Role of cardiac resynchronization therapy in the development of new-onset atrial fibrillation: A single-center prospective study.

Albeit several studies examined the association between cardiac resynchronization therapy (CRT) and atrial fibrillation (AF) in heart failure (HF), results are still unclear and quite conflicting. We thereby designed a single-center prospective study to determine whether CRT has a favorable effect on the incidence of new-onset AF in a homogeneous population of patients with non-ischemic idiopathic dilated cardiomyopathy and severe heart failure HF. We enrolled 58 patients, AF naïve when received CRT. After 1 year of follow-up our population was subdivided into responders (72.4%) and non (27.6%), so to compare the incidence of AF after 1, 2 and 3 years of follow-up in these two groups. Already after 1 year, there is a significant (p<0.05) difference in new-onset AF in non-responder patients respect to responders (18.2% vs 3.3%). These data are confirmed at 2 year (33.3% vs 12.2%) and 3 year (50.0% vs 15.0%) follow-up. In particular, at 3 year follow-up, non-responders have an increased risk to develop new-onset AF (OR=5.67, 95% confidence interval = 1.36-23.59, p=0.019). The present work suggests a possible favorable role of this non-pharmacological therapy, on the prevention of AF

24-hour blood pressure recording in patients with orthostatic hypotension.

Continuous intra-arterial blood pressure measurement and electrocardiograms were obtained in two ambulatory patients with orthostatic hypotension due to autonomic dysfunction. Systolic and diastolic arterial pressure presented marked variations which took place mainly during the day and were related to several physical activities; however, marked falls in blood pressure were also observed during sleep and at the moment of arousal. A peak incidence of hypotensive events was found in the afternoon, mainly in the hours following the afternoon meal. Recording was repeated after 3 weeks of treatment with propranolol, 40 mg t.i.d. In patient 1, beta blockade drastically reduced the number and severity of hypotensive episodes, while propranolol failed to control blood pressure in patient 2, who experienced a higher number of hypotensive events during treatment. Findings of this study may be relevant to the management of patients with orthostatic hypotension and should contribute to a more accurate characterization of blood pressure profile in autonomic dysfunction

Tissue Factor/Factor FVII Complex Inhibitors in Cardiovascular Disease. Are Things Going Well?

Blood coagulation is a complex biological mechanism aimed to avoid bleeding in which a highly regulated and coordinated interplay of specific proteins and cellular components respond quickly to a vascular injury. However, when this mechanisms occurs in the coronary circulation, it has not a “protective” effect, but rather, it plays a pivotal role in determining acute coronary syndromes. Coagulation recognizes Tissue Factor (TF), the main physiological initiator of the extrinsic coagulation pathway, as its starter

Silent Myocardial Ischemia and Late Ventricular Repolarization in the Genesis of Ventricular Fibrillation in Humans

Background We report a well-documented case of a patient, a 62-year-old man, with severe and asymptomatic left main coronary artery disease who had several episodes of silent myocardial ischemia and a syncopal attack during Holter recording. Methods and Results Ambulatory monitoring showed isolated giant U waves separated from the T wave 60 minutes before syncope that was due to reversible ventricular fibrillation lasting about 4 minutes and spontaneously reverting to asystole (7 seconds) and then to atrial fibrillation Conclusion Our experience suggests that myocardial ischemia may differently affect the repolarization times within the myocardium leading to widely disparate repolarization gradients that may represent the arrhythmogenic substrate for the occurrence of life-threatening ventricular tachyarrhythmias. A.N.E. 1999; 4(2):250–25

