Pre-procedural pacing bias among transcatheter aortic valves with higher post-procedure pacing rates: evidence from the UK TAVI Registry.

Rates of permanent pacemaker (PPM) implantation following transcatheter aortic valve implantation (TAVI) are higher than following surgery and are dependent on patient factors and valve type. There is an increasing trend towards pre-emptive PPM insertion in patients with significant conduction disease prior to TAVI. We report results from the British Cardiovascular Intervention Society (BCIS) on pre- and post-procedural PPM implantation in the TAVI population. All centres in the United Kingdom performing TAVI are required to submit data on all TAVI procedures to the National database which are then reported annually. During 2015, there were 2373 TAVI procedures in the UK. 22.4% of TAVI patients had a PPM implanted either pre-procedure (including the distant past), or during the in-hospital procedural episode. Of these, 7.9% were pre-procedure and 14.5% post-procedure. Overall PPM rates were Edwards Sapien (13.5%), Medtronic CoreValve (28.2%) and Boston Lotus (42.1%; p < 0.01). Pre-procedure pacing rates were Edwards Sapien (6.0%), Medtronic CoreValve (9.1%) and Boston Lotus (12.3%; p < 0.01). Pre-procedural pacing rates for the Boston Lotus valve have risen year-on-year from 5.8% (2013) to 8.6% (2014) to 12.3% (2015). The UK TAVI Registry demonstrates a pre-procedural permanent pacing bias amongst patients receiving transcatheter valves with higher post-procedure pacing rates. Pre-emptive permanent pacing is likely to be responsible for this difference.

Impact of mitral geometry and global afterload on improvement of mitral regurgitation after trans-catheter aortic valve implantation.

OBJECTIVE: To assess the impact of mitral geometry, left ventricular (LV) remodelling and global LV afterload on mitral regurgitation (MR) after trans-catheter aortic valve implantation (TAVI). METHODS: In this study, 60 patients who underwent TAVI were evaluated by 3D echocardiography at baseline, 1 month and 6 months after procedure. The proportional change in MR following TAVI was determined by examining the percentage change in vena contracta (VC) at 6 months. Patients having a significant reduction of at least 30% in VC were defined as good responders (GR) and the remaining patients were defined as poor responders (PR). RESULTS: After 6 months of TAVI, 27 (45%) patients were GR and 33 (55%) were PR. There was a significant decrease in 3DE-derived mitral annular diameter and area (P = 0.001), mitral valve tenting area (TA) (P = 0.05), and mitral papillary muscle dyssynchrony index (DSI) (P = 0.05) in the GR group. 3DE-derived LVESV (P = 0.016), LV mass (P = 0.001) and LV DSI, (P = 0.001) were also improved 6 months after TAVI. In addition, valvulo-arterial impedance (ZVA) was significantly higher at baseline in patients with PR (P = 0.028). 3DE-derived mitral annular area (ß: 0.47, P = 0.04), mitral papillary DSI (ß: -0.65, P = 0.012) and ZVA (ß: 0.45, P = 0.028) were the strongest independent parameters that could predict the reduction of functional MR after TAVI. CONCLUSION: GR patients demonstrate more regression in mitral annulus area and diameter after significant decrease in high LVEDP and trans-aortic gradients with TAVI. PR patients appear to have increased baseline ZVA, mitral valve tenting and restriction in mitral valve coaptation. These factors are important for predicting the impact of TAVI on pre-existing MR.

The combined treatment of aortic stenosis and abdominal aortic aneurysm using transcatheter techniques: a case report.

