New mechanisms of vesicles migration.

In multicellular organisms, both health and disease are defined by means of communication patterns involving the component cells. Despite the intricate networks of soluble mediators, cells are also programed to exchange complex messages pre-assembled as multimolecular cargo of membranous structures known as extracellular vesicles (EVs). Several biogenetic pathways produce EVs with different properties able to orchestrate neighboring cell reactions or to establish an environment ripe for spreading tumor cells. Such an effect is in fact an extension of similar physiological roles played by exosomes in guiding cell migration under nontumoral tissue remodeling and organogenesis. We start with a biological thought experiment equivalent to Bénard's experiment, involving a fluid layer of EVs adherent to an extracellular matrix, in a haptotactic gradient, then, we build and present the first Lorenz model for EVs migration. Using Galerkin's method of reducing a system of partial differential equations to a system of ordinary differential equations, a biological Lorenz system is developed. Such a physical frame distributing individual molecular or exosomal type cell-guiding cues in the extracellular matrix space could serve as a guide for tissue neoformation of the budding pattern in nontumoral or tumoral instances.

Distinct Features of Vascular Diseases in COVID-19.

The Coronavirus Disease 2019 (COVID-19) pandemic was declared in early 2020 after several unexplained pneumonia cases were first reported in Wuhan, China, and subsequently in other parts of the world. Commonly, the disease comprises several clinical features, including high temperature, dry cough, shortness of breath, and hypoxia, associated with findings of interstitial pneumonia on chest X-ray and computer tomography. Nevertheless, severe forms of acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) are not limited to the respiratory tract but also may be extended to other systems, including the cardiovascular system. The bi-directional relationship between atherosclerosis and COVID-19 is accompanied by poor prognosis. The immune response hyperactivation due to SARS-CoV-2 infection causes an increased secretion of cytokines, endothelial dysfunction, and arterial stiffness, which promotes the development of atherosclerosis. Also, due to the COVID-19 pandemic, access to healthcare amenities was reduced, resulting in increased morbidity and mortality in patients at risk. Furthermore, as lockdown measures were largely adopted worldwide, the sedentary lifestyle and the increased consumption of processed nutrients or unhealthy food increased, and in the consequence, we might observe even 70% of overweight and obese population. Altogether, with the relatively low ratio of vaccinated people in many countries, and important health debt appeared, which is now and will be for next decade a large healthcare challenge. However, the experience gained in the COVID-19 pandemic and the new methods of patients' approaching have helped the medical system to overcome this crisis and will hopefully help in the case of new possible epidemics.

Pharmacological Targets in Chronic Heart Failure with Reduced Ejection Fraction.

Heart failure management has been repeatedly reviewed over time. This strategy has resulted in improved quality of life, especially in patients with heart failure with reduced ejection fraction (HFrEF). It is for this reason that new mechanisms involved in the development and progression of heart failure, along with specific therapies, have been identified. This review focuses on the most recent guidelines of therapeutic interventions, trials that explore novel therapies, and also new molecules that could improve prognosis of different HFrEF phenotypes.

The Novel Perspectives Opened by ST2 in the Pandemic: A Review of Its Role in the Diagnosis and Prognosis of Patients with Heart Failure and COVID-19.

The increasing incidence of coronavirus disease 19 (COVID-19) and its polymorphic clinical manifestations due to local and systemic inflammation represent a high burden for many public health systems. Multiple evidence revealed the interdependence between the presence of cardiovascular comorbidities and a severe course of COVID-19, with heart failure (HF) being incriminated as an independent predictor of mortality. Suppression of tumorigenicity-2 ST2 has emerged as one of the most promising biomarkers in assessing the evolution and prognosis of patients with HF. The uniqueness of ST2 is determined by its structural particularities. Its transmembrane isoform exerts cardioprotective effects, while the soluble isoform (sST2), which is detectable in serum, is associated with myocardial fibrosis and poor outcome in patients with HF. Some recent data also suggested the potential role of sST2 as a marker of inflammation, while other studies highlighted it as a valuable prognostic factor in patients with COVID-19. In this review, we summarized the pathways by which sST2 is related to myocardial injury and its connection to the severity of inflammation in patients with COVID-19. Also, we reviewed possible perspectives of using it as a dual cardio-inflammatory biomarker, for both early diagnosis, risk stratification and prognosis assessment of patients with concomitant HF and COVID-19.

