Effects of High Intensity Interval Training Rehabilitation Protocol after an Acute Coronary Syndrome on Myocardial Work and Atrial Strain.

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.

The role of echocardiography in SARS-CoV-2 pandemic: a compromise among appropriateness, safety and clinical impact.

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.

Potential Role of Global Longitudinal Strain in Cardiac and Oncological Patients Undergoing Cardio-Oncology Rehabilitation (CORE).

Although shown to be effective in improving survival and quality of life in patients with cancer, some treatments are well-known causes of cardiotoxicity, such as anthracyclines, monoclonal antibodies against human epidermal growth factor receptor 2 (HER2) and radiotherapy. To prevent cardiovascular disease (CVD) in patients living with cancer, cardiologists and oncologists promoted the development of cardio-oncology, an interdisciplinary field which aims to further improving life expectancy in these patients. Cardio-oncology rehabilitation (CORE), through correction of risk factors, prescription of drug therapies and structured exercise programs, tries to improve symptoms, quality of life, cardiorespiratory fitness (CRF) and survival in patients with cancer. Different imaging modalities can be used to evaluate the real effectiveness of exercise training on cardiac function. Among these, the global longitudinal strain (GLS) has recently aroused interest, thanks to its high sensitivity and specificity for cardiac dysfunction detection due to advanced ultrasound programs. This review summarizes the evidence on the usefulness of GLS in patients with cancer undergoing cardiac rehabilitation programs.

Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors Use for Atherogenic Dyslipidemia in Solid Organ Transplant Patients.

Dyslipidemia is a widespread risk factor in solid organ transplant patients, due to many reasons, such as the use of immunosuppressive drugs, with a consequent increase in cardiovascular diseases in this population. PCSK9 is an enzyme mainly known for its role in altering LDL levels, consequently increasing cardiovascular risk. Monoclonal antibody PCSK9 inhibitors demonstrated remarkable efficacy in the general population in reducing LDL cholesterol levels and preventing cardiovascular disease. In transplant patients, these drugs are still poorly used, despite having comparable efficacy to the general population and giving fewer drug interactions with immunosuppressants. Furthermore, there is enough evidence that PCSK9 also plays a role in other pathways, such as inflammation, which is particularly dangerous for graft survival. In this review, the current evidence on the function of PCSK9 and the use of its inhibitors will be discussed, particularly in transplant patients, in which they may provide additional benefits.

Short-term treatment of iron deficiency anemia after cardiac surgery.

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.

Effects of exercise training on high-mobility group box-1 levels after acute myocardial infarction.

BACKGROUND: High-mobility group box-1 (HMGB1) is a novel predictor of adverse postinfarction clinical outcomes, playing a crucial role in the appropriate postinfarction healing process. METHODS AND RESULTS: Seventy-five postinfarction patients were enrolled in a single-center randomized study (clinicaltrial.gov identifier: NCT00755131). Group T patients (training, n = 37) underwent 6-month exercise-based cardiac rehabilitation (CR) program, whereas group C patients (controls, n = 38) were discharged with generic instructions for maintaining physical activity and a correct lifestyle. After 6 months, HMGB1 levels were significantly reduced in the total population (26.1 ± 23.5 vs. 16.2 ± 12.9 ng/mL; P = .0006). After adjusting for several confounders, linear regression analysis showed that the inclusion in the training group (ß = -10.54, P = .043) was associated with marked reduction of HMGB1 levels. After 6 months, HMGB1 levels were significantly lower in trained patients compared to controls (11.7 ± 7.0 vs. 20.5 ± 15.6 ng/mL, P = .0027, respectively). In trained patients, decreased HMGB1 levels were significantly associated with the improvement in peak oxygen consumption (ß = -3.879, P = .003) and heart rate recovery (ß = -2.492, P = .002), and with reduced left ventricular end-diastolic volume (ß = 1.412, P = .001) and wall motion score index (ß = 1.138, P = .002). CONCLUSIONS: The decrease in HMGB1 levels after anterior myocardial infarction was associated with exercise training and with the improvement of cardiopulmonary and autonomic function, and with favorable cardiac remodeling.

Tissue factor is induced by resistin in human coronary artery endothelial cells by the NF-ĸB-dependent pathway.

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-κB (NF-κB), as demonstrated by electrophoretic mobility shift assay and by suppression of TF expression by superoxide dismutase, catalase, and the NF-κB 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.

Inhibitors of Protein Convertase Subtilisin/Kexin 9 (PCSK9) and Acute Coronary Syndrome (ACS): The State-of-the-Art.