917-97 Decreased Resistance Against Oxidation of LDL from Patients with Homozigous Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) was the first genetic disorder recognized to cause myocardial infarction. Homozigotes (H) inherit two mutant genes at the low density lipoprotein (LDL) receptor locus, and as a result of the increased levels and prolonged residence time of LDL in plasma, there is a strong tendency toward accumulation of LDL in the arterial wall, causing early atherogenesis. It has been shown that LDL might undergo oxidation before it can be taken up by macrophages and it become foam cells. Thus, one additional explanation for atherogenesis in FH may be the extent to which LDL is susceptible to oxidation. We selected 8 homozigous FH pts (mean total-cholesterol 825±70mg/dl) matched with 8 healthy subjects to investigate the LDL oxidizability. Skin fibroblast cultures showed that one patient was receptor negative, while others were receptor-defective. LDL were isolated from serum by ultracentrifugations in KBr. Purified LDL was exposed to oxygen radicals generated by the xanthine/xanthine oxidase reaction (2mM and 100mU, respectively for 18hs at 37°C). Malonildihaldehyde (MDAI content was evaluated by the thiobarbiturate method. LDL analysis was carried on polyacrylamide (PAGE; 5 to 16% gradient) and agarose gel electrophoresis (0.8% in Tris-HCL buffer). No significant increase was observed in the basal concentration of MDA between LDL from H and controls (0.8±0.12 and 0.9±0.15nmoles of MDAlmg of protein, respectively). Instead, afteroxidation MDAwas 35.1±4.5* nmoles/mg of protein LDL from H, and 23.5±4.1 in controls (*p<0.05). PAGE confirmed the purity of LDL, present as an intact apolipoprotein B100(apo-B100). When oxidized LDL was run on PAGE an extensive apo-B100fragmentation, replaced by lower fragments ranging from 97.400 to 205.000 m.w., was only observed in LDL from H but not in controls in our experimental conditions. MDA content after oxidation of LDL correlated well with the loss of intact apo-B100. Finally, the relative LDL mobility on agarose gel was evaluated. This assay allows to detect changes in electric charge induced by oxidation. Basal LDL from H and controls migrated as homogeneous bands to 1.2±0.2 and 1.1±0.2cm from the origin. In contrast, oxidized LDL from H migrated to 2.1±0.3*cm from the origin while those of controls migrated to 1.5±0.2 (*p<0.05). Thus, in FH LDL appear to be more susceptible to oxidationin vitro; the indices for LDL oxidizability were all significantly different from those of controls. This phenomenon may be an important additional mechanism of atherogenesis in homozigous FH

Heart rate, pr, and qt intervals in normal children: A 24‐hour holter monitoring study

A dynamic electrocardiographic Holter monitoring study was performed in 32 healthy children (20 males and 12 females, age range 6-11 years old), without heart disease, according to clinical and noninvasive instrumental examination. We evaluated atrioventricular conduction time (PR), heart rate (HR), and QT interval patterns defining the range of normality of these electrocardiographic parameters. The PR interval ranged from 154 +/- 10 ms (mean +/- SD) for HR less than or equal to 60 to 102 +/- 12 ms for HR greater than or equal to 120 (range 85-180). The absolute mean HR was 87 +/- 10 beats/min (range 72-104), the minimum observed HR being 61 +/- 10 (range 51-79), the maximum 160 +/- 20 beats/min (range 129-186). Daytime mean HR gave a mean value of 93 +/- 10 (range 71-148), while during night hours it was 74 +/- 11 (range 54-98). The minimum QT interval averaged 261 +/- 10 ms for HR greater than 120 and the maximum 389 +/- 9 ms for HR less than or equal to 60; the corresponding mean value of QTc (i.e., QT corrected for HR) ranged from 388 +/- 8 for HR less than or equal to 60 beats/min to 403 +/- 14 ms for HR greater than 120 beats/min. The results of the present study provide data of normal children which can be readily compared against those of subjects in whom cardiac abnormalities are suspect or patient.(ABSTRACT TRUNCATED AT 250 WORDS