Biomarker Utility for Peripheral Artery Disease Diagnosis in Real Clinical Practice: A Prospective Study.

Peripheral arterial disease (PAD) is a common manifestation of generalized atherosclerosis, which affects more than 200 million patients worldwide. Currently, there is no ideal biomarker for PAD risk stratification and diagnosis. The goal of this research was to investigate the levels of inflammation biomarkers and cystatin C and to explore their utility for the diagnosis of PAD. The study included 296 participants, distributed in two groups: 216 patients diagnosed with PAD and 80 patients without PAD as controls. All studied biomarker levels (C-reactive protein, CRP; fibrinogen; erythrocyte sedimentation rate, ESR; neopterin; beta 2-microglobulin, B2-MG; and cystatin C) were significantly higher in the PAD group and indirectly correlated with the ankle-brachial index (ABI). The final logistic regression model included an association of neopterin, fibrinogen, and cystatin C as the most efficient markers for the prediction of PAD diagnosis. When comparing the area under the curve (AUC) for all biomarkers, the value for neopterin was significantly higher than those of all the other analyzed biomarkers. In agreement with previous studies, this research shows that markers such as fibrinogen, CRP, ESR, B2-MG, and cystatin C have significant value for the diagnosis of PAD, and also clearly underlines the accuracy of neopterin as a leading biomarker in PAD prediction.

Anticoagulation in chronic kidney disease: from guidelines to clinical practice.

BACKGROUND: Chronic kidney disease (CKD) is a major global public health problem, being closely connected to cardiovascular disease. CKD involves an elevated thromboembolic risk and requires anticoagulation, but the high rates of hemorrhage render it quite challenging. HYPOTHESIS: There are no consensus recommendations regarding anticoagulation in CKD. Due to the currently limited data, clinicians need practical clues for monitoring and optimizing the treatment. METHODS: Based on the available data, this review outlines the benefit-risk ratio of all types of anticoagulants in each stage of CKD and provides practical recommendations for accurate dosage adjustment, reversal of antithrombotic effect, and monitoring of renal function on a regular basis. RESULTS: Evidence from randomized controlled trials supports the efficient and safe use of warfarin and direct oral anticoagulants (DOACs) in mild and moderate CKD. On the contrary, the data are poor and controversial for advanced stages. DOACs are preferred in CKD stages 1 to 3. In patients with stage 4 CKD, the choice of warfarin vs DOACs will take into consideration the pharmacokinetics of the drugs and patient characteristics. Warfarin remains the first-line treatment in end-stage renal disease, although in this case the decision to use or not to use anticoagulation is strictly individualized. Anticoagulation with heparins is safe in nondialysis-dependent CKD, but remains a challenge in the hemodialysis patients. CONCLUSIONS: Although there is a need for cardiorenal consensus regarding anticoagulation in CKD, adequate selection of the anticoagulant type and careful monitoring are some extremely useful indications for overcoming management challenges.

The role of echocardiography and 99mTc-HDP scintigraphy in non-invasive diagnosis of cardiac amyloidosis: A case series and literature review.

