Association Between Preexisting Versus Newly Identified Atrial Fibrillation and Outcomes of Patients With Acute Pulmonary Embolism

Background Atrial fibrillation (AF) may exist before or occur early in the course of pulmonary embolism (PE). We determined the PE outcomes based on the presence and timing of AF. Methods and Results Using the data from a multicenter PE registry, we identified 3 groups: (1) those with preexisting AF, (2) patients with new AF within 2 days from acute PE (incident AF), and (3) patients without AF. We assessed the 90-day and 1-year risk of mortality and stroke in patients with AF, compared with those without AF (reference group). Among 16 497 patients with PE, 792 had preexisting AF. These patients had increased odds of 90-day all-cause (odds ratio [OR], 2.81; 95% CI, 2.33-3.38) and PE-related mortality (OR, 2.38; 95% CI, 1.37-4.14) and increased 1-year hazard for ischemic stroke (hazard ratio, 5.48; 95% CI, 3.10-9.69) compared with those without AF. After multivariable adjustment, preexisting AF was associated with significantly increased odds of all-cause mortality (OR, 1.91; 95% CI, 1.57-2.32) but not PE-related mortality (OR, 1.50; 95% CI, 0.85-2.66). Among 16 497 patients with PE, 445 developed new incident AF within 2 days of acute PE. Incident AF was associated with increased odds of 90-day all-cause (OR, 2.28; 95% CI, 1.75-2.97) and PE-related (OR, 3.64; 95% CI, 2.01-6.59) mortality but not stroke. Findings were similar in multivariable analyses. Conclusions In patients with acute symptomatic PE, both preexisting AF and incident AF predict adverse clinical outcomes. The type of adverse outcomes may differ depending on the timing of AF onset.info:eu-repo/semantics/publishedVersio

Evidence of a role for fibroblast transient receptor potential canonical 3 Ca2+ channel in renal fibrosis

Abstract: Transient receptor potential canonical (TRPC) Ca -permeant channels, especially TRPC3, are increasingly implicated in cardiorenal diseases. We studied the possible role of fibroblast TRPC3 in the development of renal fibrosis. In vitro, a macromolecular complex formed by TRPC1/TRPC3/TRPC6 existed in isolated cultured rat renal fibroblasts. However, specific blockade of TRPC3 with the pharmacologic inhibitor pyr3 was sufficient to inhibit both angiotensin II- and 1-oleoyl-2-acetyl-snglycerol– induced Ca entry in these cells, which was detected by fura-2 Ca imaging. TRPC3 blockade or Ca removal inhibited fibroblast proliferation and myofibroblast differentiation by suppressing the phosphorylation of extracellular signal-regulated kinase (ERK1/2). In addition, pyr3 inhibited fibrosis and inflammation-associated markers in a noncytotoxic manner. Furthermore, TRPC3 knockdown by siRNA confirmed these pharmacologic findings. In adult male Wistar rats or wild-type mice subjected to unilateral ureteral obstruction, TRPC3 expression increased in the fibroblasts of obstructed kidneys and was associated with increased Ca entry, ERK1/2 phosphorylation, and fibroblast proliferation. Both TRPC3 blockade in rats and TRPC3 knockout in mice inhibited ERK1/2 phosphorylation and fibroblast activation as well as myofibroblast differentiation and extracellular matrix remodeling in obstructed kidneys, thus ameliorating tubulointerstitial damage and renal fibrosis. In conclusion, TRPC3 channels are present in renal fibroblasts and control fibroblast proliferation, differentiation, and activation through Ca -mediated ERK signaling. TRPC3 channels might constitute important therapeutic targets for improving renal remodeling in kidney disease

Transient Receptor Potential Canonical 3 and Nuclear Factor of Activated T Cells C3 Signaling Pathway Critically Regulates Myocardial Fibrosis

