Transcatheter Aortic Valve Implantation - Yesterday, Today and Tomorrow.

Since the first transcatheter aortic valve implantation (TAVI) was performed by Alain Cribier and colleagues in 2002 [1], the technology has garnered global support with more than 200,000 devices implanted. The rapid adoption of this technology has been driven by the need for a less invasive treatment modality in a cohort of patients often denied conventional surgical valve replacement due to an unacceptably high perioperative risk, whether real or perceived [2]. This, together with evidence that the technology confers morbidity and mortality advantages compared to medical therapy [3,4] and at least equivalent outcomes to surgical valve replacement [5,6] in select cohorts, has seen clinical approval in more than 50 countries. The last 13 years has seen an evolution of practises and equipment affecting almost every aspect of the TAVI procedure from pre-procedural assessment to device design and post-procedural care. The almost exponential rate of change has both benefits and risks. Benefits, in that impactful changes are translated into clinical practice very rapidly, but risks, in that meaningful comparative research studies potentially lag behind and can be outmoded by the time they are published. This instability may in turn delay regulatory review and approval processes that are based on such studies. The aim of this review is to provide an overview of the evolution of TAVI, its current clinical position and likely future directions.

The morning blood pressure surge is related to serum cholesterol.

A morning blood pressure surge (MBPS) may be either a mechanism for, or a marker of, increased cardiovascular events. This study has examined factors which may influence the morning surge: age, gender, metabolic factors, sympathetic function, blood pressure and arterial stiffness. Four measures of the MBPS were examined--sleep-trough surge, pre-awake surge, rate of blood pressure rise and a Power function. Subjects underwent ambulatory blood pressure monitoring, glucose tolerance test, central pulse wave velocity, sympathetic autonomic function tests (mental stress and sustained handgrip). MBPS was associated with age, hypertension, blood pressure variability and serum lipids. After adjustment for age and waist circumference, all four measures of MBPS remained positively associated with low-density lipoprotein (LDL) cholesterol. The novel finding of a significant relationship between measures of MBPS and LDL-cholesterol is an intriguing link between two major cardiovascular risk factors.

The relationship between aortic stiffness and changes in retinal microvessels among Asian ischemic stroke patients.

Large-artery stiffness is a risk factor for stroke, including cerebral small-vessel disease. Retinal microvascular changes are thought to mirror those in cerebral microvessels. We investigated the relationship between aortic stiffness and retinal microvascular changes in Asian ischemic stroke patients. We studied 145 acute ischemic stroke patients in Singapore who had aortic stiffness measurements using carotid-femoral pulse wave velocity (cPWV). Retinal photographs were assessed for retinal microvessel caliber and qualitative signs of focal arteriolar narrowing, arteriovenous nicking and enhanced arteriolar light reflex. Aortic stiffening was associated with retinal arteriolar changes. Retinal arteriolar caliber decreased with increasing cPWV (r=-0.207, P=0.014). After adjusting for age, gender, hypertension, diabetes, mean arterial pressure and small-vessel stroke subtype, patients within the highest cPWV quartile were more likely to have generalized retinal arteriolar narrowing defined as lowest caliber tertile (odds ratio (OR) 6.84, 95% confidence interval (CI) 1.45-32.30), focal arteriolar narrowing (OR 13.85, CI 1.82-105.67), arteriovenous nicking (OR 5.08, CI 1.12-23.00) and enhanced arteriolar light reflex (OR 3.83, CI 0.89-16.48), compared with those within the lowest quartile. In ischemic stroke patients, aortic stiffening is associated with retinal arteriolar luminal narrowing as well as features of retinal arteriolosclerosis.

Retinal ependymoma: an immunohistologic and ultrastructural study.

