Ludgeřovice, Czechia

Cardiac Contractility Modulation Therapy in Amyloid Cardiomyopathy Patients With Heart Failure

Amyloidosis represents a group of human degenerative diseases characterized by the deposition of aggregates of abnormally folded proteins in single or multi-organs. Cardiac amyloidosis is primarily associated with the systemic production and release of a number of amyloidogenic proteins, notably immunoglobulin light chain proteins (also known as amyloid light chain or AL) or transthyretin proteins (TTR). Notably, although myocardial dysfunction is generally understood as a result of infiltration by extracellular amyloid deposits, there is experimental evidence of direct cytotoxic effect, possibly due to oxidative stress. Since neither HF optimal medical therapy nor HF devices seems to have a clear benefit in amyloid cardiomyopathy, this clinical setting needs to test other therapeutic options. Randomized clinical trials have shown that Cardiac contractility modulation (CCM) may be considered as a concrete therapeutic option in patients with symptomatic Heart Failure (HF) despite optimal medical therapy (OMT), with Left Ventricular Ejection Fraction (LVEF) between 25% and 45%, with narrow QRS complex (<130ms). CCM signal treatment reverses the cardiac maladaptive fetal gene program and normalizes expression of key sarcoplasmic reticulum Ca2+ cycling and stretch response genes. Specifically, 3-month on CCM therapy resulted in decreased expression of A- and B-type natriuretic peptides, p38 mitogen activated protein kinase (MAPK) and p21 Ras and increased expression of α-MHC, SERCA-2a, phospholamban, and ryanodine receptors. Notably, pre-clinical data suggest that triggering p38α MAPK autophosphorylation plays a crucial role in amyloidogenic light-chain mediated cellular oxidative stress, dysfunction and ultimately cell death in cardiomyocytes. Therefore CCM mechanism of action could be beneficial in cardiac amyloidosis but there are no data in this specific clinical setting.

Collection of Samples and Clinical Data From Patients With Amyloid Diseases

OBJECTIVES: - To establish and maintain a database of clinical material (i.e., blood, urine, and tissue) and information on patients with amyloid diseases. OUTLINE: Blood, urine, tissue, and bone marrow samples are collected during standard laboratory evaluations to maintain a repository of biospecimens in the Gerry Amyloid Research Laboratory, to permit the correlation of clinical results with measured biological events, and for future research studies. Bone marrow RNA samples are examined for immunoglobulin light-chain gene sequences and amino acids by polymerase chain reaction and positional cloning. Blood serum and urine samples are evaluated for amyloid protein stability by high-resolution calorimetry, isothermal-titration calorimetry, and far- and near-UV circular dichroism and fluorescence spectroscopy. Urine samples are also examined for post-translational modifications (e.g., glycosylation, sulfation, and cross-linking) to identify common features unique to amyloid proteins. Tissue samples are analyzed for biochemical and biophysical properties and for post-translational modifications in light chains. Quality of life is assessed by the 36-Item Short Form Survey (SF-36).

NatiOnal Referral cenTEr Study of Transthyretin Amyloid Cardiomyopathy(ATTR) Patients on Tafamidis

[18F]Florbetazine ([18F]92) for Beta Amyloid PET Imaging in Alzheimer's Disease

Amyloid Prediction in Early Stage Alzheimer's Disease Through Speech Phenotyping - PAST Extension

Modeling the Relationships Between Functional Connectivity and Amyloid Deposition in Alzheimer's Disease

Evaluation of Serum Amyloid A in Early Diagnosis of Spontaneous Bacterial Peritonitis

Increased serum CRP and SAA levels have been found in a number of disorders, including bacterial infections, malignancies tissue injuries and tissue rejection. Therefore, new studies of early diagnosis, prevention and treatment are needed to improve clinical outcomes.

