ursodoxicoltaurine and Heart-Failure

Patients with familial amyloidpolyneuropathies (FAP) require multidisciplinary neurologic and cardiologic management, including specific treatments to control the progression of systemic amyloidogenesis, symptomatic treatment of peripheral and autonomic neuropathies, and management of severe organ involvement (heart, eyes, kidneys). The first-line specific treatment of choice for met30 TTR-FAP is liver transplantation (LT) which suppresses the main source of mutant TTR, halts the progression of neuropathy in 70% of cases, and doubles the median survival time. Dual kidney-liver or heart-liver transplantation may be appropriate for patients with severe renal or cardiac failure. Tafamidis (Vyndaqel(R), Pfizer), a novel stabilizer of tetrameric TTR, has shown short-term effectiveness in slowing the progression of peripheral neuropathy in very early stages of met30 TTR-FAP This drug should thus be proposed for stage 1 symptomatic polyneuropathy. Other innovative medicines (RNA interference, antisense oligonucleotides) have been developed to block hepatic production of both mutant and wildtype TTR (noxious in late-onset forms of NAH after age 50 years), and to remove amyloid deposits (monoclonal anti-SAP). Clinical trials should first include patients with late-onset FAP or non-met30 TTR-FAP who are less responsive to LT7 and patients in whom Vyndaqel(R) is ineffective or inappropriate. Initial and periodic cardiac assessment is necessary, as cardiac impairment is inevitable and largely responsible for mortality. Symptomatic treatment is crucial to improve these patients' quality of life. Familial screening for carriers of the TTR gene mutation and regular clinical examination are essential to detect disease onset and to start specific therapy in a timely manner.

Topics: Amyloid Neuropathies, Familial; Antibodies, Monoclonal; Benzoxazoles; Clinical Trials as Topic; Diflunisal; Disease Progression; Doxycycline; Drug Therapy, Combination; Genetic Therapy; Heart Failure; Heart Transplantation; Humans; Kidney Failure, Chronic; Kidney Transplantation; Liver Transplantation; Myocardium; Oligonucleotides, Antisense; Renal Dialysis; RNA Interference; Serum Amyloid P-Component; Taurochenodeoxycholic Acid

We previously reported that endoplasmic reticulum (ER) stress is induced in the subfornical organ (SFO) and the hypothalamic paraventricular nucleus (PVN) of heart failure (HF) rats and is reduced by inhibition of mitogen-activated protein kinase (MAPK) signaling. The present study further examined the relationship between brain MAPK signaling, ER stress, and sympathetic excitation in HF. Sham-operated (Sham) and HF rats received a 4-wk intracerebroventricular (ICV) infusion of vehicle (Veh) or the ER stress inhibitor tauroursodeoxycholic acid (TUDCA, 10 μg/day). Lower mRNA levels of the ER stress biomarkers GRP78, ATF6, ATF4, and XBP-1s in the SFO and PVN of TUDCA-treated HF rats validated the efficacy of the TUDCA dose. The elevated levels of phosphorylated p44/42 and p38 MAPK in SFO and PVN of Veh-treated HF rats, compared with Sham rats, were significantly reduced in TUDCA-treated HF rats as shown by Western blot and immunofluorescent staining. Plasma norepinephrine levels were higher in Veh-treated HF rats, compared with Veh-treated Sham rats, and were significantly lower in the TUDCA-treated HF rats. TUDCA-treated HF rats also had lower mRNA levels for angiotensin converting enzyme, angiotensin II type 1 receptor, tumor necrosis factor-α, interleukin-1β, cyclooxygenase-2, and NF-κB p65, and a higher mRNA level of IκB-α, in the SFO and PVN than Veh-treated HF rats. These data suggest that ER stress contributes to the augmented sympathetic activity in HF by inducing MAPK signaling, thereby promoting inflammation and renin-angiotensin system activity in key cardiovascular regulatory regions of the brain.

Topics: Activating Transcription Factor 4; Activating Transcription Factor 6; Animals; Blotting, Western; Brain; Cholagogues and Choleretics; Cyclooxygenase 2; Echocardiography; Endoplasmic Reticulum Stress; Heart Failure; Heat-Shock Proteins; Inflammation; Infusions, Intraventricular; Interleukin-1beta; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; NF-KappaB Inhibitor alpha; p38 Mitogen-Activated Protein Kinases; Paraventricular Hypothalamic Nucleus; Peptidyl-Dipeptidase A; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; RNA, Messenger; Signal Transduction; Subfornical Organ; Sympathetic Nervous System; Taurochenodeoxycholic Acid; Transcription Factor RelA; Tumor Necrosis Factor-alpha; X-Box Binding Protein 1