Glial tumors of the retina are rare. Most are syndrome associated and include pilocytic astrocytoma in neurofibromatosis type 1 and subependymal giant cell astrocytoma in tuberous sclerosis complex. Acquired, more conventional, diffuse astrocytomas are less frequent. Ependymoma is exquisitely rare. Herein, we report the clinicopathologic features of the second case of retinal ependymoma. The tumor was sporadic in occurrence and unilateral, low grade, and of cellular type. Its chronic course and large size prompted an initial pathologic diagnosis of "massive retinal gliosis." The literature regarding retinal glial neoplasia including ependymoma as well as the so-called massive retinal gliosis is discussed.

Histologic studies of the intraocular toxicity of imatinib mesylate in rabbits.

PURPOSE: To evaluate histologic signs of toxicity of the protein tyrosine kinase inhibitor, imatinib mesylate, in rabbit eyes. METHODS: Twenty Dutch-belted rabbits underwent intravitreal injections of 0.1 ml solutions of imatinib mesylate. Ten rabbits were killed and enucleated 1 week after injection of imatinib mesylate (1.65 mg (four eyes), 165 microg (four eyes), and 16.5 microg (two eyes)). Ten rabbits injected with imatinib mesylate (165 microg (five eyes) and 825 microg (five eyes)) were enucleated 1 month later. Eyes were fixed in 10% formalin and stained with haematoxylin and eosin for microscopic examination. RESULTS: All four eyes injected with 1.65 mg of imatinib mesylate and enucleated at 1 week demonstrated ocular toxicity. All four eyes injected with 165 microg and enucleated at 1 week showed no ocular toxicity. One of the two eyes injected with 16.5 microg and enucleated at 1 week revealed focal areas of subretinal fluid and retinal undulations, suggestive of retinal oedema. None of the 10 eyes injected with imatinib mesylate at either the 165 or 825 microg dose and enucleated at 1 month showed ocular toxicity. CONCLUSIONS: Imatinib mesylate at 1.65 mg caused extensive retinal toxicity in rabbit eyes. In contrast, lower doses did not appear to cause toxicity, but may be associated with retinal oedema.

Intraocular use of rituximab.

PURPOSE: To evaluate the toxicity of 1 mg of intraocular rituximab and to present a small case-series of patients treated with intravitreal rituximab. METHODS: Rituximab (1 mg/0.1 ml) was injected in the vitreous of one eye of three Dutch-belted rabbits. Two animals were injected with balanced salt solution as controls. At 1 month the rabbits were killed and the eyes examined by light microscopy. Three patients (five eyes) with intraocular lymphoma were also treated with a 1 mg injection of rituximab. RESULTS: The treated rabbit eyes and the control eyes showed no light microscopic evidence of ocular toxicity at 1 month following injection. The five human eyes of three patients have shown no evidence of intraocular toxicity with a median follow-up time of 3.6 months (range 2.0-6.4 months). One patient received a total of four injections in the right eye and three injections in the left eye. CONCLUSION: Intravitreal rituximab at a dose of 1 mg does not appear to cause toxicity in rabbit eyes and in the five eyes of three patients.

The use of 31-gauge needles and syringes for intraocular injections.

PURPOSE: To describe the use of disposable 31-gauge needles for intraocular injections. METHODS: Description of the technique and photographs of the needles. RESULTS: Patients feel the injection less and a smaller postinjection bleb is noted. CONCLUSION: Consideration should be given to the use of disposable 31-gauge needles or syringes for intraocular injections.

Is venous reflux a common disease in post-thrombotic patients with unilateral deep vein thrombosis episode?