We describe the case of an 85 year old lady with symptomatic aortic stenosis (AS) with a history of previous coronary artery bypass grafting (CABG), who was referred for consideration of aortic valve replacement (AVR). Echocardiography revealed severe AS with peak gradient of 92 mmHg, orifice area of 0.6 cm2 and preserved left ventricular function. Computed tomography (CT) aortogram revealed a diffusely calcified aorta and an infrarenal abdominal aortic aneurysm (AAA) measuring 6.5 cm. For symptomatic and prognostic reasons she needed treatment of both the AAA and AS. Her calculated logistic EuroSCORE for AVR was 39%. Following discussion at a multidisciplinary forum, it was agreed that the best way to offer her treatment with the lowest risk was by using transcatheter techniques for both pathologies. She subsequently underwent transcatheter aortic valve implantation (TAVI) via the transapical approach to treat her AS, and 3 months later, endovascular stenting of her infrarenal AAA. She recovered well from both procedures. At 6 week follow up, her cardiac symptoms had improved considerably, and echocardiography revealed a mean AV gradient of 7 mmHg with good left ventricular function. Ultrasound of her abdomen revealed exclusion of the aneurysm sac with no endoleak. This is the first described case of TAVI and endovascular treatment of an AAA as a staged procedure.

A rare case of an aberrant anterior mitral valve chord resulting in severe mitral regurgitation.

A 49 year old female presented with severe dyspnoea due to mitral regurgitation. Echocardiography revealed an aberrant mitral valve chord causing severe mitral regurgitation. The aberrant chord extended between the anterior mitral valve leaflet (AMVL) and the atrial septum causing AMVL prolapse. Resection of the aberrant chord and correction of the AMVL using synthetic Gore-Tex sutures was performed. The patient made an uneventful recovery with post-op echocardiography demonstrating normal mitral valve function.

The value, qualification, and regulatory use of surrogate end points in drug development.

The acceptance and use of either surrogate end points (SEPs) or efficient clinical end points are associated with greater and more rapid availability of new medicines as compared with disease situations for which clinical end points are inefficient or no surrogates exist. This review of the history of the development, qualification, and acceptance of key SEPs shows that both successes and failures had three key characteristics: (i) apparent biologic plausibility, (ii) prognostic value for the outcome of the disease, and (iii) an association between changes in the SEP and changes in outcome with therapeutic intervention--the three factors recommended for SEPs in the International Conference on Harmonisation's "Statistical Principles for Clinical Trials." We recommend that only prognostic value be an absolute prerequisite for surrogacy, because therapeutic interventions may not exist a priori, and biological plausibility can be subjective. Ideally, all three of these factors would be traded off against one another in a consistent and transparent risk-management process.

Occlusion of internal mammary grafts: a review of the potential causative factors.

The outcome of patient undergoing CABG is largely dependant on the long-term patency of the conduit used. Internal mammary artery (IMA) is considered whenever possible due to its improved long-term functionality over saphenous vein graft. However, a 10% rate of late arterial closure is described without well-known predictors. Chronic competition induced by a moderate coronary lesion on the bypassed native vessel is thought to be a major factor of arterial graft shrinkage even if conflicting data are reported in the available literature. Therefore, the decision to use an IMA to bypass a moderate native coronary lesion should be carefully weighted. When angiography is doubtful, more accurate functional investigations should be considered. Among them, pressure-derived fractional flow reserve could give an immediate answer of whether an intermediate lesion should be bypassed.

Impaired endothelial regulation of ventricular relaxation in cardiac hypertrophy: role of reactive oxygen species and NADPH oxidase.

BACKGROUND: Endothelium-derived nitric oxide (NO) selectively enhances myocardial relaxation. In experimental left ventricular hypertrophy (LVH), this endothelium-dependent LV relaxant response is impaired despite a preserved response to exogenous NO. We investigated the potential role of reactive oxygen species (ROS) in this defect. METHODS AND RESULTS: Short-term treatment with the antioxidants vitamin C (10 micromol/L) or deferoxamine (500 micromol/L) restored LV relaxant responses to the NO agonists bradykinin (10 nmol/L) and substance P (100 nmol/L) in isolated ejecting hearts of aortic-banded guinea pigs. Substance P decreased the time to onset of LV relaxation (tdP/dt(min)) by -6.8+/-1.7 ms in the presence of vitamin C and by -8.9+/-2.2 ms in the presence of deferoxamine compared with -0.8+/-2.2 ms in the absence of antioxidants (P<0.05 either antioxidant versus control). A similar restoration of relaxant response to substance P was observed in the presence of the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (10 micromol/L), but not with tetrahydrobiopterin or L-arginine. Protein expression of the NADPH oxidase subunits gp91-phox and p67-phox and myocardial NADPH oxidase activity were significantly increased (P<0.05) in the banded group compared with shams. CONCLUSIONS: An increase in ROS, most likely derived at least in part from NADPH oxidase, is responsible for the impaired endothelial regulation of LV relaxation in LVH. These are the first data to potentially link increased NADPH oxidase-derived ROS with a defect in cardiac contractile function in a pathological setting.