Acute Coronary Syndrome (ACS) remains one of the most frequent causes of morbidity and mortality in the world. Although the age- and gender-adjusted incidence of ACS is decreasing, the mortality associated with this condition remains high, especially 1-year after the acute event. Several studies demonstrated that PCSK9 inhibitors therapy determine a significant reduction of major adverse cardiovascular events (MACE) in post-ACS patients, through a process of plaque modification, by intervening in lipid metabolism and platelet aggregation and finally determining an improvement in endothelial function. In the EVACS (Evolocumab in Acute Coronary Syndrome) study, evolocumab allows >90% of patients to achieve LDL-C < 55 mg/dL according to ESC/EAS guidelines compared to 11% of patients who only receive statins. In the EVOPACS (EVOlocumab for Early Reduction of low-density lipoprotein (LDL)-cholesterol Levels in Patients With Acute Coronary Syndromes) study, evolocumab determined LDL levels reduction of 40.7% (95% CI: 45.2 to 36.2; p < 0.001) and allowed 95.7% of patients to achieve LDL levels <55 mg/dL. In ODYSSEY Outcome trial, alirocumab reduced the overall risk of MACE by 15% (HR = 0.85; CI: 0.78-0.93; p = 0.0003), with a reduced risk of all-cause mortality (HR = 0.85; CI: 0.73-0.98: nominal p = 0026), and fewer deaths for coronary heart disease (CHD) compared to the control group (HR = 0.92; CI: 0.76-1.11; p = 0.38). The present review aimed at describing the beneficial effect of PCSK9 inhibitors therapy early after ACS in reducing LDL circulating levels (LDL-C) and the risk of major adverse cardiovascular events, which was very high in the first year and persists higher later after the acute event.

The core components of cardio-oncology rehabilitation.

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.

Frailty in Acute and Chronic Coronary Syndrome Patients Entering Cardiac Rehabilitation.

Worldwide population ageing is partly due to advanced standard of care, leading to increased incidence and prevalence of geriatric syndromes such as frailty and disability. Hence, the age at the onset of acute coronary syndromes (ACS) keeps growing as well. Moreover, ageing is a risk factor for both frailty and cardiovascular disease (CVD). Frailty and CVD in the elderly share pathophysiological mechanisms and associated conditions, such as malnutrition, sarcopenia, anemia, polypharmacy and both increased bleeding/thrombotic risk, leading to a negative impact on outcomes. In geriatric populations ACS is associated with an increased frailty degree that has a negative effect on re-hospitalization and mortality outcomes. Frail elderly patients are increasingly referred to cardiac rehabilitation (CR) programs after ACS; however, plans of care must be tailored on individual's clinical complexity in terms of functional capacity, nutritional status and comorbidities, cognitive status, socio-economic support. Completing rehabilitative intervention with a reduced frailty degree, disability prevention, improvement in functional state and quality of life and reduction of re-hospitalization are the goals of CR program. Tools for detecting frailty and guidelines for management of frail elderly patients post-ACS are still debated. This review focused on the need of an early identification of frail patients in elderly with ACS and at elaborating personalized plans of care and secondary prevention in CR setting.

Exercise for slowing the progression of atherosclerotic process: effects on inflammatory markers.

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 aimed at investigating the effect of physical exercise on inflammatory mediators, both the positive ones that have a proinflammatory effect (interleukin 6, c-reactive protein and tumor necrosis factor α, interferon γ, 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 can directly modulate the activity of inflammatory cytokines slowing down or preventing the formation of the atherosclerotic stage.

New Ultrasound Technologies for Ischemic Heart Disease Assessment and Monitoring in Cardiac Rehabilitation.

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.

Association between Very Low-Density Lipoprotein Cholesterol (VLDL-C) and Carotid Intima-Media Thickness in Postmenopausal Women Without Overt Cardiovascular Disease and on LDL-C Target Levels.

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.