OBJECTIVES: To investigate reflux development and changes in resting venous diameters in the DVT and the non-DVT lower limbs. METHODS: Twenty subjects (40 limbs) with acute unilateral proximal DVT diagnosed by ultrasound, who were treated with low-molecular-weight-heparin (LMWH), followed by at least three months of oral warfarin therapy, were enrolled in the study. The limbs were classified according to CEAP (clinical, aetiologic, anatomic, pathophysiology) clinical classification on a scale of 0-6. Duplex ultrasound (DUS) was employed to assess DVT resolution, vein diameter and venous reflux in both limbs at intervals of zero, three, six and 12 months. Venous reflux was defined as a valve closure time more than 1 s. RESULTS: There were 13 men and seven women, average age was 40.8 years and average body mass index 27.7 kg/m2. In the DVT limbs at three, six and 12 months, deep veins were non-occluded in 40%, 60% and 85%, respectively. By 12 months, 16 (80%) had developed venous reflux, mostly in the femoral (FV) and popliteal veins (PV); eight limbs (40%) were in clinical classes 4-6. In the contralateral 20 non-DVT limbs, four limbs developed borderline reflux at the sapheno-femoral junction (SFJ) after six months and mean diameters of SFJ, FV and PV increased significantly. CONCLUSIONS: Venous reflux is highly likely to occur in DVT limbs within a year follow-up period. Venous dilatation can occur in the contralateral unaffected lower limb, consistent with a systemic effect. Our results are suggestive and further studies are needed.

Genetic modification of human trabecular meshwork with lentiviral vectors.

Glaucoma, a group of optic neuropathies, is the leading cause of irreversible blindness. Neuronal apoptosis in glaucoma is primarily associated with high intraocular pressure caused by chronically impaired outflow of aqueous humor through the trabecular meshwork, a reticulum of mitotically inactive endothelial-like cells located in the angle of the anterior chamber. Anatomic, genetic, and expression profiling data suggest the possibility of using gene transfer to treat glaucomatous intraocular pressure dysregulation, but this approach will require stable genetic modification of the differentiated aqueous outflow tract. We injected transducing unit-normalized preparations of either of two lentiviral vectors or an oncoretroviral vector as a single bolus into the aqueous circulation of cultured human donor eyes, under perfusion conditions that mimicked natural anterior chamber flow and maintained viability ex vivo. Reporter gene expression was assessed in trabecular meshwork from 3 to 16 days after infusion of 1.0 x 10(8) transducing units of each vector. The oncoretroviral vector failed to transduce the trabecular meshwork. In contrast, feline immunodeficiency virus and human immunodeficiency virus vectors produced efficient, localized transduction of the trabecular meshwork in situ. The results demonstrate that lentiviral vectors permit efficient genetic modification of the human trabecular meshwork when delivered via the afferent aqueous circulation, a clinically accessible route. In addition, controlled comparisons in this study establish that feline and human immunodeficiency virus vectors are equivalently efficacious in delivering genes to this terminally differentiated human tissue.

Gender differences in the timing of arterial wave reflection beyond differences in body height.

OBJECTIVES: The timing of arterial wave reflection affects the shape of the arterial waveform and thus is a major determinant of pulse pressure. This study assessed differences in wave reflection between genders beyond the effect of body height. METHODS: From 1123 elderly (aged 71 +/- 5 years) currently untreated hypertensives, we selected 104 pairs of men and women with identical body height (average 164 +/- 4 cm). All subjects underwent echocardiography, including measurement of aortic arch expansion, automated blood pressure measurements, measurement of ascending aortic blood flow and simultaneous carotid artery tonometry. RESULTS: Women had higher pulse (80 +/- 17 versus 74 +/- 17 mmHg, P < 0.05) and lower diastolic pressure (79 +/- 11 versus 82 +/- 10 mmHg, P < 0.05). Whilst heart rate was similar, women had a longer time to the systolic peak (210 +/- 28 versus 199 +/- 34 ms, P < 0.01) and a longer ejection time (304 +/- 21 versus 299 +/- 25 ms, P < 0.001). Wave reflection occurred earlier in women (time between maxima 116 +/- 55 versus 132 +/- 47 ms, P < 0.05) and augmentation index was higher (36 +/- 11 versus 28 +/- 12%, P < 0.001). Aortic diameter was smaller in women and the aortic arch was stiffer (median Ep 386 versus 302 kN/m2, P < 0.05). Hence, systemic arterial compliance was less in women (0.8 +/- 0.2 versus 1.0 +/- 0.3 ml/mmHg). CONCLUSIONS: We conclude that elderly hypertensive men and women have a different timing of both left ventricular ejection and arterial wave reflection when both genders are matched for body height. Women have smaller and stiffer blood vessels resulting in an earlier return of the reflected wave, which is likely due to an increased pulse wave velocity in women.