Aims: Cardiac fibroblasts (CFs) are emerging as major contributors to myocardial fibrosis (MF), a final common pathway of many etiologies of heart disease. Here, we studied the functional relevance of transient receptor potential canonical 3 (TRPC3) channels and nuclear factor of activated T cells c3 (NFATc3) signaling in rodent and human ventricular CFs, and whether their modulation would limit MF. Results: A positive feedback loop between TRPC3 and NFATc3 drove a rat ventricular CF fibrotic phenotype. In these cells, polyphenols (extract of grape pomace polyphenol [P.E.]) decreased basal and angiotensin II-mediated Ca 2+ entries through a direct modulation of TRPC3 channels and subsequently NFATc3 signaling, abrogating myofibroblast differentiation, fibrosis and inflammation, as well as an oxidative stress-associated phenotype. N(ω)-nitro-l-arginine methyl ester (l-NAME) hypertensive rats developed coronary perivascular, sub-epicardial, and interstitial fibrosis with induction of embryonic epicardial progenitor transcription factors in activated CFs. P.E. treatment reduced ventricular CF activation by modulating the TRPC3-NFATc3 pathway, and it ameliorated echocardiographic parameters, cardiac stress markers, and MF in l-NAME hypertensive rats independently of blood pressure regulation. Further, genetic deletion (TRPC3 -/- ) and pharmacological channel blockade with N-[4-[3,5-Bis(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]-4-methyl-benzenesulfonamide (Pyr10) blunted ventricular CF activation and MF in l-NAME hypertensive mice. Finally, TRPC3 was present in human ventricular CFs and upregulated in MF, whereas pharmacological modulation of TRPC3-NFATc3 decreased proliferation and collagen secretion. Innovation and Conclusion: We demonstrate that TRPC3-NFATc3 signaling is modulated by P.E. and critically regulates ventricular CF phenotype and MF. These findings strongly argue for P.E., through TRPC3 targeting, as potential and interesting therapeutics for MF management.Fil: Saliba, Youakim. Université Saint Joseph; LíbanoFil: Jebara, Victor. Université Saint Joseph; LíbanoFil: Hajal, Joelle. Université Saint Joseph; LíbanoFil: Maroun, Richard. Université Saint Joseph; LíbanoFil: Chacar, Stéphanie. Université Saint Joseph; LíbanoFil: Smayra, Viviane. Université Saint Joseph; LíbanoFil: Abramowitz, Joel. National Institute of Environmental Health Sciences,; Estados UnidosFil: Birnbaumer, Lutz. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina. National Institute of Environmental Health Sciences,; Estados UnidosFil: Farès, Nassim. Université Saint Joseph; Líban

Hypothyroidism and Its Rapid Correction Alter Cardiac Remodeling

<div><p>The cardiovascular effects of mild and overt thyroid disease include a vast array of pathological changes. As well, thyroid replacement therapy has been suggested for preserving cardiac function. However, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels. The purpose of this paper is to study the effect of hypothyroidism and thyroid replacement therapy on cardiac alterations. Thirty Wistar rats were divided into 2 groups: a control (n = 10) group and a group treated with 6-propyl-2-thiouracil (PTU) (n = 20) to induce hypothyroidism. Ten of the 20 rats in the PTU group were then treated with L-thyroxine to quickly re-establish euthyroidism. The serum levels of inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin 6 (IL6) and pro-fibrotic transforming growth factor beta 1 (TGF-β1), were significantly increased in hypothyroid rats; elevations in cardiac stress markers, brain natriuretic peptide (BNP) and cardiac troponin T (cTnT) were also noted. The expressions of cardiac remodeling genes were induced in hypothyroid rats in parallel with the development of fibrosis, and a decline in cardiac function with chamber dilation was measured by echocardiography. Rapidly reversing the hypothyroidism and restoring the euthyroid state improved cardiac function with a decrease in the levels of cardiac remodeling markers. However, this change further increased the levels of inflammatory and fibrotic markers in the plasma and heart and led to myocardial cellular infiltration. In conclusion, we showed that hypothyroidism is related to cardiac function decline, fibrosis and inflammation; most importantly, the rapid correction of hypothyroidism led to cardiac injuries. Our results might offer new insights for the management of hypothyroidism-induced heart disease.</p></div

