Measures of right ventricular function after transcatheter versus surgical aortic valve replacement.

Objectives: Describe changes in measures of right ventricular (RV) function in patients treated for aortic stenosis using open-chest surgery (SAVR) or transcatheter treatment (TAVR). Methods: Patients in the Nordic Aortic Valve Intervention (NOTION) trial were randomized 1:1 to TAVR (n = 114) or SAVR (n = 106). Echocardiography was performed at baseline and 3 and 12 months post-procedure. Tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RVFAC) were used as measures of longitudinal and transverse RV contraction. Left ventricular ejection fraction (LVEF) and LV atrioventricular plane displacement (AVPD) were recorded as measures of LV function. Association to NYHA class was examined. Results: There were no differences in echocardiographic measurements between TAVR and SAVR at baseline. In the SAVR group, TAPSE was reduced after 3 months (2.4 ± 0.5 cm vs 1.6 ± 0.4 cm; P < 0.001), and 12 months (2.4 ± 0.5 cm vs 1.7 ± 0.4 cm; P < 0.001). RVFAC was reduced after 3 months (44% ± 11% vs 39% ± 10%; P = 0.001), but recovered at 12 months (43% ± 10%; P = 0.39). AVPD lateral increased during follow-up (1.4 ± 0.3 cm vs 1.6 ± 0.4 cm (P = 0.001) and 1.7 ± 0.4 cm, respectively; P < 0.001), whereas AVPD medial remained stable (baseline vs 3 months: P = 0.06 and baseline vs 12 months: P = 0.59). In the TAVR group, all echocardiographic measures remained unchanged from baseline to 12 months postoperatively. We found no association between echocardiographic changes and NYHA class. Conclusions: TAPSE and AVPD lateral differed between TAVR and SAVR at 3 and 12 months follow-up, but these findings were not related to any changes in NYHA class. These observations indicate that following SAVR, echocardiographic changes may not reflect right ventricular function, but merely a change in the physiological conditions. Clinicaltrials.gov identifier: NCT01057173.

Two-Year Outcomes in Patients With Severe Aortic Valve Stenosis Randomized to Transcatheter Versus Surgical Aortic Valve Replacement: The All-Comers Nordic Aortic Valve Intervention Randomized Clinical Trial.

BACKGROUND: The Nordic Aortic Valve Intervention (NOTION) trial was the first to randomize all-comers with severe native aortic valve stenosis to either transcatheter aortic valve replacement (TAVR) with the CoreValve self-expanding bioprosthesis or surgical aortic valve replacement (SAVR), including a lower-risk patient population than previous trials. This article reports 2-year clinical and echocardiographic outcomes from the NOTION trial. METHODS AND RESULTS: Two-hundred eighty patients from 3 centers in Denmark and Sweden were randomized to either TAVR (n=145) or SAVR (n=135) with follow-up planned for 5 years. There was no difference in all-cause mortality at 2 years between TAVR and SAVR (8.0% versus 9.8%, respectively; P=0.54) or cardiovascular mortality (6.5% versus 9.1%; P=0.40). The composite outcome of all-cause mortality, stroke, or myocardial infarction was also similar (15.8% versus 18.8%, P=0.43). Forward-flow hemodynamics were improved following both procedures, with effective orifice area significantly more improved after TAVR than SAVR (effective orifice area, 1.7 versus 1.4 cm(2) at 3 months). Mean valve gradients were similar after TAVR and SAVR. When patients were categorized according to Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) (<4% versus ≥4%), there was no statistically significant difference for TAVR and SAVR groups in the composite outcome for low-risk (14.7%, 95% confidence interval, 8.3-21.2 versus 16.8%; 95% confidence interval, 9.7-23.8; P=0.58) or intermediate-risk patients (21.1% versus 27.1%; P=0.59). CONCLUSIONS: Two-year results from the NOTION trial demonstrate the continuing safety and effectiveness of TAVR in lower-risk patients. Longer-term data are needed to verify the durability of this procedure in this patient population. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01057173.

Significance of K(ATP) channels, L-type Ca²âº channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles in vivo.