Women exhibit a greater age-related increase in proximal aortic stiffness than men.

BACKGROUND: Large artery mechanical properties are a major determinant of pulse pressure and cardiovascular outcome. Sex differences in these properties may underlie the variation in cardiovascular risk profile between men and women, in relation to age. OBJECTIVE: To investigate sex differences in the age-related stiffening of large arteries. DESIGN: Cross-sectional. METHODS: One hundred and twenty healthy men and women were recruited and divided equally into tertiles by age: young (mean +/- SD, 23 +/- 5 years), middle-age (47 +/- 3 years) and older (62 +/- 7 years). Lipids, mean arterial pressure and heart rate were matched within each tertile. Carotid tonometry and Doppler velocimetry were used to measure indices of large artery stiffness. RESULTS: There was no sex difference in systemic arterial compliance (SAC) in the young group (mean +/- SEM, 0.61 +/- 0.05 arbitrary compliance units (ACU) in women compared with 0.67 +/- 0.04 ACU in men), but in the older population women had lower SAC than men (0.27 +/- 0.03 ACU compared with 0.57 +/- 0.04 ACU respectively; P < 0.001). Measures independent of aortic geometry (distensibility index and aortic impedance) indicated that stiffness was lower in young women than in men (P < 0.05), but the reverse was true in the older population (P < 0.01). This paralleled the brachial and carotid pulse pressures, which were lower in young (P < 0.01) and higher in older women compared with those in men (P < 0.05). Follicle stimulating hormone concentrations correlated strongly (r values 0.39-0.65) with all indices of central, but not peripheral, arterial function, whereas concentrations of luteinizing hormone, progesterone and oestradiol correlated less strongly. CONCLUSIONS: In men and women matched for mean pressures, the age-related stiffening of large arteries is more pronounced in women, which is consistent with changes in female hormonal status.

Carotid pressure is a better predictor of coronary artery disease severity than brachial pressure.

The mechanisms relating pulse pressure to cardiovascular outcome may include surrogacy for coronary disease severity. Although pulse pressure is typically measured at the brachial artery, central pulse pressure and its principal determinant, large-artery stiffness, may relate more closely to disease severity. This study aimed to determine the relationships between large-artery stiffness and carotid and brachial blood pressures and coronary artery disease severity. One hundred fourteen male patients with coronary artery disease (age 60+/-8 years, mean+/-SD) and 57 age-matched healthy male controls (age 59+/-9 years) were recruited. Patients were classified into 2 groups based on the magnitude of their maximum coronary stenosis: moderate (50% to 89%) and severe (>/=90%). Large-artery stiffness was assessed as systemic arterial compliance and carotid-femoral pulse wave velocity. Mean pressure was not different between the 3 groups. Systemic compliance and carotid pulse pressure were significantly different between all 3 groups, with compliance lowest and pressure highest in the severe group (P<0.05). Pulse wave velocity was higher in patients with severe stenosis than in those with moderate stenosis (P<0.01) and those in the control group (P<0.001). Brachial pulse pressure was higher in patients than in controls (P<0.05), but there was no difference between the 2 disease groups. In separate multivariate analyses, carotid pressures and systemic arterial compliance were determinants of coronary artery disease severity, independent of age, smoking status, body mass index, mean arterial pressure, heart rate, cholesterol levels (total, LDL, and HDL), triglycerides, and beta-antagonist and lipid-lowering therapy (P<0.001), whereas brachial pressures and pulse wave velocity were not. In conclusion, central blood pressures and systemic arterial compliance are more sensitive markers of coronary artery disease severity than brachial pressures.

Aerobic exercise training does not modify large-artery compliance in isolated systolic hypertension.