CRT prevents new-onset AF

SUMMARY Aim: The aim of this study was to determine whether or not cardiac resynchronization therapy (CRT) has a favourable effect on the incidence of new-onset atrial fibrillation (AF) in a homogeneous population of patients with non-ischaemic idiopathic-dilated cardiomyopathy and severe heart failure. Methods: We designed a single-centre prospective study and enrolled 58 patients AF nao¨ve when received CRT. After 1 year of follow-up our population was subdivided into responders (72.4%) and non-responders (27.6%), so as to compare the incidence of AF after 1, 2 and 3 years of follow-up in these two groups. Results: Already after 1 year, there was a significant (p < 0.05) difference in new-onset AF in non-responder patients with respect to responders (18.2% vs. 3.3%). These data were confirmed at 2 years (33.3% vs. 12.2%) and 3 years (50.0% vs. 15.0%) follow-up. In particular, 3 years after device implantation non-responders had an increased risk to develop new-onset AF (OR = 5.67). Conclusions: This is the first study analysing long-term effects of CRT in a homogeneous population of patients with nonischaemic dilated cardiomyopathy, indicating the favourable role of this non-pharmacological therapy on the prevention of AF. What's known Albeit several studies examined the association between cardiac resynchronization therapy and atrial fibrillation in heart failure, results are still unclear and quite conflicting. What's new In this study we show that in patients with non-ischemic dilated cardiomyopathy a positive response to cardiac resynchronization therapy has a favorable role on the prevention of new-onset atrial fibrillation.

Activation of the Erk8 Mitogen-activated Protein (MAP) Kinase by RET/PTC3, a Constitutively Active Form of the RET Proto-oncogene

Mitogen-activated protein (MAP) kinases have a central role in several biological functions, including cell adhesion and spreading, chemotaxis, cell cycle progression, differentiation, and apoptosis. Extracellular signal-regulated kinase 8 (Erk8) is a large MAP kinase whose activity is controlled by serum and the c-Src non-receptor tyrosine kinase. Here, we show that RET/PTC3, an activated form of the RET proto-oncogene, was able to activate Erk8, and we demon- strate that such MAP kinase participated in RET/PTC3-dependent stimulation of the c-jun promoter. By using RET/PTC3 molecules mutated in specific tyrosine autophosphorylation sites, we charac- terized Tyr981, a known binding site for c-Src, as a major determi- nant of RET/PTC3-induced Erk8 activation, although, surprisingly, the underlying mechanism did not strictly depend on the activity of Src. In contrast, we present evidence that RET/PTC3 acts on Erk8 through Tyr981-mediated activation of c-Abl. Furthermore, we localized the region responsible for the modulation of Erk8 activity by the RET/PTC3 and Abl oncogenes in the Erk8 C-terminal domain. Altogether, these results support a role for Erk8 as a novel effector of RET/PTC3 and, therefore, RET biological functions

Complication of nasal piercing by Staphylococcus aureus endocarditis: a case report and a review of literature

Body piercing, a growing trend especially in young people, is often complicated by severe infections. We present a case of acute bacterial endocarditis by Staphylococcus aureus complicated by multiple cerebral, kidney, spleen embolisms in a young girl, with no known previous cardiac abnormalities, following the piercing of nasal septum. This case highlights the importance of education of patients with and without structural heart disease to the potential dangerous and even life threatening infectious complications of piercing, and stimulate further discussion on the possibility of antibiotic prophylaxis of such procedures

Targeted inhibition of Hedgehog-GLI signaling by novel acylguanidine derivatives inhibits melanoma cell growth by inducing replication stress and mitotic catastrophe

Aberrant activation of the Hedgehog (HH) signaling is a critical driver in tumorigenesis. The Smoothened (SMO) receptor is one of the major upstream transducers of the HH pathway and a target for the development of anticancer agents. The SMO inhibitor Vismodegib (GDC-0449/Erivedge) has been approved for treatment of basal cell carcinoma. However, the emergence of resistance during Vismodegib treatment and the occurrence of numerous side effects limit its use. Our group has recently discovered and developed novel and potent SMO inhibitors based on acylguanidine or acylthiourea scaffolds. Here, we show that the two acylguanidine analogs, compound (1) and its novel fluoride derivative (2), strongly reduce growth and self-renewal of melanoma cells, inhibiting the level of the HH signaling target GLI1 in a dose-dependent manner. Both compounds induce apoptosis and DNA damage through the ATR/CHK1 axis. Mechanistically, they prevent G2 to M cell cycle transition, and induce signs of mitotic aberrations ultimately leading to mitotic catastrophe. In a melanoma xenograft mouse model, systemic treatment with 1 produced a remarkable inhibition of tumor growth without body weight loss in mice. Our data highlight a novel route for cell death induction by SMO inhibitors and support their use in therapeutic approaches for melanoma and, possibly, other types of cancer with active HH signaling