RATIONALE: Cardiac amyloidosis, considered for the last years to be a rare disease, is one of the determinants of HFpEF. The non-specific clinical presentation and the difficulties related to endomyocardial biopsy have made cardiac amyloidosis an underdiagnosed clinical entity. Improvement of non-invasive diagnostic techniques and the development of new therapies increased clinical awareness for this form of restrictive cardiomyopathy. We here summarize echocardiography and Tc-HDP scintigraphy findings in 6 cases of cardiac amyloidosis and review the literature data of this progressive and fatal cardiomyopathy. PATIENTS CONCERNS: The main clinical manifestations were fatigue, low exercise tolerance and edemas. The right heart failure symptoms usually dominated the clinical picture. DIAGNOSES: All cases were evaluated by echocardiography; 3 cases were further examined by bone scintigraphy and 4 cases a peripheral biopsy was performed. Electrocardiography showed low-voltage QRS complexes and "pseudo-infarct" pattern in the precordial leads, contrary to the echocardiographic aspect, which revealed thickening of ventricle walls. Biatrial dilation and diastolic disfunction were observed. Impaired systolic function was detected in advanced stages of the disease. Tc-HDP scintigraphy revealed cardiac uptake of radiopharmaceutical and managed to confirm the diagnosis in 1 case of cardiac amyloidosis in which salivary gland biopsy was negative. INTERVENTIONS: The treatment was based on managing fluid balance, with the mainstream therapy represented by diuretics. Neurohormonal agents, usually used in heart failure treatment were avoided, due to poor tolerance and worsening of disease course. The management of these 6 cases was challenging due to the refractory manifestation of congestive heart failure. OUTCOMES: During follow-up, 4 of the 6 patients from the current study died in the first year after the final diagnosis was established. LESSONS: Nuclear imaging of cardiac amyloidosis has a revolutionary development nowadays. Bone scintigraphy presents promising results for identifying patients at early stages of disease and to differentiate between cardiac amyloidosis types. Further studies are necessary for the standardization of imaging protocol and development of non-invasive diagnostic tools, especially in assessing the response to treatment and disease progression, for which little is known.

Pharmacokinetic Interactions between Cardiovascular Medicines and Plant Products.

The growing use of plant products among patients with cardiovascular pharmacotherapy raises the concerns about their potential interactions with conventional cardiovascular medicines. Plant products can influence pharmacokinetics or/and pharmacological activity of coadministered drugs and some of these interactions may lead to unexpected clinical outcomes. Numerous studies and case reports showed various pharmacokinetic interactions that are characterized by a high degree of unpredictability. This review highlights the pharmacokinetic clinically relevant interactions between major conventional cardiovascular medicines and plant products with an emphasis on their putative mechanisms, drawbacks of herbal products use, and the perspectives for further well-designed studies.

Morphological and functional renovascular changes as cause of resistant arterial hypertension - case report and literature review.

Resistant hypertension is defined by the inability to maintain within normal limits the blood pressure values of an individual, while he is under treatment with maximal tolerated doses of three antihypertensive agents. One of the most common types of resistant hypertension is renovascular hypertension (RVH), which is caused by the narrowing of the renal arteries, in the context of existing atherosclerotic plaques at that level. We are presenting the case of a hypertensive 56-year-old man admitted in the Clinic of Cardiology for a sudden rise of his blood pressure values, despite undergoing the scheduled treatment. The abdominal bruit discovered at the clinical examination and the hypokalemia, together with the mild impairment of the renal function raised the suspicion of an existing stenosis of the main renal blood vessels. Simple grey scale kidney ultrasound, Doppler ultrasound of the renal arteries, abdominal computed tomography and magnetic resonance angiography of the renal arteries, along with invasive renal angiography demonstrated a smaller right kidney, adrenal incidentalomas, reduced vascular diameter of renal arteries due to atheromatous lesions, thrombosis of the infrarenal segment of the abdominal aorta, and reduced vascular hemodynamics in the same territories. After the renal arteries revascularization and with minimal antihypertensive treatment, the patient had a favorable outcome, with normalization of blood pressure and renal function. Atherosclerotic disease causing renal artery stenosis is essential to be taken into consideration in the etiopathogenesis of resistant hypertension especially because RVH is a potentially curable disease.

