fumarates and Syndrome

Hospitalizations for acute heart failure syndromes (AHFS) are associated with high post-discharge mortality and readmission rates in spite of available therapies. Renin-angiotensin-aldosterone system (RAAS) antagonists improve outcomes in outpatients with heart failure (HF) and reduced ejection fraction, however these therapies have not been tested in AHFS. Aliskiren is a direct renin inhibitor (DRI) that is known to enhance RAAS inhibition, which may result in improved clinical outcomes in AHFS. The aim of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) study is to evaluate the effect of aliskiren on cardiovascular death and HF in AHFS patients.. ASTRONAUT will be an event-driven trial with an estimated enrolment of 1782 patients hospitalized with worsening chronic HF, a left ventricular ejection fraction ≤40%, and an estimated glomerular filtration rate ≥40 mL/min/1.73 m(2). Patients will be randomized 1:1 in a double-blind fashion to receive aliskiren or placebo, in addition to standard HF therapy. The primary endpoint will be a composite of time to either cardiovascular death or first occurrence of HF re-hospitalization.. Aliskiren is a DRI with a favourable neurohormonal and haemodynamic profile that may benefit patients hospitalized with worsening HF. Given the neurohormonal abnormalities that are present during and after hospitalization for AHFS, it is hypothesized that adding aliskiren to standard therapy will reduce post-discharge mortality and re-hospitalization. NCT00894387.

Topics: Amides; Antihypertensive Agents; Double-Blind Method; Europe; Fumarates; Glomerular Filtration Rate; Heart Failure; Hemodynamics; Hospitalization; Humans; Multivariate Analysis; Outpatients; Placebos; Proportional Hazards Models; Renin; Renin-Angiotensin System; Research Design; Stroke Volume; Syndrome; Time Factors; United States; Ventricular Function, Left

Background Noninvasive in vivo detection of fumarate accumulation may help identify fumarate hydratase deficiency in renal cancer related to hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. Purpose To investigate the feasibility of MR spectroscopy (MRS) in detecting elevated fumarate levels in HLRCC-associated renal cancers. Materials and Methods This study included an experimental xenograft mouse model and prospective clinical cohort. First, MRS was performed on patient-derived tumor xenograft models and control models to detect fumarate. Then, consecutive participants with clinical suspicion of HLRCC-associated renal tumors were enrolled. For the detection of fumarate, MRS results were classified as detected, borderline, undetected, or technical failure. The sensitivity, specificity, and accuracy of MRS for diagnosing HLRCC-associated renal cancer were assessed. The signal-to-noise ratio (SNR) of the fumarate peak was calculated and evaluated with receiver operating characteristic curve analysis. Results Fumarate peaks were detected at 6.54 parts per million in all three patient-derived xenograft models. A total of 38 participants (21 men; mean age, 47 years [range, 18-71 years]) with 46 lesions were analyzed. All primary HLRCC-associated renal cancers showed a fumarate peak; among the seven metastatic HLRCC-associated lesions, a fumarate peak was detected in three lesions and borderline in two. When only detected peaks were regarded as positive findings, the sensitivity, specificity, and accuracy of MRS at the lesion level were 69% (nine of 13 lesions), 100% (33 of 33 lesions), and 91% (42 of 46 lesions), respectively. When borderline peaks were also included as a positive finding, the sensitivity, specificity, and accuracy reached 85% (11 of 13 lesions), 88% (29 of 33 lesions), and 87% (40 of 46 lesions), respectively. The SNR of fumarate showed an area under the receiver operating characteristic curve of 0.87 for classifying HLRCC-associated tumors. Conclusion MR spectroscopy of fumarate was sensitive and specific for hereditary leiomyomatosis and renal cell carcinoma-associated tumors. © RSNA, 2022

Topics: Animals; Carcinoma, Renal Cell; Female; Fumarates; Humans; Kidney Neoplasms; Leiomyomatosis; Magnetic Resonance Spectroscopy; Mice; Neoplastic Syndromes, Hereditary; Prospective Studies; Skin Neoplasms; Syndrome; Uterine Neoplasms

Topics: Amides; Calcium Channel Blockers; Female; Fumarates; Humans; Hypertension; Hyponatremia; Middle Aged; Nifedipine; Renal Artery Obstruction; Renin; Syndrome; Thirst

Individuals with hemizygous germline fumarate hydratase (FH) mutations are predisposed to renal cancer. These tumors predominantly exhibit functional inactivation of the remaining wild-type allele, implicating FH inactivation as a tumor-promoting event. Hypoxia-inducible factors are expressed in many cancers and are increased in clear cell renal carcinomas. Under normoxia, the HIFs are labile due to VHL-dependent proteasomal degradation, but stabilization occurs under hypoxia due to inactivation of HIF prolyl hydroxylase (HPH), which prevents HIF hydroxylation and VHL recognition. We demonstrate that FH inhibition, together with elevated intracellular fumarate, coincides with HIF upregulation. Further, we show that fumarate acts as a competitive inhibitor of HPH. These data delineate a novel fumarate-dependent pathway for regulating HPH activity and HIF protein levels.

Topics: Adult; Alleles; Basic Helix-Loop-Helix Transcription Factors; Carcinoma, Renal Cell; DNA-Binding Proteins; Female; Fumarate Hydratase; Fumarates; Gene Expression Regulation, Neoplastic; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; Ketoglutaric Acids; Kidney Neoplasms; Leiomyomatosis; Male; Middle Aged; Nuclear Proteins; Procollagen-Proline Dioxygenase; Syndrome; Transcription Factors; Up-Regulation

Seven boys with an apparently X-linked syndrome of dilated cardiomyopathy, growth retardation, neutropenia, and persistently elevated urinary levels of 3-methylglutaconate, 3-methylglutarate, and 2-ethylhydracrylate were studied. The natural history of the disorder was characterized by severe or lethal cardiac disease and recurrent infections during infancy and early childhood but relative improvement in later childhood. The initial presentation of the syndrome varied from congenital dilated cardiomyopathy to infantile congestive heart failure to isolated neutropenia without clinical evidence of heart disease. The excretion of 3-methylglutaconate and 3-methylglutarate appeared to be independent of the metabolism of leucine, the presumed precursor of these organic acids in humans. Although the cause of the organic aciduria remains obscure, the constellation of biochemical and clinical abnormalities forms a distinct syndrome that may be a relatively common cause of dilated cardiomyopathy or neutropenia in boys during infancy and childhood.

Topics: Adult; Cardiomyopathy, Dilated; Child; Child, Preschool; Chromatography, High Pressure Liquid; Fumarates; Glutarates; Growth Disorders; Heart Failure; Humans; Male; Meglutol; Muscular Diseases; Neutropenia; Pedigree; Syndrome; X Chromosome