The Added Value of Advanced Echocardiography for the Morpho-Functional and Prognostic Evaluation of the Right Heart in Dilated Cardiomyopathy: Do Not Forget about the Right Atrium.

(1) Introduction and Aims: Right ventricular (RV) remodeling significantly impacts the prognosis of dilated cardiomyopathy (DCM) patients, and right atrial (RA) size and function are still often neglected in DCM patients. Accordingly, our aims were to (i) evaluate right heart subclinical changes and (ii) the prognostic value of RA compared to left atrial (LA) size and function in patients with DCM by advanced echocardiography. (2) Materials and Methods: Sixty-eight patients with DCM (with a mean age of 60 years; 35 men) were evaluated by comprehensive transthoracic echocardiography, compared to 62 age- and sex-matched healthy controls (with a mean age of 61 years; 32 men), and followed up for 12.4 ± 5 months. (3) Results: DCM patients have RV and RA global longitudinal dysfunction by 2DSTE, higher RA minimum volumes and tricuspid annulus areas despite having normal RV volumes, ejection fractions, and RA maximum volumes by 3DE compared to the controls. The RA strain and RV strain are correlated with each other. The RA reservoir strain (with an AUC = 0.769) has an increased value for outcome prediction compared to that of the LA strain. (4) Conclusion: Patients with DCM have RV longitudinal dysfunction and decreased RA function, in the absence of clinical RV involvement or atrial arrhythmias, and the RA strain is associated with an increased risk of hospitalization and cardiac death.

Predictors for Super-Responders in Cardiac Resynchronization Therapy.

BACKGROUND: Prediction of cardiac resynchronization therapy (CRT) response, particularly a super-response, is of great importance. STUDY QUESTION: The aim of our study was to assess the predictors for super-responders in CRT. STUDY DESIGN: We conducted a retrospective, observational study, which finally included 622 patients with heart failure treated with CRT between January 2008 and May 2020 who had a minimal follow-up of 6 months after CRT. MEASURES AND OUTCOMES: A total of 192 super-responders, defined by a left ventricular ejection fraction (LVEF) of at least 45%, and/or minimum 15% increase in LVEF and an improvement of the New York Heart Association functional class by at least 2 degrees at the last follow-up, and the rest of 430 patients who did not fulfill the super-responder criteria. RESULTS: The highest rate of super-responders (41.91%, n = 171) was at patients with left ventricle-only pacing with optimal fusion (OPT) compared with patients with biventricular (BiV) pacing (9.81%, n = 21, P < 0.000). In the OPT group, univariable analysis showed that nonischemic cardiomyopathy, a smaller degree of mitral regurgitation, and better left ventricle function at enrollment were predictors for super-response compared with the BiV group where a narrower QRS after implantation, nonischemic cardiomyopathy, and a better baseline LVEF were predictors for super-responders. In the multivariable analysis, both narrower QRS after implantation and nonischemic cardiomyopathy were independent predictors for super-response in the BiV group compared with OPT where nonischemic cardiomyopathy remained the only independent predictor for super-response. CONCLUSIONS: In this retrospective study, OPT CRT programing was an additional predictor of super-response to CRT besides nonischemic cardiomyopathy.

Contribution of Modern Echocardiographic Techniques in the Detection of Subclinical Heart Dysfunction in Young Adults with Non-Alcoholic Fatty Liver Disease.

Non-alcoholic fatty liver disease affects about 30% of the population and it has a growing tendecy with the increasing incidence of obesity. Currently, a large amount of clinical evidence has shown that cardiovascular disease represents the main cause of mortality in patients suffering from non-alcoholic fatty liver disease. OBJECTIVE: In this study we investigated the structural and functional changes of the left ventricle in young adults with hepatic steatosis using modern echocardiographic techniques. METHODS: By using tissue Doppler imaging and also Speckle tracking echocardiography the left ventricle systolic function was assessed. RESULTS: All patients included in the study had a normal left ventricular ejection fraction but, when the longitudinal function of the left ventricle was assessed using the tissue Doppler technique (maximum systolic velocity S) statistically significant differences were found in both the group of patients with non-alcoholic fatty liver as well as in the group of patients associated with diabetes. Using speckle tracking echocardiography, we found a statistically significant decrease of the global longitudinal strain in the endocardium, in the group of patients with non-alcoholic liver disease but also in the group of those with diabetes. The overall longitudinal strain at the myocardium was significantly reduced only in the group of patients with non-alcoholic fatty liver disease and diabetes, while the overall longitudinal strain at the epicardium showed no changes in any of the groups studied. Also, no changes were observed at the circumferential strain. CONCLUSION: Non-alcoholic fatty liver disease, diagnosed in asymptomatic young adults may be a risk factor for remodeling the left ventricle over time, being associated with subclinical myocardial dysfunction, regardless of the presence of other cardiovascular risk factors.