Amyloidosis - a rare cause of refractory heart failure in a young female.

Cardiac amyloidosis may occur in any type of systemic amyloidosis. The clinical picture is often characterized by restrictive cardiomyopathy. We report the case of a 41-year-old female patient admitted to the Department of Cardiology with clinical signs of right heart failure: congested jugular veins, hepatomegaly, peripheral edema, ascites associated with atrial fibrillation, low values of arterial blood pressure and oliguria. Echocardiographic findings were helpful for the diagnosis of cardiac amyloidosis: enlarged atrial cavities, normal size ventricles, thickened ventricular septum and posterior left ventricle wall with normal left ventricular ejection fraction, mitral and tricuspid regurgitation. Two-dimensional echocardiography revealed additional features: thickened papillary muscles and a specific "granular sparkling" appearance of the thickened cardiac walls - probably due to the amyloid deposit. Gingival biopsy showing amorphous eosinophilic material located in the vessel walls and the specific dichroism and "apple-green" birefringence under polarized light on Congo red stained slides completed the diagnosis of systemic amyloidosis. We recommend cardiologists to take into account a possible cardiac amyloidosis in a patient with unexplained refractory heart failure and a typical pattern of restrictive cardiomyopathy revealed by echocardiographic examination. We also emphasize the fact that the complete diagnosis cannot be set without a biopsy that should reveal the presence of amyloid. Although endomyocardial biopsy, completed with histochemical and immunohistochemical stains, is a valuable diagnostic method, in cases with advanced cardiac failure, the best site for this biopsy may be the gingiva.

THE "DARK SIDE" OF DEEP VEIN THROMBOSIS--CASE REPORT.

Venous thromboembolism (VTE) is an increasingly common cause of morbidity and mortality in cancer patients. In various malignancies the incidence of thrombosis ranges from 5% to 60%, that is four times higher in cancer patients compared to the general population. Large retrospective studies have shown that in men the tumors which are most commonly associated with VTE are lung cancer and pancreatic cancer and, in women cancer of the genital area, pancreas, colon and rectum. Thromboembolic events may often occur before the cancer diagnosis. We present the case of a 41-year-old female patient with a history of genital cancer which was surgically treated and who is now admitted for clinical signs of ileofemoral deep vein thrombosis (DVT) of the left leg. The diagnosis was confirmed by laboratory data and Doppler ultrasound and the patient received anticoagulant treatment. Given the history of the patient, abdominal and pelvic ultrasound and computer tomography (CT) were performed to detect the cause who predisposed to the thrombotic event. These confirmed the ovarian cancer, this time on the right side, and the presence of hepatic and pulmonary metastasis. This case highlights the importance of screening for a cause of the thromboembolic event in patients, especially in those who have a history of a neoplasia.

DEPRESSION--A FELLOW TRAVELER WITH SYSTEMIC LUPUS ERYTHEMATOSUS.

Systemic lupus erythematosus (SLE) is a chronic multisystem inflammatory disorder that occurs primarily in women of childbearing age, immunologic abnormalities being a prominent feature of the disease. Psychiatric disorders frequently coexist, depression being the most common mood disorder in neuropsychiatric lupus. This literature review was performed through searching MEDLINE database for full-text English-language articles--original research, systematic review and updates published in the last five years (2010-2015), using the keywords "depression and systemic lupus erythematosus". The main outcomes identified were prevalence and predictors of depression in various cultural and ethnic groups, depression-related clinical issues (suicidal ideation, cognitive impairment, altered body image, sleep and sexual disturbances, influence of SLE treatment), and influence on quality of life. A multidisciplinary approach that takes into account the polymorphism and individual variability of the SLE clinical manifestations helps to improve early detection of depression, which is responsible for the increased risk of comorbidities, suicidal attempts, decreased treatment adherence, and impaired quality of life. Physicians across all specialties involved in the care for lupus patients should be aware of the major prevalence of this condition, while helping patients to cope with their disabling disease.

