Apixaban or Warfarin in Patients with an On-X Mechanical Aortic Valve.

BACKGROUND: Vitamin K antagonists are the only oral anticoagulants approved to prevent valve thrombosis and valve-related thromboembolism in patients with mechanical heart valves. Whether patients with an On-X mechanical aortic valve can be safely anticoagulated with apixaban is unknown. METHODS: Patients with an On-X aortic valve implanted at least 3 months before enrollment were randomly assigned to receive apixaban 5 mg twice daily or warfarin (target international normalized ratio 2.0 to 3.0). The primary efficacy end point was the composite of valve thrombosis or valve-related thromboembolism with coprimary analyses comparing apixaban with warfarin for noninferiority and comparing the apixaban event rate with an objective performance criterion (OPC). RESULTS: The trial was stopped after 863 participants were enrolled owing to an excess of thromboembolic events in the apixaban group. Most (94%) participants took aspirin. A total of 26 primary end-point events occurred, 20 (in 16 participants) in the apixaban group (4.2%/patient-year; 95% confidence interval [CI], 2.3 to 6.0) and 6 (in 6 participants) in the warfarin group (1.3%/patient-year; 95% CI, 0.3 to 2.3). The difference in primary end-point rates between the apixaban and warfarin groups was 2.9 (95% CI, 0.8 to 5.0); noninferiority and OPC success criteria were not met. Major bleeding rates were 3.6%/patient-year with apixaban and 4.5%/patient-year with warfarin. CONCLUSIONS: Apixaban did not demonstrate noninferiority to warfarin and is less effective than warfarin for the prevention of valve thrombosis or thromboembolism in patients with an On-X mechanical aortic valve. (Funded by Artivion; ClinicalTrials.gov number, NCT04142658.)

Nitric oxide and prostacyclin-dependent pathways involvement on in vitro induced hypothermia.

Nitric oxide and prostacyclin are endogenous endothelium-derived vasodilators, but little information is available on their release during hypothermia. This study was carried out to test the hypothesis that endothelium may modulate vascular reactivity to decreased temperature changes. Segments of contracted (prostaglandin F(2alpha), 2x10(-6)M) canine coronary, femoral, and renal arteries, with and without endothelium, were in vitro ("organ chambers") exposed to progressive hypothermia (from 37 to 10 degrees C) in graded steps. The study is limited to physiological measurements of vascular tone, in the presence or absence of PGI(2) and/or NOS inhibitors, which show correlation with the relaxation. Hypothermia induced vasodilatation of vessels with intact endothelium, which became endothelium-independent below 20 degrees C. This vasodilatation began at 35 degrees C and, in the presence of indomethacin (2x10(-6)M), at 30 degrees C. Endothelium-dependent vasodilatation to hypothermia was blocked by L-NMMA or L-NOARG (10(-5)M), two competitive inhibitors of nitric oxide synthase (n=5 each, P<0.05). Oxyhemoglobin (2x10(-6)M) also inhibited vasodilatation induced by hypothermia (n=6, P<0.05). Pretreatment with either atropine or pirenzepine (10(-6)M) inhibited hypothermia-mediated vasodilatation (n=5 each, P<0.05). The present in vitro study concluded that the endothelium is sensitive to temperature variations and indicated that PGI(2) and NO-dependent pathways may be involved endothelium-dependent relaxation to hypothermia. The endothelium-dependent vasodilatation to hypothermia, in systemic and coronary arteries, is mediated by the M1 muscarinic receptor.

Prolonged exposure of canine coronary arteries to a nitric oxide donor desensitizes soluble guanylate cyclase.

BACKGROUND: This study investigated the role of soluble guanylate cyclase desensitization in the development of tolerance to organic nitrates. MATERIALS AND METHODS: In organ baths, canine coronary arteries were exposed to either sodium nitroprusside (SNP) (experimental group) or papaverine (control group) at various concentrations (10(-9), 10(-7), or 10(-5) M) for 3 h. Arteries were then compared for response to vascular agonists and for inducible cyclic guanine monophosphate (cGMP) formation. RESULTS: KCl (5 to 50 mM) and prostaglandin F(2alpha) (10(-9) to 10(-5) M) induced similar vascular contractions (n = 7, P > 0.05). Vascular relaxation in response to calcium ionophore A23187 (10(-9) to 10(-6) M) and to authentic nitric oxide (NO) (3 x 10(-9) to 10(-5) M) was attenuated in arteries exposed to SNP at 10(-7) and 10(-5) M concentrations but not at a 10(-9) M concentration (n = 7 each, P < 0.05 versus the respective papaverine group). Pretreatment of arteries with methylene blue (10(-5) M) abolished the responses to authentic NO (n = 4). In cGMP determinations, control arteries demonstrated an increase in cGMP from 364 +/- 89 to 778 +/- 175 pg/mg of protein with A23187 (3 x 10(-5) M) stimulation (n = 5). Conversely, arteries exposed to SNP (10(-5) M) demonstrated similar levels of cGMP before (562 +/- 126 pg/mg of protein) and after (641 +/- 98 pg/mg of protein) A23187 stimulation. CONCLUSIONS: Prolonged exposure of coronary arteries to SNP did not alter vascular smooth muscle function, but it markedly attenuated the relaxation in response to both A23187 and authentic NO at concentrations above 10(-9) M in a concentration-dependent fashion. The constant levels of cGMP in response to an NO donor suggest that the attenuation of relaxation is due to desensitization of soluble guanylate cyclase. Thus, this study supports the role of soluble guanylate cyclase desensitization in the development of tolerance to organic nitrates.