A Phase 2 Trial of ALN-APP in Patients With Cerebral Amyloid Angiopathy

Haemodynamic Effects of Dobutamine in Patients With Wild-type Transthyretin Amyloid Cardiomyopathy (ATTRwt)

AIMS - To investigate the hemodynamic effects of increasing dosages of dobutamine infusion on cardiac output and filling pressures in patients with symptomatic ATTRwt, assessed simultaneously by right heart catheterization (RHC) and echocardiography. - To assess the safety of dobutamine infusion in ATTRwt patients. HYPOTHESIS - Dobutamine infusion can increase myocardial contractility in patients with symptomatic ATTRwt with an increase of CO by 10%. - The left ventricular filling pressure as expressed by the pulmonary artery wedge pressure (PAWP) and/or mean pulmonary artery pressure (mPAP) will decrease by ≥ 10% during increasing dobutamine dosages. - Dobutamine is well-tolerated and safe to use in symptomatic ATTRwt patients. MATERIALS AND METHODS Study population Symptomatic participants with ATTRwt, age ≥ 65 years, who have reduced left ventricular ejection fraction (LVEF) and/or stroke volume index (SVI), without significant valvular diseases or severe coronary artery diseases. Study design Eligible patients will be assessed in the trial day (one day) as following: Step1; Baseline assessment: Blood pressure, pulse and ECG will be obtained. All participants will also undergo a comprehensive resting transthoracic echocardiographic assessment according to current guidelines. Step 2; Invasive right heart catheterization (RHC): The subjects will be instructed not to eat for 6 hours and not to drink for 2 hours before the procedure. RHC will be performed in the cardiac invasive laboratory using right internal jugular vein access. Rarely, right femoral vein access will be used, if the right internal jugular vein is difficult to canulate, as a result of anatomical anomalies or local skin or muscle deformities. A 7 Fr sheath will be inserted in the vein aseptic, and ultrasound guided in local anaesthesia. Subsequently, a pulmonary catheter (Swan-Ganz) will be advanced through the sheath guided by pressure waves and fluoroscopy, through the right atrium, the right ventricle, and ultimately in a stable position in the pulmonary artery (PA). The standard Swan-Ganz catheter is equipped with an inflatable balloon at the tip, which facilitates its placement into the PA through the flow of blood. The balloon, when inflated, causes the catheter to "wedge" in a small pulmonary blood vessel. While wedged, the catheter can provide an indirect measurement of the mean left atrium pressure. Central oxygenation of the blood (SvO2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) will be assessed from blood taken from the pulmonary artery at rest and at peak dobutamine infusion according to the protocol. The PA catheter location will be confirmed with fluoroscopy before leaving the laboratory and both the sheath and the catheter will be fixed to the skin. RHC is performed using a standard 7 Fr triple lumen Swan-Ganz catheter (Edwards Lifesciences, Irvine, California, USA). The following parameters will be measured by RHC: - PAWP - Mean right atrial pressure - Systolic and diastolic PA pressure - mPAP - CO All pressures at rest are measured at end-expiration as the average of five measurements. CO is measured using thermodilution methods as the average of at least four measurements not differing more than 10% and indexed to body surface area as the Cardiac Index (CI). SV is calculated as CO divided by heart rate. Step 3; Dobutamine challenge: Step 4; Recovery period: The pulmonary catheter and sheath will be removed after a-5-minute recovery period, right after obtaining the final images and invasive measurements. The participants will be observed for 2 hours after the end of the test and will be discharged if no complications arise. Blood sample will be taken to measure NT-proBNP after 1-2 hours after the end of dobutamine challenge. The investigators expect the study will last for about 6-7 hours, including preparations, waiting time, the procedures themselves and the observation period.

Safety and Efficacy of Remote Ischemic Conditioning on Cerebral Amyloid Angiopathy. (RIC-CAA)

CAA is a cerebrovascular disease caused by the deposition of β-amyloid in the walls of arteries, arterioles, and capillaries in the cerebral cortex and overlying leptomeninges. It is often associated with repeated lobar intracerebral hemorrhages, progressive cognitive decline, transient neurological symptoms and gait disturbances. No treatment is specific for symptomatic management of CAA up to date. Remote ischemic conditioning is a non-invasive strategy to protect the brain. The clinical trials have demonstrated that daily limb RIC seems to be potentially effective in patients with cerebral small-vessel disease in slowing cognition decline and reducing white matter hyperintensities. Thereby, investigators design this study to assess whether RIC has a beneficial effect on CAA.