The present study characterized large-artery properties in patients with isolated systolic hypertension (ISH) and determined the efficacy of exercise training in modifying these properties. Twenty patients (10 male and 10 female) with stage I ISH and 20 age- and gender-matched control subjects were recruited, and large-artery properties were assessed noninvasively. Ten ISH patients (5 male and 5 female) were enrolled in a randomized crossover study comparing 8 weeks of moderate intensity cycling with 8 weeks of sedentary activity. Brachial and carotid systolic, diastolic, mean, and pulse pressures were higher in the ISH group than in the control group. Systemic arterial compliance (0.43+/-0.04 versus 0.29+/-0.02 arbitrary compliance units for the control versus ISH groups, respectively; P=0.01) was lower, and carotid-to-femoral pulse-wave velocity (9.67+/-0.36 versus 11.43+/-0.51 m. s(-1) for the control versus ISH groups, respectively; P=0.007), input impedance (2.39+/-0.19 versus 3.27+/-0.34 mm Hg. s. cm(-1) for the control versus ISH groups, respectively; P=0.04), and characteristic impedance (1.67+/-0.17 versus 2.34+/-0.27 mm Hg. s. cm(-1) for the control versus ISH groups, respectively; P=0.05) were higher in the ISH group than in the control group. Training increased maximal oxygen consumption by 13+/-5% (P=0.04) and maximum workload by 8+/-4% (P=0.05); however, there was no effect on arterial mechanical properties, blood lipids, or left ventricular mass or function. These results suggest that the large-artery stiffening associated with ISH is resistant to modification through short-term aerobic training.

Correction of carotid augmentation index for heart rate in elderly essential hypertensives. ANBP2 Investigators. Australian Comparative Outcome Trial of Angiotensin-Converting Enzyme Inhibitor- and Diuretic-Based Treatment of Hypertension in the Elderly.

Carotid augmentation index (AI) is used as a surrogate measure of arterial stiffness. Although arterial stiffness has been shown to either remain unchanged or increase with an increase in heart rate, AI decreases as heart rate increases. This study aimed to quantify this confounding effect of heart rate on AI. We investigated 873 hypertensives, mean age 72 +/- 5 years, 44% men, mean brachial blood pressure 161 +/- 21/82 +/- 11 mm Hg. Carotid artery tonometry with simultaneous continuous wave Doppler measurement of ascending aortic blood flow was performed. AI was calculated from the carotid pressure waveform. Waveforms were decomposed into their forward and backward components and the time to reflection between the maxima of the forward and backward pressure waves was measured. AI showed a stronger (P < .001) association with ejection time (r = 0.48, P < .001) than with heart rate (r = -0.28, P < .001). Although AI is strongly related to the time to reflection (r = -0.51, P < .001), only a weak association was seen between time to reflection and heart rate (r = 0.16, P < .001) or ejection time (r = -0.12, P < .001). Our analysis in an elderly cohort of patients with essential hypertension demonstrates that AI is related to the time to reflection. It also reiterates that AI is confounded by heart rate without any underlying heart rate-dependent change in wave reflection. In population-based studies the confounding effect of heart rate can potentially be corrected. AI remains strongly (r = -0.52) related to time to reflection after correction for the effects of ejection time on AI.

Impact of physical and physiological factors on arterial function.

1. Arterial function measurements are increasingly used as surrogate markers of cardiovascular disease and it is important to define which non-pathological factors may influence these measurements. 2. The present study examined the influence of gender, height, body mass index (BMI), waist : hip ratio, heart rate and arterial pressure on pulse wave velocity (PWV), systemic arterial compliance (SAC) and central pressure augmentation index (AI) in 285 normal subjects, 98 males and 187 females, aged 50-82 years. 3. There were significant gender differences in PWV (higher in men), SAC (higher in men) and central pressure AI (lower in men). 4. Both SAC and AI were correlated with height in men and women and height largely accounted for gender differences. 5. Systemic arterial compliance was positively, whereas AI was negatively, correlated with BMI. 6. Both PWV and AI were significantly correlated with heart rate and central pulse pressure. 7. These findings may have implications for cardiovascular disorders. Reduced central arterial compliance and increased central pressure augmentation are potential mediators for the increased cardiovascular risk of short stature. A slow heart rate may contribute to increased central arterial pressure with potentially adverse consequences in older subjects.