Assessment of Left Ventricular Diastolic Function in Young Adults with Nonalcoholic Fatty Liver Disease.

There is strong evidence that, in addition to increasing the risk of cirrhosis as well as hepatocellular carcinoma, nonalcoholic liver disease represents an independent risk factor for different diseases including cardiovascular and chronic kidney disease and also type 2 diabetes. OBJECTIVE: to assess whether nonalcoholic fatty liver disease is associated with diastolic dysfunction of the left ventricle, independent of other classic risk factors. METHODS: we included 79 patients aged 15-45, diagnosed with non-alcoholic liver disease, and a group of 80 healthy people in the same age group. We assessed left ventricular diastolic function using Doppler pulsed wave transmitral flow and Tissue Doppler Imaging methods. RESULTS: there were lower velocities of E and e' wave, a decrease in E/A ratio and an increase in E/e' ratio in the group of patients with hepatic steatosis and in those with associated diabetes compared to the control group, but not the same was observed when comparing patients with steatosis alone vs. hepatic steatosis and associated diabetes mellitus. CONCLUSION: nonalcoholic steatosis is linked to echocardiographic features of early diastolic dysfunction that are present in patients suffering from diabetes.

The Prognostic Correlation of Heart Rate Variability at Diagnosis with Survival of Patients with Hepatocellular Carcinoma.

BACKGROUND: Heart rate variability (HRV) indices have been shown to be associated with prognosis in various types of cancer. This study aims to assess the ability of these indices to predict survival in hepatocellular carcinoma (HCC) patients after diagnosis. METHODS: We retrospectively collected data from 231 patients diagnosed with HCC between January 2014 and March 2018. The baseline clinical-pathological variables and HRV indices (extracted from Holter electrocardiogram recordings) were analyzed. RESULTS: Univariate and multivariate analyses were performed to identify the predictive value of the above factors for overall survival (OS). The univariate analysis revealed that an age > 60 years, hepatitis C, portal vein involvement (thrombosis), a tumor size > 5 cm, alpha-fetoprotein (AFP) > 400 ng/mL, serum albumin, and C-reactive protein (CRP) were risk factors for poor OS. Multivariable Cox regression analyses identified that a tumor size > 5 cm and AFP > 400 ng/mL predict poorer outcomes in HCC patients. It should be mentioned that, in both the univariate analysis and in the multivariate analysis, between HRV indices, SDNN (standard deviation of all normal-to-normal (NN) intervals) < 110 ms was an independent risk factor for OS with an HR of 3.646 (95% CI 2.143 to 6.205). CONCLUSION: This study demonstrates that HRV indices identify HCC patients at high risk of death and suggests that such monitoring might guide the need for early therapy in these types of patients, as well as the fact that HRV can be a potential noninvasive biomarker for HCC prognosis.

Assessment of Epinephrine and Norepinephrine in Gastric Carcinoma.

The aim of our study was to assess the sympathetic nervous system's involvement in the evolution of gastric carcinoma in patients by analyzing the mediators of this system (epinephrine and norepinephrine), as well as by analyzing the histological expression of the norepinephrine transporter (NET). We conducted an observational study including 91 patients diagnosed with gastric carcinoma and an additional 200 patients without cancer between November 2017 and October 2018. We set the primary endpoint as mortality from any cause in the first two years after enrolment in the study. The patients were monitored by a 24-h Holter electrocardiogram (ECG) to assess sympathetic or parasympathetic predominance. Blood was also collected from the patients to measure plasma free metanephrine (Meta) and normetanephrine (N-Meta), and tumor histological samples were collected for the analysis of NET expression. All of this was performed prior to the application of any antineoplastic therapy. Each patient was monitored for two years. We found higher heart rates in patients with gastric carcinoma than those without cancer. Regarding Meta and N-Meta, elevated levels were recorded in the patients with gastric carcinoma, correlating with the degree of tumor differentiation and other negative prognostic factors such as tumor invasion, lymph node metastasis, and distant metastases. Elevated Meta and N-Meta was also associated with a poor survival rate. All these data suggest that the predominance of the sympathetic nervous system's activity predicts increased gastric carcinoma severity.

The Neuroprotective Role of Alpha Thioctic Acid and Vitamin B Complex in Diabetic Neuropathy - an Experimental Study.