Venous pulmonary thromboembolism and atherothrombosis: need for a new approach.

Pulmonary venous thromboembolism and atherothrombosis are traditionally considered as distinct diseases. As the two entities share common risk factors and mechanisms current experimental and clinical studies support their mutual causal relationship. For the clinician, the current concept requires a different clinical, laboratory and therapeutic approach. The patient with a first arterial or venous thrombosis should be fully assessed for the risk of future clinical events, and, simultaneously addressed to aggressive preventive non-pharmacological and pharmacotherapy intervention. In this context, antiplatelet agents and statins have a potentially beneficial role.

Iron hypothesis of cardiovascular disease: still controversial.

Iron hypothesis has been a controversial subject for over 30 years as many studies support its role as a risk factor for cardiovascular disease, while other studies found no evidence to support it. The conflicting results are accounted for by the non-homogeneity of trial design in terms of population inclusion criteria and different endpoints, non-uniform use of parameters for assessing iron role, and incomplete understanding of the mechanisms of action. The nature of iron is dual, being of crucial importance for the human body, but also toxic as "free iron" induces oxidative stress. Under physiological conditions, there are efficient and complex mechanisms against iron-induced oxidative stress, which could be reproduced for creating new, intelligent antioxidants. Iron depletion improves the cardiovascular prognosis only if serum concentration is at the lowest limit of normal ranges. However, low iron levels and the type of dietary iron intake correlate with atherosclerotic cardiovascular disease, influence the ischemic endpoints in the elderly, and exert negative impact on heart failure prognosis. So far, the causal relation and involved mechanisms are not fully elucidated. Iron overload is a difficult and frequent condition, involving the cardiovascular system by specific pathogenic pathways, therefore determining a particular form of restrictive cardiomyopathy and vaso-occlusive arterial damage.

Peripartum cardiomyopathy: a challenge for cardiologist.

Peripartum cardiomyopathy (PPCM) is a rare but potentially life-threatening condition that occurs in previously healthy women during the last month of pregnancy and up to 5-6 months postpartum. The etiology and pathophysiology remain uncertain, although recent observations strongly suggest the specific role of prolactin cleavage secondary to unbalanced peri/postpartum oxidative stress. PPCM is a diagnosis of exclusion, as it shares many clinical characteristics with other forms of systolic heart failure secondary to cardiomyopathy. The management of heart failure requires a multidisciplinary approach during pregnancy, considering the possible adverse effects on the fetus. After delivery, the treatment is in accordance with the current guidelines for heart failure. Some novel therapies, such as prolactin blockade, are proposed to either prevent or treat the patients with PPCM. A critical individual counseling concerning the risks of subsequent pregnancy must be considered. Because of its rare incidence, geographical differences, and heterogeneous presentation, PPCM continues to be incompletely characterized and understood. For all these reasons, PPCM remains a challenge in clinical practice, so future epidemiological trials and national registries are needed to learn more about the disease.

Resistant hypertension: the role of interventional therapy.

Resistant hypertension still represents a major health problem, incompletely resolved by the current therapeutic interventions. Based on the interference of sympathetic over activity in resistant hypertension, novel invasive strategies such as sympathetic renal denervation and carotid baroreceptor stimulation have recently emerged. Despite the promising results and their good tolerability profile, the optimal role of these non-pharmacologic therapies relative to conventional medical regimens, remains unknown. Further investigation is also necessary to establish their real long-term efficacy and safety in clinical practice.

Nature or the natural evolution of plaque: what matters?

ABSTRACT: Progression to major acute cardiovascular events often is triggered by an atherosclerotic plaque complicated by rupture or erosion, namely the vulnerable plaque. Early and secure identification of these plaques would allow the development of individualized therapeutic and pharmacological strategies, applied in a timely manner. Imaging methods have a huge potential in detecting and monitoring the evolution of vulnerable plaque. Even though there are multiple invasive and noninvasive techniques, clinical application is for now a matter of choosing the relevant imaging feature for the prognosis, the methodo-logy of study and the target population.