Effects of nitric oxide synthase inhibition on Basal function and the force-frequency relationship in the normal and failing human heart in vivo.

BACKGROUND: Nitric oxide (NO) exerts autocrine/paracrine effects on cardiac function, including alterations of the inotropic state. In vitro studies suggest that NO modulates the myocardial force-frequency relationship. Basal left ventricular (LV) contractility is depressed and the force-frequency relationship is blunted in human heart failure, and it is speculated that an increase in NO production is involved. METHODS AND RESULTS: We compared the effects of intracoronary NO synthase inhibition with N(G)-monomethyl-L-arginine (L-NMMA; 25 micromol/min) on basal LV function and the response to incremental atrial pacing in patients with dilated cardiomyopathy (n=11; mean age, 51 years) and in control subjects with atypical chest pain and normal cardiac function (n=7; mean age, 54 years). In controls, L-NMMA significantly reduced basal LV dP/dt(max) (from 1826 to 1578 mm Hg/s; P<0.002), but had no effect on heart rate, mean aortic pressure, or right atrial pressure. Pacing-induced increases in LV dP/dt(max) were unaltered by L-NMMA. In patients with dilated cardiomyopathy, L-NMMA had no effect on baseline LV dP/dt(max) (from 1313 to 1337 mm Hg/s; P=NS). The blunted pacing-induced rise in LV dP/dt(max) in these patients was unaltered by L-NMMA. CONCLUSION: Endogenous NO has a small baseline positive inotropic effect in the normal human heart, which is lost in heart failure patients. NO does not significantly influence the force-frequency relationship in either the normal or failing human heart in vivo. Because this study was performed in patients with moderate heart failure, whether the findings apply to subjects with more severe heart failure requires further investigation.

Divergent biological actions of coronary endothelial nitric oxide during progression of cardiac hypertrophy.

Coronary endothelial NO synthase expression and NO bioactivity were investigated at sequential stages during the progression of left ventricular hypertrophy. Male guinea pigs underwent abdominal aortic banding or sham operation. Left ventricular contractile function was quantified in isolated ejecting hearts. Coronary endothelial and vasodilator function were assessed in isolated isovolumic hearts in response to boluses of bradykinin (0.001 to 10 micromol/L), substance P (0.01 to 100 micromol/L), diethylamine NONOate (DEA-NO) (0.1 to 1000 micromol/L), N(G)-monomethyl-L-arginine monoacetate (L-NMMA) (10 mmol/L), and adenosine (10 mmol/L). At a stage of compensated left ventricular hypertrophy (3 weeks), left ventricular endothelial NO synthase protein expression was unaltered (Western blot and immunocytochemistry). Vasoconstriction in response to L-NMMA was increased in banded animals compared with sham-operated animals (13.8+/-2.1% versus 6.2+/-1.3%, n=10; P<0.05), but agonist- and DEA-NO-induced vasodilation was similar in the 2 groups. At a stage of decompensated left ventricular hypertrophy (8 to 10 weeks), left ventricular endothelial NO synthase protein expression was significantly lower in banded animals (on Western analysis: banded animals, 7.8+/-0.4 densitometric units; sham-operated animals, 12.2+/-1.7 densitometric units; n=5; P<0.05). At this time point, vasoconstriction in response to L-NMMA was similar in the 2 groups, but vasodilatation in response to bradykinin (30.9+/-2.4% versus 39.7+/-2.2%, n=10; P<0.05), DEA-NO (26.2+/-1.8% versus 34.6+/-1.8%, n=10; P<0.05), and adenosine (24.3+/-2.0% versus 35.7+/-2.0%, n=10; P<0.01) was attenuated in banded animals. These findings indicate that there is an increase in the basal activity of NO (without a significant change in endothelial NO synthase expression) in early compensated left ventricular hypertrophy, followed by a decrease in both endothelial NO synthase expression and NO bioactivity during the transition to myocardial failure.