Worldwide, approximately 463 million people are estimated to suffer from a form of diabetes mellitus, with diabetic neuropathy being one of its most common complication. Using streptozotocin to induce diabetes in C57BL/6J mice, we assess the neuroprotective role of alpha thioctic acid and vitamin B complex in diabetic neuropathy. In order to highlight the peripheral nerve changes produced by diabetes, we performed an electroneurographic recording of the animals and compared the amplitude of the compound muscle action potential (CMAP). Treatment with alpha thioctic acid (A), or vitamin B complex (B), or A+B caused a smaller decrease in CMAP amplitude than if these therapies had not been applied. On the other hand, we found that in group A+B a smaller decrease of CMAP amplitude was observed compared to the control group (6 weeks after the onset of diabetes p<0.0001). Also, separate treatment with alpha thioctic acid alone caused a smaller decrease in CMAP amplitude compared to the control group (6 weeks after the onset of diabetes mellitus p<0.0436), but also separate treatment with vitamin B complex alone resulted in a smaller decrease of CMAP amplitude compared to the Control group (6 weeks after the onset of diabetes p<0.0070). The combined therapy with alpha thioctic acid and vitamin B complex has a greater effect in preventing axonal degeneration in diabetic neuropathy than the single therapy only with alpha thioctic acid or only with vitamin B complex.

Alpha-lipoic acid and vitamin B complex slow down the changes in mice diabetic cardiomyopathy.

AIM: The aim of our study was to assess histologically and by cardiac ultrasound the effects of alpha-lipoic acid (ALA) and vitamin B complex, as pathogenic therapies, in diabetic cardiomyopathy (DCM) in mice. MATERIALS AND METHODS: We performed an experimental animal study, in which we analyzed from a structural and functional point of view the changes produced in DCM. To produce DCM, we induced diabetes mellitus (DM) in C57BL∕6 mice by intraperitoneal injection of a single 150 mg∕kg body weight dose of streptozotocin (STZ). We formed a sham group (animals without DM), a control group (animals with DM but without treatment, DM_Control) and a group of animals with DM that were treated with ALA and vitamin B complex (DM_Treated). RESULTS: At six weeks after STZ administration, there was no decrease in left ventricular ejection fraction (LVEF) in the sham group, while in the control group there was a significant decrease in LVEF, about 43.75±3.37%, compared to the group that received treatment with ALA and vitamin B complex, in which LVEF decreased to 49.6±5.02% (p=0.0432). Also, the degree of interstitial myocardial fibrosis was higher in animals with DM compared to animals without DM, but the applied therapeutic protocol considerably improved the accumulation of interstitial collagen. The same observation was maintained regarding the evaluation of polysaccharide deposits. CONCLUSIONS: We can say that the administration of ALA and vitamin B complex in mice with STZ-induced DM, improves the degree of myocardial fibrosis, the accumulation of polysaccharides, and prevents severe deterioration of systolic and diastolic function of the heart.

NT-proBNP and Echocardiographic Parameters in Liver Cirrhosis - Correlations with Disease Severity.

determined. Liver disease severity in patients with cirrhosis was established by Child-Pugh class, MELD score and presence/absence of ascites. Results: Plasma levels of NT-proBNP were significantly higher in cirrhotic patients than in the healthy subjects. NT-proBNP levels were also significantly elevated in Child-Pugh class C patients compared to those in class B and A. Left atrium size, diastolic function, left ventricular wall thickness and left ventricular ejection fraction were significantly altered in cirrhotic patients compared to controls. Advanced cirrhosis and high levels of NT-proBNP were significantly associated with increased left atrium volume and signs of cardiac diastolic dysfunction. We also observed significant differences between quartile groups of MELD score for the following: NT-proBNP, Troponin I, left atrium volume, left ventricle wall thickness, lateral wall and septum systolic tissue doppler velocities and global longitudinal strain. Conclusion: NT-proBNP is increased in patients with cirrhosis and is correlated with the severity of liver disease as established by Child-Pugh class, MELD score and presence of ascites.

B2 adrenergic receptors and morphological changes of the enteric nervous system in colorectal adenocarcinoma.

