digoxin and Calcinosis

Calcification of soft tissues, such as heart valves and tendons, is a common clinical problem with limited therapeutics. Tissue specific stem/progenitor cells proliferate to repopulate injured tissues. But some of them become divergent to the direction of ossification in the local pathological microenvironment, thereby representing a cellular target for pharmacological approach. We observed that HIF-2alpha (encoded by EPAS1 inclined form) signaling is markedly activated within stem/progenitor cells recruited at calcified sites of diseased human tendons and heart valves. Proinflammatory microenvironment, rather than hypoxia, is correlated with HIF-2alpha activation and promoted osteochondrogenic differentiation of tendon stem/progenitor cells (TSPCs). Abnormal upregulation of HIF-2alpha served as a key switch to direct TSPCs differentiation into osteochondral-lineage rather than teno-lineage. Notably, Scleraxis (Scx), an essential tendon specific transcription factor, was suppressed on constitutive activation of HIF-2alpha and mediated the effect of HIF-2alpha on TSPCs fate decision. Moreover, pharmacological inhibition of HIF-2alpha with digoxin, which is a widely utilized drug, can efficiently inhibit calcification and enhance tenogenesis in vitro and in the Achilles's tendinopathy model. Taken together, these findings reveal the significant role of the tissue stem/progenitor cells fate decision and suggest that pharmacological regulation of HIF-2alpha function is a promising approach for soft tissue calcification treatment.

Topics: Achilles Tendon; Aged; Animals; Basic Helix-Loop-Helix Transcription Factors; Calcinosis; Cell Differentiation; Cell Proliferation; Cells, Cultured; Cellular Microenvironment; Chondrogenesis; Digoxin; Humans; Male; Middle Aged; Rats; Rheumatic Heart Disease; Stem Cells; Therapy, Soft Tissue

The isoprenoid pathway produces three key metabolites-digoxin (membrane sodium-potassium ATPase inhibitor and regulator of intracellular calcium-magnesium ratios), dolichol (regulator of N-glycosylation of proteins) and ubiquinone (free radical scavenger). The pathway was assessed in a rare and specific type of familial basal ganglia calcification described. The family had a coexistence of basal ganglia calcification (six out of 10 cases), schizophrenia, Parkinson's disease, Alzheimer's disease, rheumatoid arthritis, systemic tumours and syndrome X and were all right hemispheric dominant. The isoprenoid pathway was also studied for comparison in right hemispheric dominant, bihemispheric dominant and left hemispheric dominant individuals. The isoprenoid pathway was upregulated with increased digoxin synthesis in familial basal ganglia calcification. Membrane sodium-potassium ATPase inhibition can lead on to increase in intracellular calcium and calcification of the basal ganglia. There was increase in tryptophan catabolites and a reduction in tyrosine catabolites. There was also an increase in dolichol and glycoconjugate levels with reduced lysosomal stability in these patients. The ubiquinone levels were low and free radical levels increased. The cholesterol-phospholipid ratio was increased and glycoconjugate level of the RBC membrane reduced in these group of patients. No significance difference was noted in family members with and without basal ganglia calcification. This findings were correlated with the pathogenesis of syndrome X, immune mediated diseases, degenerations, tumours and psychiatric disorders noted in the familial basal ganglia calcification described. The biochemical patterns obtained in familial basal ganglia calcification correlated with those in right hemispheric dominance.

Topics: Adult; Aged; Basal Ganglia Diseases; Calcinosis; Cell Membrane; Cerebral Cortex; Digoxin; Female; Functional Laterality; Humans; Hypothalamus; Male; Middle Aged; Pedigree; Polyisoprenyl Phosphate Monosaccharides; Sodium-Potassium-Exchanging ATPase

Two hundred consecutive catheterized patients with unstable angina pectoris were reviewed to find clinical and noninvasive indicators of left main coronary artery disease (greater than or equal to 50% lesion). Thirty-five patients (17.5% of total) had left main coronary artery disease. There were no differences between patients with and without left main coronary artery disease in age, sex, results of resting electrocardiogram, congestive heart failure, dyspnea during pain, duration of longest pain, arrhythmias, response to medical therapy, or other risk factors. Crescendo angina pectoris (worsening of pre-existing angina), transient ST-segment depression with pain, simultaneous anterior and inferior ST changes during pain, and fluoroscopic calcification of the left main coronary artery were all significantly more common in patients with left main coronary artery disease. However, low sensitivity or low predictive value, or both, limit the usefulness of these clinical predictors. Left main coronary artery disease cannot be reliably predicted in patients with unstable angina pectoris before coronary arteriography.

Topics: Angina Pectoris; Angiography; Anticoagulants; Calcinosis; Cardiac Catheterization; Cardiomegaly; Collateral Circulation; Coronary Angiography; Coronary Circulation; Coronary Disease; Digoxin; Electrocardiography; Female; Heart Conduction System; Heart Failure; Humans; Male; Middle Aged; Nitrates; Propranolol; Risk

22 patients with syncope and significant aortic stenosis underwent electrophysiological evaluation in addition to the hemodynamic study. Abnormalities of impulse formation or conduction were present in 12 patients. 6 patients demonstrated HV times greater than or equal to 55 msec. There was no correlation between the aortic valve gradient and the HV interval, between the enddiastolic volume of the ventricle and the HV time and between aortic valve calcification and the HV time. Syncopal attacks were corrected with aortic valve replacement even in patients with prolonged HV times.

Topics: Adult; Aged; Aortic Valve; Aortic Valve Stenosis; Bundle of His; Bundle-Branch Block; Calcinosis; Digoxin; Electrocardiography; Female; Heart Conduction System; Heart Valve Prosthesis; Hemodynamics; Humans; Male; Middle Aged; Pacemaker, Artificial; Recurrence; Syncope

Topics: Aged; Aminophylline; Atrial Flutter; Calcinosis; Cardiomegaly; Cefazolin; Digoxin; Heart Block; Humans; Male; Oxygen Inhalation Therapy; Pericarditis; Respiratory Insufficiency

Topics: Aging; Animals; Aorta; Body Weight; Bone and Bones; Calcinosis; Digoxin; Feeding Behavior; Female; Heart Rate; Hypothalamus; Longevity; Male; Mice; Mice, Inbred Strains; Myocardium; Organ Size; Sex Factors; Species Specificity; Spectrophotometry; Tooth