The physiological role of endogenous endothelin in the regulation of human coronary vasomotor tone.

OBJECTIVES: The study was done to investigate the physiological role of endogenous endothelin-1 in the human coronary circulation by studying the effect of an intracoronary infusion of the specific endothelin receptor subtype A (ETA) receptor antagonist BQ123 on coronary vasomotor tone. BACKGROUND: Endothelin-1 contributes to the maintenance of peripheral vascular tone in humans. However, its physiological role in the human coronary vasculature is unknown. METHODS: We studied 12 patients (mean age 54.7 +/- 2.5 years, 3 men) undergoing cardiac catheterization for investigation of atypical chest pain, with angiographically normal coronary arteries. Coronary artery cross-sectional area was measured with digital quantitative coronary angiography, and coronary blood flow was assessed with an intracoronary Doppler flow wire. Flow-mediated (adenosine, 18 microg) and agonist-mediated (substance P, 20 pmol/min for 2 min) endothelial responses were measured prior to study. BQ123 (40 nmol/min for 15 min and monitored for a further 15 min) was infused into the left coronary artery. RESULTS: The BQ123 caused significant dilation of the proximal (artery cross-sectional area: 8.08 +/- 0.9 to 8.88 +/- 0.9 mm2; p < 0.05), mid (5.32 +/- 0.8 to 6.49 +/- 0.8 mm2; p < 0.001) and distal study vessel (2.11 +/- 0.2 to 2.50 +/- 0.2 mm2; p < 0.05). There was an increase in coronary blood flow (26.8 +/- 2.8 to 32.8 +/- 3.4 ml/min; p < 0.001) but no change in systemic hemodynamics. Baseline flow- or substance P-induced epicardial vasodilation did not correlate with the degree of vasodilation induced by BQ123. CONCLUSIONS: These data uncover a role of endogenous endothelin-1 in the maintenance of basal vasomotor tone in patients with angiographically normal coronary arteries.

Impaired endothelium-dependent regulation of ventricular relaxation in pressure-overload cardiac hypertrophy.

BACKGROUND: Endothelium-derived nitric oxide (NO) selectively enhances myocardial relaxation and may benefit diastolic function. Left ventricular hypertrophy (LVH) is characterized by abnormal myocardial relaxation and endothelial dysfunction. We investigated endothelium-dependent regulation of LV relaxation in moderate pressure-overload LVH induced by aortic banding in guinea pigs. METHODS AND RESULTS: Isolated ejecting hearts of banded or sham-operated animals (shams) were studied. The specific agonists for endothelial release of NO, bradykinin (10 nmol/L), and substance P (100 nmol/L) both induced earlier onset of LV relaxation in shams (time to LV dP/dt(min) [tdP/dt(min)], -13.4+/-3.0 and -10.4+/-2.5 ms, respectively) without altering peak LV pressure or LV dP/dt(max). Neither agent altered tdP/dt(min) in banded animals. The ACE inhibitor captopril (1 micromol/L) also selectively reduced tdP/dt(min) in shams via a bradykinin/NO-dependent mechanism but had no effect in banded animals. An exogenous NO donor, sodium nitroprusside (0.1 micromol/L), selectively reduced tdP/dt(min) to a similar extent in both shams and banded animals. Endothelial-type NO synthase (eNOS) protein expression in whole LV homogenate was unaltered in banded animals. CONCLUSIONS: Endothelium-dependent enhancement of LV relaxation is impaired in moderate pressure-overload LVH, despite a preserved response to exogenous NO. This is not accounted for by altered eNOS expression. These abnormalities may contribute to diastolic dysfunction in LVH.