Hirudin (desulfated, 54-65) contracts canine coronary arteries: extracellular calcium influx mediates hirudin-induced contractions.

OBJECTIVE: Although the anticoagulatory properties of hirudin are well known, its direct vasoactive effects have not been investigated extensively. Hirudin stimulates nitric oxide and prostacyclin production in noncoronary vascular beds, but its actions on coronary arteries are unknown. MATERIALS AND METHODS: Five-millimeter segments of canine left circumflex coronary arteries were obtained for organ chamber experiments. Some segments were denuded of endothelium before study. Segments were exposed to hirudin (10(-10)-10(-6) mol/L) following precontraction with prostaglandin F(2alpha) with or without pretreatment with indomethacin or calcium channel blockers (verapamil and nifedipine). RESULTS: Hirudin stimulated endothelium-independent contraction in coronary arterial segments. Maximum tension (hirudin 10(-6) mol/L) above precontraction baseline was 33.6 +/- 9.0% (n = 10, P < 0.05) for endothelium-intact and 31.8 +/- 11.5% (n = 8, P < 0.05) for endothelium-denuded arterial segments. Differences between endothelium-intact and endothelium-denuded segments were not significant. Contractile responses to hirudin were unaffected by the presence of indomethacin. Pretreatment with either verapamil or nifedipine (10(-4) mol/L) for 1 h attenuated these contractions. The maximal increase in tension above baseline (hirudin 10(-6) mol/L) for verapamil and nifedipine was only 6.2 +/- 12.4 and 3.8 +/- 7.0% (n = 6, P < 0.05 versus endothelium-intact control), respectively. CONCLUSIONS: Hirudin stimulates endothelium-independent contractions of canine coronary arteries in vitro. Pretreatment with calcium channel blockers attenuates this response, suggesting that extracellular influx of calcium has an important mechanistic role in hirudin-mediated coronary artery constriction.

Endothelium-dependent vasodilation during acute rejection in dogs.

BACKGROUND: Acute rejection, which is a major cause of death after cardiac transplantation, is associated with increased coronary artery resistance and decreased coronary blood flow, leading to congestive heart failure. MATERIALS AND METHODS: To examine the contribution of endothelium-derived vasoactive factors on coronary artery tone during acute rejection, dogs underwent orthotopic heart transplantation without immunosuppression. Plasma levels of endothelin, a potent endogenous vasoconstrictor peptide, and atrial natriuretic peptide, an endogenous coronary vasodilator of cardiac origin, were measured daily by radioimmunoassay until sacrifice. RESULTS: Over 7 days, all animals developed acute rejection accompanied by progressive increases in plasma endothelin (10 +/- 3 to 25 +/- 4 pg/ml, n = 6, P < 0.05) and atrial natriuretic peptide (57 +/- 10 to 188 +/- 42 pg/ml, n = 6, P < 0.05). However, in organ chamber experiments, coronary artery segments from rejecting hearts exhibited normal endothelium-dependent vasodilation to acetylcholine, adenosine diphosphate, and the calcium ionophore A23187. In addition, coronary arteries exhibited normal relaxation to sodium nitroprusside (cyclic guanosine monophosphate-dependent) and isoproterenol (cyclic adenosine monophosphate-dependent). CONCLUSIONS: In early, untreated acute rejection after orthotopic heart transplantation, graft dysfunction is not associated with impaired endothelium-dependent coronary artery vasodilation but may result from enhanced production of endothelin, a potent vasoconstrictor.

Systemic thrombolytic therapy after recent abdominal aortic aneurysm repair: an absolute contraindication?

Systemic thrombolysis in the early postoperative period can cause fatal hemorrhage. Systemic thrombolysis is often considered contraindicated after major vascular procedures; thus, experience with this scenario is limited. A 67-year-old man experienced massive pulmonary embolization after his abdominal aortic aneurysm was repaired with a bifurcated, woven Dacron graft. Because systemic thrombolysis was the only option for our patient's survival, he underwent this procedure with recombinant tis-sue-type plasminogen activator just 2 weeks after the Dacron graft repair of his abdominal aortic aneurysm. After clinical stabilization, abdominal and pelvic computed tomography showed no periprosthetic graft hemorrhage. The successful systemic thrombolysis suggests that this therapy may prove useful in extreme situations.

Clustering of recurrent pericarditis with effusion and constriction in a family.

OBJECTIVE: To describe a cluster of cases of pericarditis in a midwestern family of German and Danish ancestry. PATIENTS AND METHODS: Retrospective review of available medical records identified 5 family members in 2 generations with confirmed diagnosis of pericarditis. RESULTS: Five family members, 3 males and 2 females, presented for medical evaluation of recurrent chest pain between 1969 and 1991. Physical examination resulted in the diagnosis of pericarditis with effusive and constrictive features. The age at presentation ranged from 8 to 46 years. Despite extensive investigations, an idiopathic etiology was assigned to each case. In follow-up, all 5 family members had recurrent episodes of chest pain, self-limiting or responsive to medical therapy, but the effusive component remained a notable feature of the syndrome. CONCLUSIONS: Diagnosis of pericarditis in 5 family members may represent the first description of familial clustering of isolated pericarditis. In addition, 3 other family members had symptoms of chest pain, but pericarditis remained undiagnosed. The aggregate history suggests autosomal dominant inheritance with incomplete penetrance.