Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018799 (heart disease)
 34,133 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pimobendan is an oral inodilator compound available in many countries for use in canine heart failure. It combines calcium-sensitizing effects with PDE III inhibition, resulting in positive inotropic effects and veno- and ergic signal transduction pathway in the failing heart, the calcium-sensitizing effects may assume greater importance in patients with heart failure. Clinical studies in human patients have shown sustained improvement in hemodynamics and exercise tolerance, with favorable neurohormonal effects. One study showed a nonsignificant trend toward increased mortality [20], but proarrhythmic effects have not ben observed. Studies in naturally occurring canine heart failure suggest that pimobendan's effects are at least comparable to those of ACE inhibitors, if not superior. Pimobendan is likely to play an increasing role in the future in the treatment of canine heart disease.
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PMID:Use of pimobendan in the management of heart failure. 1532 74

Pulmonary hypertension (PH) occurs commonly in patients with left heart disease, and is associated with increased morbidity and mortality. The pathophysiologic mechanisms of PH in left heart disease are complex, and are thought to be a composite of both passive and active components. PH that is disproportionate to the underlying left heart disease may be attributable to reactive pulmonary vascular remodelling. Management of these patients is focused upon treatment of the underlying left heart disease and its associated comorbidities. There is no supporting evidence for the routine use of specific PH therapies in these patients at present. However, there is some suggestion that PDE-5 inhibitors may be useful, but their safety and efficacy needs to be formally evaluated in controlled trials before further recommendations are made.
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PMID:Pulmonary hypertension in left heart disease: a review. 2170 99

Cyclic guanosine monophosphate (cGMP) is a second messenger molecule that transduces nitric-oxide- and natriuretic-peptide-coupled signalling, stimulating phosphorylation changes by protein kinase G. Enhancing cGMP synthesis or blocking its degradation by phosphodiesterase type 5A (PDE5A) protects against cardiovascular disease. However, cGMP stimulation alone is limited by counter-adaptions including PDE upregulation. Furthermore, although PDE5A regulates nitric-oxide-generated cGMP, nitric oxide signalling is often depressed by heart disease. PDEs controlling natriuretic-peptide-coupled cGMP remain uncertain. Here we show that cGMP-selective PDE9A (refs 7, 8) is expressed in the mammalian heart, including humans, and is upregulated by hypertrophy and cardiac failure. PDE9A regulates natriuretic-peptide- rather than nitric-oxide-stimulated cGMP in heart myocytes and muscle, and its genetic or selective pharmacological inhibition protects against pathological responses to neurohormones, and sustained pressure-overload stress. PDE9A inhibition reverses pre-established heart disease independent of nitric oxide synthase (NOS) activity, whereas PDE5A inhibition requires active NOS. Transcription factor activation and phosphoproteome analyses of myocytes with each PDE selectively inhibited reveals substantial differential targeting, with phosphorylation changes from PDE5A inhibition being more sensitive to NOS activation. Thus, unlike PDE5A, PDE9A can regulate cGMP signalling independent of the nitric oxide pathway, and its role in stress-induced heart disease suggests potential as a therapeutic target.
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PMID:Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. 2590 45

No current treatment targets cardiac proteotoxicity or can reduce mortality of heart failure (HF) with preserved ejection fraction (HFpEF). Selective degradation of misfolded proteins by the ubiquitin-proteasome system (UPS) is vital to the cell. Proteasome impairment contributes to HF. Activation of cAMP-dependent protein kinase (PKA) or cGMP-dependent protein kinase (PKG) facilitates proteasome functioning. Phosphodiesterase 1 (PDE1) hydrolyzes both cyclic nucleotides and accounts for most PDE activities in human myocardium. We report that PDE1 inhibition (IC86430) increases myocardial 26S proteasome activities and UPS proteolytic function in mice. Mice with CryABR120G-based proteinopathy develop HFpEF and show increased myocardial PDE1A expression. PDE1 inhibition markedly attenuates HFpEF, improves mouse survival, increases PKA-mediated proteasome phosphorylation, and reduces myocardial misfolded CryAB. Therefore, PDE1 inhibition induces PKA- and PKG-mediated promotion of proteasomal degradation of misfolded proteins and treats HFpEF caused by CryABR120G, representing a potentially new therapeutic strategy for HFpEF and heart disease with increased proteotoxic stress.
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PMID:PDE1 inhibition facilitates proteasomal degradation of misfolded proteins and protects against cardiac proteinopathy. 3113 29