Paracrine and autocrine effects of nitric oxide on myocardial function.

Complex paracrine interactions exist between endothelial cells and cardiac myocytes in the heart. Cardiac endothelial cells release (or metabolize) several diffusible agents (e.g., nitric oxide [NO], endothelin-1, angiotensin II, adenylpurines) that exert direct effects on myocyte function, independent of changes in coronary flow. Some of these mediators are also generated by cardiac myocytes, often under pathological conditions. This review focuses on the role of NO in this paracrine/autocrine pathway. NO modulates several aspects of "physiological" myocardial function (e.g., excitation-contraction coupling; myocardial relaxation; diastolic function; the Frank-Starling response; heart rate; beta-adrenergic inotropic response; and myocardial energetics and substrate metabolism). The effects of NO are influenced by its cellular and enzymatic source, the amount generated, the presence of reactive oxygen species, interactions with neurohumoral and other stimuli, and the relative activation of cyclic GMP-dependent and -independent signal transduction pathways. The relative physiological importance of endothelium- and myocyte-derived NO remains to be established. In pathological situations (e.g., ischemia-reperfusion, left ventricular hypertrophy, heart failure, transplant vasculopathy and rejection, myocarditis), NO can potentially exert beneficial or deleterious effects. Beneficial effects of NO can result from endothelial-type nitric oxide synthase-derived NO or from spatially and temporally restricted expression of the inducible isoform, inducible-type nitric oxide synthase. Deleterious effects may result from (1) deficiency of NO or (2) excessive production, often inducible-type nitric oxide synthase-derived and usually with concurrent reactive oxygen species production and peroxynitrite formation. The balance between beneficial and deleterious effects of NO is of key importance with respect to its pathophysiological role.

Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart: studies with an intracoronary ET(A) receptor antagonist.

BACKGROUND: Endothelin-1 (ET-1) is a potent positive inotrope in vitro, but its physiological effects on intrinsic myocardial contractile function in humans in vivo are unknown. Plasma ET-1 levels are elevated in heart failure, and ET-1 may be involved in the pathophysiology of this condition. However, its effects on contractile function of the failing human heart are also unknown. METHODS AND RESULTS: A specific ET(A) receptor antagonist, BQ123, was infused (40 nmol/min, 16 minutes) into the left coronary artery in 8 patients with atypical chest pain (normal left ventricular ¿LV function and coronary arteries) and 8 patients with nonischemic dilated cardiomyopathy (DCM) who were undergoing diagnostic catheterization. In normal subjects, BQ123 rapidly induced a significant reduction in LV dP/dt(max) (-270+/-71 mm Hg/s after 16 minutes; P<0.05) and in LV dP/dt at a developed pressure of 40 mm Hg (LV dP/dt(40)) (-179+/-54 mm Hg/s; P<0.05). In DCM patients, however, BQ123 caused no reductions in LV dP/dt(max) (62+/-49 mm Hg/s after 16 minutes) or LV dP/dt(40) (83+/-51 mm Hg/s;P<0.05 compared with normal subjects). BQ123 had no effect on heart rate, LV relaxation, LV end-diastolic pressure, right atrial pressure, or pulmonary pressure in either patient group. CONCLUSIONS: Endogenous ET-1 has a tonic positive inotropic effect in normal subjects, independent of effects on the peripheral vasculature and unmasked by inhibition of ET(A) receptors. However, the effect of short-term ET(A) blockade in DCM patients was opposite to that in normal subjects, which suggests that ET-1 may cause negative inotropic effects in the failing heart.

ATP is involved in myocardial and vascular effects of exogenous bradykinin in ejecting guinea pig heart.