AIM: To study the morphology of the enteric nervous system and the expression of beta-2 adrenergic (B2A) receptors in primary colorectal cancer. METHODS: In this study, we included forty-eight patients with primary colorectal cancer and nine patients for control tissue from the excision of a colonic segment for benign conditions. We determined the clinicopathological features and evaluated the immunohistochemical expression pattern of B2A receptors as well as the morphological changes of the enteric nervous system (ENS). In order to assess statistical differences, we used the student t-test for comparing the means of two groups and one-way analysis of variance with Bonferroni's post hoc analysis for comparing the means of more than two groups. Correlations were assessed using the Pearson's correlation coefficient. RESULTS: B2A receptors were significantly associated with tumor grading, tumor size, tumor invasion, lymph node metastasis (P < 0.05), while there were no statistically significant associations with gender, CRC location and gross appearance (P > 0.05). We observed, on one hand, a decrease of the relative area for both Auerbach and Meissner plexuses with the increase of the tumor grading, and on the other hand, an increase of the relative area of other nervous elements not in the Meissner plexus or in the Auerbach plexus with the tumor grading. For G1 tumors we found that epithelial B2A area showed an inverse correlation with the Auerbach plexus areas [r(14) = -0.531, P < 0.05], while for G2 tumors, epithelial B2A areas showed an indirect variation with both the Auerbach plexus areas [r(14) = -0.453, P < 0.05] and the Meissner areas [r(14) = -0.825, P < 0.01]. For G3 tumors, the inverse dependence increased for both Auerbach [r(14) = -0.587, P < 0.05] and Meissner [r(14) = -0.934, P < 0.05] plexuses. CONCLUSION: B2A receptors play an important role in colorectal carcinogenesis and can be utilized as prognostic factors. Furthermore, study of the ENS in colorectal cancer may lead to targeted molecular therapies.

Synaptophysin expression as prognostic factor for survival in colorectal carcinomas.

The aim of this study is to assess the status of synapses in normal colorectal tissue compared to neoplastic colorectal tissue, and to correlate this status with survival in patients with colorectal neoplasia. Our study included 61 patients diagnosed with colorectal adenocarcinoma, representing the study group, and 53 patients diagnosed with benign conditions, that required a resection of a colorectal segment, representing the control group. We performed the immunohistochemical staining by using anti-synaptophysin antibody, which identifies synaptic vesicles and, so, we managed to analyze the expression of synapses in colorectal adenocarcinoma. Regarding both the signal area and integrated optical density (IOD) of the synaptophysin, the univariate analysis with a log-rank (Mantel-Cox) test indicated that patients with a low level of synaptophysin had a better overall survival rate than those with a high-level synaptophysin. Also, we noticed that tumor size, tumor invasion and lymph node metastasis were significantly associated with the overall survival rate, whereas the other clinicopathological features were not. In conclusion, the status of synaptic vesicles evaluated via synaptophysin expression in patients with colorectal cancer positively correlates with the survival rate and it can play a role in the neoplastic therapy process.

Neuro-neoplastic interrelationships in colorectal level - immunohistochemical aspect in three cases and review of the literature.

Colorectal cancer represents a severe public health issue. Recent studies have shown the essential role played by nerves and their neurotransmitters in tumor initiation and progression. The aim of this study is to asses the expression of beta 2-adrenergic receptors (ß2A) for adrenaline and noradrenaline, and the expression of M3 muscarinic receptors (M3R) for acetylcholine (neurotransmitters produced and released by sympathetic and parasympathetic afferents of the digestive tract and also by the enteric nervous system) in different tumor gradings of colorectal adenocarcinoma, and also the tropomyosin receptor kinase A (TrkA) for the nerve growth factor produced by the cells of colorectal adenocarcinoma. Beta 2-adrenergic receptors were expressed both in normal colic tissue and in the tumor tissues, from the three patients included in the study. It was observed that both area and integrated optical density (IOD) are more elevated for this type of receptor in tumor tissues than in normal colic tissue. For the M3 muscarinic receptors, similarly to beta 2-adrenergic receptors, it was observed a growth both of the area and of the IOD with the tumor grading. The presence of TrkA receptors was also observed both in the normal colic mucosa and in the tumor tissues examined, but with a significant reduction of the signal in the poorly differentiated tumor tissue. Understanding the neurobiology of cancer in this context becomes necessary for establishing much more complex and targeted molecular targeted therapies.

From molecular mechanism to morphological changes in cardiomyopathy.

The aim of this study is to make a foray in the world of constitutive elements of the architectural and functional organizing of the cardiomyocytes involved in cardiomyopathies and of the genetic molecules that they express. Primary cardiomyopathies represent a group of diseases characterized by primary structural and functional changes of the myocardium, without myocardial ischemic disease, hypertension, valvulopathies or congenital cardiac diseases being involved. In the pathogenesis of the cardiomyopathies proteins, especially from the sarcomere, Z-disc, cellular cytoskeleton, sarcolemma, intercalated discs, nuclear envelope and other constitutive proteins of the cardiomyocytes are involved. Deciphering of these pathophysiological mechanisms is part of the new model of personalized medicine, and it is useful in developing and in the optimization of new strategies for the management of the patients diagnosed with this type of disease.