Sacubitril/Valsartan Improves Autonomic Function and Cardiopulmonary Parameters in Patients with Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Heart rate recovery (HRR) is a marker of vagal tone, which is a powerful predictor of mortality in patients with cardiovascular disease. Sacubitril/valsartan (S/V) is a treatment for heart failure with reduced ejection fraction (HFrEF), which impressively impacts cardiovascular outcome. This study aims at evaluating the effects of S/V on HRR and its correlation with cardiopulmonary indexes in HFrEF patients. METHODS: Patients with HFrEF admitted to outpatients' services were screened out for study inclusion. S/V was administered according to guidelines. Up-titration was performed every 4 weeks when tolerated. All patients underwent laboratory measurements, Doppler-echocardiography, and cardiopulmonary exercise stress testing (CPET) at baseline and at 12-month follow-up. RESULTS: Study population consisted of 134 HFrEF patients (87% male, mean age 57.9 ± 9.6 years). At 12-month follow-up, significant improvement in left ventricular ejection fraction (from 28% ± 5.8% to 31.8% ± 7.3%, p < 0.0001), peak exercise oxygen consumption (VO2peak) (from 15.3 ± 3.7 to 17.8 ± 4.2 mL/kg/min, p < 0.0001), the slope of increase in ventilation over carbon dioxide output (VE/VCO2 slope )(from 33.4 ± 6.2 to 30.3 ± 6.5, p < 0.0001), and HRR (from 11.4 ± 9.5 to 17.4 ± 15.1 bpm, p = 0.004) was observed. Changes in HRR were significantly correlated to changes in VE/VCO2slope (r = -0.330; p = 0.003). After adjusting for potential confounding factors, multivariate analysis showed that changes in HRR were significantly associated to changes in VE/VCO2slope (Beta (B) = -0.975, standard error (SE) = 0.364, standardized Beta coefficient (Bstd) = -0.304, p = 0.009). S/V showed significant reduction in exercise oscillatory ventilation (EOV) detection at CPET (28 EOV detected at baseline CPET vs. 9 EOV detected at 12-month follow-up, p < 0.001). HRR at baseline CPET was a significant predictor of EOV at 12-month follow-up (B = -2.065, SE = 0.354, p < 0.001). CONCLUSIONS: In HFrEF patients, S/V therapy improves autonomic function, functional capacity, and ventilation. Whether these findings might translate into beneficial effects on prognosis and outcome remains to be elucidated.

Increased high mobility group box-1 protein levels are associated with impaired cardiopulmonary and echocardiographic findings after acute myocardial infarction.

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 (VO(2 peak)) = 14.4 +/- 4.2 mL x kg x min and a slope of increase in ventilation over carbon dioxide output (VE/VCO(2 slope)) = 32.1 +/- 6.2, whereas Doppler-echocardiography values were: left ventricular end-diastolic volume (LVEDV) = 53.4 +/- 8.2 mL/m(2); left ventricular ejection fraction (LVEF) = 41.7 +/- 7.0%. Multiple linear regression analysis (stepwise method) showed that VO(2 peak) (beta = -0.276, P = .012), VE/VCO(2 slope) (beta = 0.244, P = .005), LVEDV (beta = 0.267, P = .018), peak creatine kinase-MB (beta = 0.339, P = .004), peak Troponin I (beta = 0.244, P = .002), and LVEF (beta = -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.

Leptin stimulated C-reactive protein production by human coronary artery endothelial cells.

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 Cbeta 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.

[Early interventricular septum rupture after systemic thrombolysis in a patient with STEMI]. / Rottura precoce di setto interventricolare dopo trombolisi sistemica nell'infarto miocardico acuto con ST elevation.

Intraventricular septal rupture (ISR) is one of the most dreadful complications during AMI, requiring early diagnosis and urgent surgery. However, medical (90%) and surgical (50%) mortality remain elevated. We report a case of a 59 years old patient with infero-posterior AMI complicated by ISR after thrombolysis. Despite early recognition of this complication by trans-thoracic echocardiography at bedside and prompt surgical intervention the patient died on the second post-surgical day.

Insights into pathophysiology of smoke-related cardiovascular disease.

The deleterious effects of cigarette smoke (CS) on cardiovascular morbidity and mortality are well established. Both active and passive smoking represent a major health hazard for both men and women. The great 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 health impact of cigarette smoking has driven a huge number of researches at the epidemiological, 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 as yet. The present paper reviews the main observations on the pathophysiology of smoke-related cardiovascular diseases, providing an up-to-date perspective about one of the main cardiovascular killers of our days.

HMG-CoA reductase inhibitors reduce nicotine-induced expression of cellular adhesion molecules in cultured human coronary endothelial cells.

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 kappaB (NF-kappaB) play a pivotal role in modulating these effects. Indeed, nicotine caused oxygen free radical production as well as activation of Rho A and NF-kappaB pathways, evaluated by malondialdehyde levels, pulldown assay and by electrophoretic mobility shift assay, respectively. Superoxide dimutase, Rho A (Y-27639) and NF-kappaB 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-kappaB 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.

The role of neopterin in cardiovascular disease.

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.