Epidemiological characteristics of peripheral artery disease: retrospective study.

UNLABELLED: Peripheral artery disease (PAD) is a common condition. Over the past 20 years the risk factors for PAD have changed. AIMS: To identify the regional characteristics of the patients with PAD and the sex- and urban/rural-related differences. MATERIAL AND METHODS: Retrospective study on patients admitted to the Iasi "St. Spiridon' University Hospital in the interval 2007-2012. The dataset was prepared for t student analysis in in view of determining statistical significance. RESULTS: Of the 361,248 patients admitted to the 20 units of the hospital, 2,623 patients were diagnosed with advanced stages of PAD (Leriche--Fontain III and IV). Significant statistical differences were found between men and women, and between rural and urban men (p = 0.001). 20.5% of the patients underwent amputations. CONCLUSIONS: This is one of the first studies that has identified urban/rural differences. The characteristics specific to PAD patients from North-Eastern Romania are presented.

[Comparative evaluation of prognostic scores in pulmonary embolism ]. / Evaluarea comparativa a scorurilor prognostice in embolia pulmonara.

AIM: Pulmonary embolism is a life threatening disease and one of the main causes of in-hospital mortality. There are multiple risk stratification scoring systems for the forecast of the outcomes in patients with pulmonary embolism. MATERIAL AND METHODS: We conducted a prospective observational cohort study to evaluate the comparative validity of four prognostic models: pulmonary embolism severity index (PESI), simplified PESI score, PESI risk classes and shock index, for predicting short-term mortality in acute pulmonary embolism. The PESI and PESI--simplified scores and shock-index were calculated. PESI scores were segregated into risk class (I-V) obtaining PESI classes. Shock index was dichotomized into 0 (for value < 1) versus 1 (for value > 1) risk groups. We determined the area under Receiver Operating Characteristic curve, the sensitivity, specificity, likelihood ratio (LR+, LR-) for PESI score, simplified PESI score, PESI risk classes and shock index, to compare the ability of these scoring tools. RESULTS: The cohort consisted of 362 subjects. The mortality was 21.54%. The sensitivity, specificity and likelihood ratios were different between scores but the area under Receiver Operating Characteristic curve showed values in range 0.6-0.7. CONCLUSIONS: The assessed prognostic scores performed comparably for identifying pulmonary embolism patients at short-term risk of mortality, even for PESI score segregated in risk classes and dichotomized version of shock index.

[Newly diagnosed peripheral arterial disease in patients with cardiovascular risk factor]. / Boala arteriala periferica nou diagnosticata la pacientul cu risc cardiovascular.

UNLABELLED: The goal of this study is to investigate the utility of ankle-brachial index (cut-off value < 0,90) as an indicator of peripheral arterial disease in a group of patients hospitalized in the Medical Clinic and to assess the prevalence of risk factor and associated comorbidities in patients with low index. MATERIAL AND METHODS: A total of 202 patients older than 50 years with established cardiovascular or cerebrovascular disease or at least one cardiovascular risk factor (smoking, diabetes, dyslipidemia and hypertension) underwent ankle-brachial index measurement for this study. Demographic data and cardiovascular risk factors were analyzed. We assessed medical history, symptoms and clinical examination. RESULTS: In this study, a number of 72 patients (35.64%) were diagnosed with peripheral arterial disease. Our results indicated that advanced age, greater number of total risk factors and presence of peripheral arterial disease related physical findings were associated with increased likelihood of low ankle-brachial index. CONCLUSIONS: We should recommend ankle-brachial index as screening test in patients older than 50 years, in the presence of at least one cardiovascular risk factor, for early detection of peripheral arterial disease and systemic atherosclerosis, to improve prevention and early aggressive treatment.