients who followed the HIIT rehabilitation program showed improved LV diastolic function compared to the MCT group (E/e’: 3.4 ± 3.1 vs. 6.4 ± 2.8, respectively, p < 0.01). Similarly, LV systolic function showed significant improvement in the group of patients performing HIIT (ejection fraction: 53.1 ± 6.4 vs. 52.3 ± 5.4%, p < 0.01; GLS: −17.8 ± 3.8 vs. −15.4 ± 4.3, p < 0.01). In addition, LA strain was improved. MW efficiency was also increased in the HIIT group (91.1 ± 3.3 vs. 87.4 ± 4.1%, p < 0.01), and was closely related to peak effort measurements expressed in peak VO2 by CPET. Conclusions: In patients with recent ACS, the HIIT rehabilitation program determined reverse cardiac remodeling, with the improvement of diastolic and systolic function, assessed by standard echocardiography. In addition, cardiac deformation index as GLS, LA strain and MW efficiency improved significantly after HIIT, and were associated with functional capacity during effort.

Atherosclerosis is a dynamic process driven by all cardiovascular risk factors that can be briefly divided into an early and a late phase. Inflammation is one of the fundamental substrates that initiates the atherosclerotic process in the early stages and promotes and maintains it in the final stages. In the last decades, clinical and experimental data have shown that inflammation is supported by mediators that respond to physical activity. The present review aims at investigating the effect of physical exercise on inflammatory mediators, both the positive ones that therefore have a pro-inflammatory effect (interleukin 6, c-reactive protein and tumor necrosis factor alpha, interferon gamma, high-mobility group box-1), and the negative ones which have an anti-inflammatory effect (interleukin 10). Pooled data support the evidence that physical exercise is able to directly modulate the activity of inflammatory cytokines slowing down or preventing the formation of the atherosclerotic stage.

The increased efficacy of cancer therapy has resulted in greater cancer survival and increasing number of people with cancer and cardiovascular diseases. The sharing of risk factors, the bidirectional relationship between cancer and cardiovascular diseases and the cardiotoxic effect of chemotherapy and radiotherapy, are the cause of the rapid expansion of cardio-oncology. All strategies to preserve cardiovascular health and mitigate the negative effect of cancer therapy, by reducing the cardiovascular risk, must be pursued to enable the timely and complete delivery of anticancer therapy and to achieve the longest remission of the disease. Comprehensive cardiac rehabilitation is an easy-to-use model, even in cancer care, and is the basis of Cardio-Oncology REhabilitation (CORE), an exercise-based multi-component intervention. In addition, CORE, besides using the rationale and knowledge of cardiac rehabilitation, can leverage the network of cardiac rehabilitation services to offer to cancer patients exercise programs, control of risk factors, psychological support, and nutrition counseling. The core components of CORE will be discussed, describing the beneficial effect on cardiorespiratory fitness, quality of life, psychological and physical well-being, and weight management. Furthermore, particular attention will be paid to how CORE can counterbalance the negative effect of therapies in those at heightened cardiovascular risk after a cancer diagnosis. Barriers for implementation, including personal, family, social and of the health care system barriers for a widespread diffusion of the CORE will also be discussed. Finally, there will be a call-to-action, for randomized clinical trials that can test the impact of CORE, on morbidity and mortality.

SARS-CoV-2 infection, responsible for COVID-19, can determine cardiac events, which require a quick diagnosis and management, and should not be overlooked due to the presence of COVID-19 infection. In some cases, cardiovascular symptoms can also be the first and only manifestation of SARS-CoV-2 infection. In patients with COVID-19, the full cardiovascular disease diagnostic algorithm can be hindered by logistic restrain mainly derived from the difficulty of transporting patients in critical conditions to Radiology or Hemodynamics wards. The echocardiography in SARS-CoV-2 pandemic can help for differential diagnosis of cardiac events, which can be related or unrelated by the infection and can likely impact on short-term prognosis. Indeed, transthoracic echocardiography plays a key role in the screen for CV complications of COVID-19 infection: it must be focused cardiac ultrasound study (FoCUS) performed at bedside. All transthoracic, transesophageal and stress echocardiograms in patients in which test results are unlikely to change the management strategy should be postponed.