BACKGROUND: ATP-sensitive K⁺ channels (KATP channels), NO, prostaglandins, 20-HETE and L-type Ca²âº channels have all been suggested to be involved in oxygen sensing in skeletal muscle arterioles, but the role of the individual mechanisms remain controversial. We aimed to establish the importance of these mechanisms for oxygen sensing in arterioles in an in vivo model of metabolically active skeletal muscle. For this purpose we utilized the exteriorized cremaster muscle of anesthetized mice, in which the cremaster muscle was exposed to controlled perturbation of tissue PO2. RESULTS: Change from "high" oxygen tension (PO2 = 153.4 ± 3.4 mmHg) to "low" oxygen tension (PO2 = 13.8 ± 1.3 mmHg) dilated cremaster muscle arterioles from 11.0 ± 0.4 µm to 32.9 ± 0.9 µm (n = 28, P < 0.05). Glibenclamide (KATP channel blocker) caused maximal vasoconstriction, and abolished the dilation to low oxygen, whereas the KATP channel opener cromakalim caused maximal dilation and prevented the constriction to high oxygen. When adding cromakalim on top of glibenclamide or vice versa, the reactivity to oxygen was gradually restored. Inhibition of L-type Ca²âº channels using 3 µM nifedipine did not fully block basal tone in the arterioles, but rendered them unresponsive to changes in PO2. Inhibition of the CYP450-4A enzyme using DDMS blocked vasoconstriction to an increase in PO2, but had no effect on dilation to low PO2. CONCLUSIONS: We conclude that: 1) L-type Ca²âº channels are central to oxygen sensing, 2) KATP channels are permissive for the arteriolar response to oxygen, but are not directly involved in the oxygen sensing mechanism and 3) CYP450-4A mediated 20-HETE production is involved in vasoconstriction to high PO2.

Oxygen-dependent vasomotor responses are conducted upstream in the mouse cremaster microcirculation.

BACKGROUND: A new method was evaluated where local changes in oxygen tension were induced in a tissue while being studied under a microscope in vivo. We tested whether hypoxic vasodilation and hyperoxic vasoconstriction in arterioles in striated muscle are being propagated upstream, and whether the endothelium and smooth muscle cell layers are necessary components in the signaling pathway. METHODS: The study was performed in mouse cremaster muscle superfused with Krebs buffer. A section of the capillary bed was then superfused with human red blood cell suspension equilibrated with either 95% nitrogen or 95% oxygen, and 5% carbon dioxide. RESULTS: The superfusions caused a 12.9 ± 2.4% (p < 0.01) dilation and a 12.3 ± 2.7% (p < 0.01) constriction of the supplying non-exposed arteriole. Vasomotor responses could be detected 1 mm upstream of the stimulation site. The responses to hypoxia and hyperoxia were not affected by inhibition of nitric oxide (NO) synthases by L-NAME. Damage to the wall of an intervening segment of the arteriole abolished upstream changes. CONCLUSIONS: The method is capable of changing the oxygen tension locally in a membranous tissue and elicits NO-independent local and upstream vasomotor responses. Upstream responses were transmitted by a conducted vascular response.

Oxygen sensing and conducted vasomotor responses in mouse cremaster arterioles in situ.

This study examines mechanisms by which changes in tissue oxygen tension elicit vasomotor responses and whether localized changes in oxygen tension initiates conducted vasomotor responses in mouse cremaster arterioles. Intravital microscopy was used to visualize the mouse cremaster microcirculation. The cremaster was superfused with Krebs' solution with different oxygen tensions, and a gas exchange chamber was used to induce localized changes in oxygen tension. In arterioles where red blood cells were removed by buffer perfusion, arterioles responded with same magnitudes of vasodilatation (DeltaD = 16.0 +/- 4.9 microm) when changing from high (PO(2) = 242.5 +/- 13.3 mm Hg) to low (PO(2) = 22.5 +/- 4.8 mm Hg) oxygen tension as seen in the intact cremaster circulation (DeltaD = 18.7 +/- 1.0 microm). Blockade of NO synthases by L: -NAME and adenosine receptors by DPCPX had no effects on vasomotor responses to low or high oxygen. Induction of localized low (PO(2) = 23.3 +/- 5.7 mmHg) or high (PO(2) = 300.0 +/- 25.7 mm Hg) oxygen tension caused vasodilatation or -constriction locally and at a site 1,000 microm upstream (distantly). Glibenclamide blocker of ATP-sensitive K(+) channels inhibited vasodilatation and -constriction to low (PO(2) = 16.0 +/- 6.4 mm Hg) and high (PO(2) = 337.4 +/- 12.8 mm Hg) oxygen tension. 1) ATP-sensitive K(+) channels seem to mediate, at least in part, vasodilatation and vasoconstriction to low and high oxygen tension; 2) Red blood cells are not necessary for inducing vasodilatation and vasoconstriction to low or high oxygen tension; 3) localized changes in the oxygen tension cause vasomotor responses, which are conducted upstream along arterioles in mouse cremaster microcirculation.