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.

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.

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.

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.

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.

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.

Excess sucrose and glucose ingestion acutely elevate blood pressure in spontaneously hypertensive rats.

Spontaneously hypertensive rats (SHR) were fed 6 different diets. The baseline diet (I) derived equal calories from sucrose, proteins, and fats. Three other diets (II, III, VI) derived the majority of calories from refined CHO, sucrose or glucose, with decreases in calories from proteins or fats. The last two diets (IV, V) were relatively low in sucrose with a higher percentage of the total calories from proteins and fats, respectively. From 3 to 15 weeks on the diets, the highest average BP was in rats consuming high concentrations of sucrose or glucose (II, III, VI). Urinary excretory rates of norepinephrine (NE) at 5, 10 and 15 weeks and epinephrine at 5 and 10 weeks were significantly elevated in rats ingesting diets high in refined CHO, and NE positively correlated with blood pressure (BP) at 5 and 10 weeks of the study. At the end of the study, serum insulin levels were not different, but plasma renin and serum glucagon levels were lower in SHR consuming the diets with high CHO concentrations. We conclude that equally elevated BP are seen with relatively high intakes of either sucrose or glucose, whether the balance of calories is derived from lessening fat or protein. This is secondary, at least in part, to alterations in NE metabolism.

Prospective randomized trial of single clamp technique versus intermittent ischaemic arrest: myocardial and neurological outcome.

OBJECTIVE: To explore the hypothesis that intermittent ischaemic arrest (IIA) provides better myocardial preservation but generates a larger number of cerebral microemboli (ME) and consequently a higher incidence of post-operative cerebral dysfunction compared with the single clamp technique (SCT). METHODS: Ninety-one patients with stable angina undergoing elective CABG with no clinical evidence of aortic or cerebro-vascular or neurological disease were prospectively randomized to: IIA (n = 43) or SCT with intermittent anterograde cold blood cardioplegia (n = 48). Myocardial preservation was assessed by measuring serum CK-MB, Troponin-T (TnT) and Troponin-I (TnI) and from pre- and post-operative ECGs and left ventricular (LV) function by echocardiography. Intra-operative cerebral ME were counted by transcranial Doppler of the right middle cerebral artery. All patients completed the Luria Nebraska Neuropsychological Battery (LNNB) tests for motor, visual, reading, memory and intellectual processes the day before surgery and at 1 week and 6 months post-operatively. Serum levels of the neuro-specific protein S-100 were measured. RESULTS: The two groups were comparable for age, sex, extent of coronary disease, previous myocardial infarction, diabetes, hypertension and number of arterial and venous grafts. The median number of ME detected per patient was 34 (range 4-208) and was similar in both groups. Protein S-100 levels remained normal and similar in both groups at all times except in one patient with SCT who had an operative stroke. LNNB scores were similarly depressed at 1 week and recovered in all cases at 6 months. There was no correlation between the number of ME and LNNB scores. Median peak TnI levels were 0.64 microg/l with IIA vs. 0.87 microg/l with SCT (P = NS) and TnT 0.8 microg/l vs. 1.08 microg/l (P < 0.03). SCT was however associated with longer mean ischaemic (67.6 +/- 16.1 vs. 34.5 +/- 16.5 min, P < 0.001) and mean bypass time (88.5 +/- 18.2 vs. 74.6 +/- 26.3 min, P < 0.004) than IIA. Four patients with SCT and none with IIA had ECG changes suggestive of MI (P = 0.04). CONCLUSION: During elective CABG in patients with no clinical evidence of aortic or cerebro-vascular disease the incidence of peri-operative ME and post-operative neuropsychological disturbances are comparable with both techniques of myocardial preservation. Biochemical analysis suggests that IIA provides more effective myocardial preservation.

A discussion of Schubert's ion-exchange equations.

A discrepancy which exists in the literature, concerning the derivation of Schubert's ion-exchange equations, is resolved.

The arterial basis of pharyngeal flaps.

The arterial basis of pharyngeal flaps is unknown. Injection and dissection studies have been used in 41 adult human cadavers to study the arterial supply of pharyngoplasties in current use. Superiorly based posterior pharyngeal flaps are "random" in nature, inferiorly based posterior pharyngeal flaps may include an "axial" vessel, laterally based posterior pharyngeal flaps will include an "axial" vessel, and laterally based "sphincter" pharyngoplasties, although supplied segmentally, will contain an "axial" vessel if raised up to but not beyond the upper pole of the tonsil.

The arterial supply of the palate: implications for closure of cleft palates.

Little is known of the arterial anatomy of the palate. Injection studies and dissection of a total of 49 cadavers have shown the principal arterial supply of the soft palate to be the ascending pharyngeal artery, which anastomoses with the greater palatine artery at the junction of the hard and soft palates. The position and relations of the branches of the ascending palatine artery put it at risk during palate repair.

Implications of a selective policy in the management of spina bifida.

Of 307 patients with myelomeningocele 132 were treated nonoperatively during the 6 yr period from 1973 to 1978. Of the nonoperatively managed patients, 86% died within 1 yr. The policy of nonoperative management was changed to one of active intervention in 25% of the infants. Despite this a large number died.

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.

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 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.

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.