It has recently been reported that bradykinin induces selective left ventricular (LV) relaxation in isolated guinea pig hearts via the release of nitric oxide. Exogenous bradykinin also induces vasodilation, which is only partly due to nitric oxide release. In the present study we investigated the role of adenyl purines on these bradykinin-induced effects. Isolated ejecting guinea pig hearts were studied. LV pressure was monitored by a 2-Fr micromanometer-tipped catheter. ATP concentrations were measured using a luciferin-luciferase assay. Bradykinin (1 and 100 nM) caused a progressive acceleration of LV relaxation together with a transient increase in coronary flow. These effects were inhibited by the nonselective P(2) purinoceptor antagonist suramin (1 microM, n = 6) but were unaffected by the selective P(2x) purinoceptor antagonist pyridoxal phosphate 6-azophenyl-2',4'-disulfonic acid (1 microM, n = 6). These myocardial and vascular effects of bradykinin were associated with increased ATP levels in coronary effluent. These data suggest that the selective enhancement of LV relaxation and rise in coronary flow induced by exogenous bradykinin involve endogenous ATP and the subsequent stimulation of P(2) purinoceptors.

Myocardial bradykinin production during coronary balloon angioplasty in humans.

BACKGROUND: Recent studies have implicated the peptide bradykinin as a potential trigger of ischaemic preconditioning, the phenomenon whereby a brief episode of myocardial ischaemia induces an increased tolerance to subsequent more prolonged ischaemia. Brief myocardial ischaemia occurring during percutaneous transluminal coronary balloon angioplasty in humans is reported to be capable of inducing preconditioning. DESIGN: We studied the intracardiac production of bradykinin in eight patients (seven men, mean age 53.5 years) undergoing elective percutaneous transluminal coronary angioplasty for a single left anterior descending coronary artery stenosis. Paired blood samples were obtained from the coronary sinus and the proximal aorta at baseline, immediately before balloon deflation after a 2-min inflation, and at 1, 3 and 5 min post deflation. Bradykinin levels were measured by radioimmunoassay. RESULTS: There was no significant change either in aortic or coronary sinus bradykinin levels at any time point. CONCLUSIONS: Intracardiac production of bradykinin is unlikely to be a trigger for ischaemic preconditioning after brief myocardial ischaemia in humans.

Nitric oxide enhances the inotropic response to beta-adrenergic stimulation in the isolated guinea-pig heart.

Nitric oxide (NO) exerts several effects on myocardial contraction, including enhancement of relaxation and diastolic function, modulation of beta-adrenergic inotropic responses, and inotropic effects in the absence of agonist pre-stimulation. Different effects have been observed in different species and preparations, and it is unclear whether they are species- or preparation-specific, or whether they represent a range of responses that can manifest in most mammalian species. We therefore examined the effects of NO on the inotropic response to beta-adrenergic stimulation in the isolated guinea-pig heart, a species in which we have previously shown that NO enhances basal left ventricular (LV) relaxation and modulates the Frank-Starling response. Isolated ejecting hearts were perfused with Krebs buffer at constant placed heart rate (1 microM) indomethacin, 37 degrees C, constant loading conditions), and high fidelity LV pressure was monitored by an apical 2 F Millar catheter. All hearts were initially treated with dobutamine (0.1 microM) and then, once the peak inotropic and chronotropic response had been established, with either (a) no further treatment (n = 6), (b) the NO donor sodium nitroprusside (1 microM, n = 6; 10 microM, n = 6), or (c) the specific agonist for NO release, substance P (0.1 microM, n = 6). Dobutamine (0.1 microM) produced a rapid positive inotropic and chronotropic response, associated with a fall in LV end-diastolic pressure (LVEDP) and a rise in coronary flow. The positive inotropic effect of dobutamine declined over 20-28 minutes, while the chronotropic response persisted over this period. Low dose sodium nitroprusside (1 microM) delayed the decline in the inotropic response to dobutamine and exaggerated the fall in LVEDP. Similar effects were observed with substance P (0.1 microM). In contrast, a higher dose of sodium nitroprusside (10 microM) did not alter the response to dobutamine. These data indicate that "low dose" NO augments the inotropic response to beta-adrenergic stimulation in the isolated ejecting guinea-pig heart, in addition to its previously reported effects on basal LV relaxation in the same preparation.