TRPC3 regulates islet beta-cell insulin secretion

Abstract: Insulin release is tightly controlled by glucose-stimulated calcium (GSCa) through hitherto equivocal pathways. This study investigates TRPC3, a non-selective cation channel, as a critical regulator of insulin secretion and glucose control. TRPC3’s involvement in glucose-stimulated insulin secretion (GSIS) is studied in human and animal islets. TRPC3-dependent in vivo insulin secretion is investigated using pharmacological tools and Trpc3−/− mice. TRPC3’s involvement in islet glucose uptake and GSCa is explored using fluorescent glucose analogue 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-D-glucose and calcium imaging. TRPC3 modulation by a small-molecule activator, GSK1702934A, is evaluated in type 2 diabetic mice. TRPC3 is functionally expressed in human and mouse islet beta cells. TRPC3-controlled insulin secretion is KATP-independent and primarily mediated by diacylglycerol channel regulation of the cytosolic calcium oscillations following glucose stimulation. Conversely, glucose uptake in islets is independent of TRPC3. TRPC3 pharmacologic inhibition and knockout in mice lead to defective insulin secretion and glucose intolerance. Subsequently, TRPC3 activation through targeted small-molecule enhances insulin secretion and alleviates diabetes hallmarks in animals. This study imputes a function for TRPC3 at the onset of GSIS. These insights strengthen one’s knowledge of insulin secretion physiology and set forth the TRPC3 channel as an appealing candidate for drug development in the treatment of diabetes

Primers for the different genes.

<p>Forward and reverse primers used for quantitative real-time PCR. Abbreviations: <i>Anp</i>: Atrial natriuretic peptide; <i>Bnp</i>: Brain natriuretic peptide; <i>α-Mhc</i>: α-Myosin heavy chain; <i>β-Mhc</i>: β-Myosin heavy chain; <i>α-Sma</i>: α-Smooth muscle actin; <i>Tgf-β1</i>: Transforming growth factor beta 1; <i>cTgf</i>: Connective tissue growth factor; <i>Il1</i>: Interleukin 1; <i>Mcp1</i>: Monocyte chemoattractant protein 1; <i>Col1</i>: Collagen type I; <i>Col3</i>: Collagen type III; <i>Rpl32</i>: Ribosomal protein L32.</p><p>Primers for the different genes.</p

Serum levels of fT3 (A), fT4 (A) and TSH (B) in the different rat groups at different times after the PTU or LT4 treatments and sacrifice.

<p>Data are represented as the mean ± SEM. n = 10 animals for each group. Statistical analysis was performed with two-way ANOVA tests followed by post hoc Tukey's multiple comparison tests. *<i>p</i><0.001 <i>vs.</i> control; ^#<i>p</i><0.001 <i>vs.</i> control and reverse; ^$<i>p</i><0.001 <i>vs</i>. 7 and 12 weeks reverse and 12 weeks PTU; ^§<i>p</i><0.001 <i>vs.</i> 7 and 12 weeks reverse; ⁺<i>p</i><0.001 <i>vs</i>. 7 and 12 weeks reverse and 7 weeks PTU.</p

The LT4 treatment reversed cardiac dilation and improved systolic function.

<p><b>A</b>: Heart weight to tibia length ratio (mg/cm) in the different treatment groups. Statistical analysis was performed with Kruskal-Wallis One-way ANOVA on rank tests followed by post hoc Dunn's multiple comparison tests. **<i>p</i><0.01 <i>vs.</i> control and reverse. <b>B</b> and <b>C</b>: Echocardiographic measurements of the ejection fraction (%) and fractional shortening (%) in the control, PTU-treated and LT4-treated rats at different time points. Statistical analysis was performed with two-way ANOVA tests followed by post hoc Tukey's multiple comparison tests. *<i>p</i><0.05 <i>vs.</i> control as well as 7 and 12 weeks reverse; ^#<i>p</i><0.05 <i>vs.</i> PTU. <b>D</b>: M-mode echocardiographic tracings from the control, PTU and reverse groups. Echocardiography scale bars: 0.25 s and 0.5 mm. Data are represented as the mean ± SEM. n = 10 animals for each group.</p

Adiponectin (A) and TGF-β1 (B) plasma levels in the different groups of animals.

<p>Data are represented as the mean ± SEM. n = 10 animals for each group. Statistical analysis was performed with Kruskal-Wallis One-way ANOVA on rank tests followed by post hoc Dunn's multiple comparison tests. *<i>p</i><0.01 <i>vs.</i> control; ^#<i>p</i><0.05 <i>vs.</i> PTU.</p