Cancer and cardiovascular diseases are globally the leading causes of mortality and morbidity. These conditions are closely related, beyond that of sharing many risk factors. The term bidirectional relationship indicates that cardiovascular diseases increase the likelihood of getting cancer and vice versa. The biological and biochemical pathways underlying this close relationship will be analyzed. In this new overlapping scenario, physical activity and exercise are proven protective behaviors against both cardiovascular diseases and cancer. Many observational studies link an increase in physical activity to a reduction in either the development or progression of cancer, as well as to a reduction in risk in cardiovascular diseases, a non-negligible cause of death for long-term cancer survivors. Exercise is an effective tool for improving cardio-respiratory fitness, quality of life, psychological wellbeing, reducing fatigue, anxiety and depression. Finally, it can counteract the toxic effects of cancer therapy. The protection obtained from physical activity and exercise will be discussed in the various stages of the cancer continuum, from diagnosis, to adjuvant therapy, and from the metastatic phase to long-term effects. Particular attention will be paid to the shelter against chemotherapy, radiotherapy, cardiovascular risk factors or new onset cardiovascular diseases. Cardio-Oncology Rehabilitation is an exercise-based multi-component intervention, starting from the model of Cardiac Rehabilitation, with few modifications, to improve care and the prognosis of a patient’s cancer. The network of professionals dedicated to Cardiac Rehabilitation is a ready-to-use resource, for implementing Cardio-Oncology Rehabilitation.

Background Several markers of systemic inflammation seem to play an active role in the pathophysiology of acute coronary syndrome and its evolution. High mobility group box-1 (HMGB-1), a ubiquitous nuclear protein constitutively expressed in quiescent cells, was recently recognized as a newer critical mediator of inflammatory diseases. The present study aimed to evaluate the possible association between HMGB-1 levels and structural and functional indices of cardiovascular performance such as cardiopulmonary and Doppler-echocardiography indices in patients after acute myocardial infarction (MI). Methods and Results Fifty-four consecutive patients (mean age 58.3 years, 83% males) recovering from acute MI were included in the study protocol. All patients underwent Doppler-echocardiography, cardiopulmonary exercise, and HMGB-1 assay. HMGB-1 levels in acute MI patients were significantly higher compared with age- and body mass index–matched controls (14.8 ± 6.8 vs. 2.3 ± 1.0 ng/mL, P < .0001, respectively). Postinfarction patients showed oxygen consumption at peak exercise (VO2peak) = 14.4 ± 4.2 mL·kg·min and a slope of increase in ventilation over carbon dioxide output (VE/VCO2slope) = 32.1 ± 6.2, whereas Doppler-echocardiography values were: left ventricular end-diastolic volume (LVEDV) = 53.4 ± 8.2 mL/m2; left ventricular ejection fraction (LVEF) = 41.7 ± 7.0%. Multiple linear regression analysis (stepwise method) showed that VO2peak (β = –0.276, P = .012), VE/VCO2slope (β = 0.244, P = .005), LVEDV (β = 0.267, P = .018), peak creatine kinase-MB (β = 0.339, P = .004), peak Troponin I (β = 0.244, P = .002), and LVEF (β = –0.312, P = .021) were significantly associated with HMGB-1 levels. Conclusions The present study demonstrated that in postinfarction patients, HMGB-1 levels were significantly higher compared with controls, and significantly correlated with cardiopulmonary and Doppler-echocardiography parameters.

Background: Smoking predisposes to the development of atherosclerosis and of its complications. The mechanisms responsible for these effects are not completely understood. We have investigated whether nicotine might promote a proatherosclerotic state in human coronary endothelial cells (HCAECs), studying the role of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors in preventing these phenomena. Methods and Results: Real-time PCR showed that nicotine induced a dose-dependent increase in mRNA levels for vascular cellular adhesion molecule-1 (VCAM-1)/intercellular adhesion molecule-1 (ICAM-1). Fluorescent-activated cell sorting analysis showed that nicotine induced expression of functionally active VCAM-1/ICAM-1, since they increased leukocyte adherence to HCAECs. Oxygen free radicals, Rho A and nuclear factor ĸB (NF-ĸB) play a pivotal role in modulating these effects. Indeed, nicotine caused oxygen free radical production as well as activation of Rho A and NF-ĸB pathways, evaluated by malondialdehyde levels, pulldown assay and by electrophoretic mobility shift assay, respectively. Superoxide dimutase, Rho A (Y-27639) and NF-ĸB inhibitors (pyrrolidine dithiocarbamate ammonium, Bay 11-7082) suppressed nicotine effects on CAM expression. HMG-CoA reductase inhibitors prevented these nicotine-mediated effects by inhibiting free radical generation and by modulating activation of Rho A and NF-ĸB pathways. Conclusions: Nicotine promotes CAM expression on HCAECs, shifting them toward a proatherosclerotic state. These effects might explain, at least in part, the deleterious cardiovascular consequences of cigarette smoking. HMG-CoA reductase inhibitors play an important role in preventing these phenomena.

Summary. Background and objectives: Cigarette smoking is associated with an increased risk to develop myocardial infarction and ischemic stroke. However, the mechanisms responsible for these effects are still poorly understood. Aim: To investigate whether nicotine, the major component of cigarette smoking, and its main metabolite, cotinine, might induce a pro-thrombotic state via stimulation of tissue factor (TF) expression in two cell population widely represented in the arterial wall such as endothelial cells (ECs), and smooth muscle cells (SMCs). Methods and results: Incubation of ECs and SMCs with nicotine and cotinine induced TF expression in both cell types in a dose-dependent fashion, exerting its effect at the transcriptional level, as demonstrated by semiquantitative and by real-time PCR. Nicotine- and cotinine-induced TF expression was mediated by the activation of the transcription factor, nuclear factor-kappa B (NF-κB), as demonstrated by electrophoretic mobility shift assay and by the suppression of TF expression by the NF-κB inhibitor, pyrrolidine dithio carbamate ammonium. Conclusions: These data indicate that nicotine and cotinine exert direct effects on ECs and SMCs, shifting them toward a pro-thrombotic state via induction of TF expression. These effects on cells of the vessel wall might explain, at least in part, the deleterious cardiovascular consequences of cigarette smoking.

Left ventricular outflow tract (LVOT) obstruction is a typical recognized feature in hypertrophic cardiomyopathy. However, it has been shown in other clinical scenarios such as acute ischemia. In some patients, LVOT obstruction may only be detectable with provocation testing such as exercise stress. Accurate and timely diagnosis, therefore, relies on recognizing an echocardiographic substrate in which LVOT obstruction may occur, such as ventricular hypertrophy. This report describes the case of a patient presenting with effort ECG and signs of myocardial ischemia, with no significant narrowing of coronary arteries but with latent LVOT obstruction due to the presence of an abnormal hypertrophic papillary muscle instead of a typical ventricle hypertrophy.

Objective: Atherosclerosis is characterized by endothelial inflammation and dysfunction. Adipose tissue has increasingly been recognized as an active endocrine organ secreting so-called adipokines. Among these, resistin – recently described, but not yet extensively studied – has been defined as a novel inflammatory marker in atherosclerosis. The pathophysiology underlying this interplay, however, remains to be fully characterized. The aim of the study is to determine whether resistin might affect prothrombotic characteristics of human coronary artery endothelial cells (HCAECs). Methods and Results: Incubation of HCAECs with resistin caused upregulation of tissue factor (TF) expression as demonstrated by FACS analysis. Moreover, TF activity was induced in a dose-dependent manner, as shown by real-time PCR and colorimetric assay. Resistin-induced TF expression was mediated by oxygen free radicals through the activation of the transcription factor nuclear factor-ĸB (NF-ĸB), as demonstrated by electrophoretic mobility shift assay and by suppression of TF expression by superoxide dismutase, catalase, and the NF-ĸB inhibitors PDTC and BAY 11-7082. Conclusions: These data confirm the hypothesis that resistin may contribute to atherothrombosis, exerting direct effects on HCAECs by promoting TF expression; thus, it represents an effector molecule able to induce a prothrombotic phenotype in cells present in the vessel wall.

The deleterious effects of cigarette smoke on cardiovascular morbidity and mortality are well established. Both active and passive smoking represent a major health hazard for both men and women. The big concerns related to the deleterious effects of CS on cardiovascular disease have been translated into various kinds of social interventions and targeted health policies since ever. The high impact of cigarette smoking on health has driven a huge number of researches both at the epidemiologic, clinical and biological level. Nevertheless, even though many progresses have been made in understanding the mechanisms underlying the high disease burden associated to cigarette smoke, the exact components and the mechanisms by means of which it exerts its effects remain to be completely clarified yet. The present article reviews the main observations on the pathophysiology of smoke-related cardiovascular diseases, providing an up-to-date perspective about one of the bigger cardiovascular killers of our days.

To investigate the effects of exercise training (ET) on left ventricular (LV) volumes, cardiopulmonary functional capacity and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in postinfarction patients with moderate LV dysfunction.Sixty-one postinfarction patients were randomized into two groups: group T [n=30, LV ejection fraction (EF) 41.6+/-11.3%, mean+/-SD] entered a 6-month ET programme, whereas group C (n=31, EF 42.0+/-7.6%, P=NS) did not. NT-proBNP assay, Doppler-echocardiography and cardiopulmonary exercise test were performed upon enrolment and at sixth months.At sixth months, trained patients showed an improvement in workload (+26%, P0.001), Vo2peak (+31%, P0.001), LV end-diastolic volume index (LVEDVI; -9%, P0.001), a reduction in NT-proBNP (-71%, P0.001) and a significant correlation between changes in NT-proBNP and in LVEDVI (r=0.858, P0.001). Baseline NT-proBNP correlated with changes in LVEDVI in both trained (r=0.673, P0.001) and untrained (r=0.623, P0.001) patients. Group C showed unfavourable LVEDVI dilation (+8%, P0.001; T vs. C group, P0.001) and a smaller reduction in NT-proBNP (-40%, P0.001; T vs. C group, P0.001).Six month ET induced a favourable LV remodelling and a marked fall in NT-proBNP that could predict LV remodelling in postinfarction patients with moderate LV dysfunction.

Background: Obesity and cardiovascular disease are closely related. Leptin, an adipocyte-produced hormone, is associated with increased cardiovascular risk. Increased plasma levels of leptin are measurable in the plasma of obese individuals. However, the possible links between obesity and cardiovascular disease are not completely understood. C-reactive protein (CRP) is a predictor of future cardiovascular events and plays a role in atherothrombotic disease. Thus, we evaluated whether leptin might play a role in cardiovascular disease, investigating its effects on CRP production by human coronary artery endothelial cells in culture. Methods and Results: Leptin induced CRP mRNA transcription as demonstrated by semiquantitative and real-time polymerase chain reaction as well as the release of CRP in the culture medium in a concentration-dependent fashion. Leptin-induced production of CRP was mediated through the RhoA activation of protein kinase Cβ since both protein kinase C and RhoA pathway inhibitors prevented these leptin effects. Lovastatin, a hydroxymethylglutaryl coenzyme A reductase inhibitor, by modulating the RhoA activation, significantly reduced leptin-induced CRP production. Conclusions: This study describes the close relationship between leptin and CRP, providing support to the view that this adipokine, besides being involved in the pathophysiology of obesity, might play a relevant role as an active partaker in obesity, inflammation and atherothrombosis.