Ventriculocoronary artery bypass (VCAB), a novel approach to myocardial revascularization.

BACKGROUND: The long-term patency rate of saphenous vein grafts for myocardial revascularization is poor (50% at 10 years). Half of the patent grafts develop severe atherosclerosis. In this paper, we report on an implantation technique and an in vivo evaluation of a device that creates a ventriculocoronary artery bypass (VCAB), a permanent transmyocardial channel between the left ventricle and a coronary artery. METHODS: An L-shaped titanium tube with an exterior polyester cuff was implanted from the base of the left ventricle to the proximal left anterior descending coronary artery in 11 juvenile domestic pigs using a beating heart approach. Flow rates were measured at implantation. Patency was assessed when explanted at 2 weeks. RESULTS: The flow rate through the device after implantation was 76% of baseline. Forward flow occurred during systole. The patency rate was 91% at 2 weeks. Histologic analysis showed the formation of an organizing tissue at the coronary interface. CONCLUSIONS: These preliminary studies show the promise of perfusing ischemic myocardium with systolic flow. Patency of the transmyocardial titanium conduit was excellent at 2 weeks and warrants longer duration studies.

Long-term oestrogen treatment does not alter systemic arterial compliance and haemodynamics in biological males.

BACKGROUND: Studies have shown that chronic oestrogen treatment improves both lipid profile and vascular reactivity in postmenopausal women, in whom it also appears to have a beneficial effect on vascular haemodynamics and compliance. Whether oestrogen has a similar effect in men is unknown. OBJECTIVE: To determine whether long-term oestrogen treatment alters arterial compliance and haemodynamics in biological males. METHODS: We compared the effects of chronic oestrogen treatment on blood pressure, heart rate and arterial compliance in 21 male-to-female transsexuals prescribed long-term oestrogen treatment with those in 20 age-matched healthy males. Systemic arterial compliance was assessed using the 'area method', by the simultaneous measurement of aortic flow and driving pressure. RESULTS: Mean systemic arterial compliance was similar in transsexuals and age-matched males (mean +/- SE 0.66 +/- 0.06 ml/mmHg compared with 0.58 +/- 0.05 ml/mmHg, P = 0.34). These results did not differ after the exclusion of transsexuals with coronary risk factors or vascular disease. Heart rate (67 +/- 2 beats/min compared with 64 +/- 3 beats/min, P = 0.41), systolic blood pressure (119 +/- 3 mmHg compared with 119 +/- 2 mmHg, P = 0.95), pulse pressure (55 +/- 3 mmHg compared with 50 +/- 2 mmHg, P = 0.13), diastolic blood pressure (64 +/- 2 mmHg compared with 69 +/- 2 mmHg, P = 0.06) and mean arterial pressure (84 +/- 2 mmHg compared with 89 +/- 2 mmHg, P = 0.09) were also similar at baseline between the two groups. Serum testosterone (an index of oestrogen treatment) was markedly suppressed in the transsexuals compared with the males (0.8 +/- 0.5 nmol/l compared with 25.3 +/- 12.6 nmol/l, P < 0.0001). Univariate analysis revealed that the best predictors of arterial compliance were the pulse pressure (rs = -0.41, P = 0.02) and the systolic blood pressure (rs = -0.35, P = 0.02). On multivariate analysis, the best combination of predictors of compliance were the pulse pressure, testosterone and low-density lipoprotein cholesterol concentrations (R2 = 0.29, P = 0.01). CONCLUSIONS: Although previous evidence suggests chronic oestrogen treatment can improve endothelium-dependent vasodilatation and favourably alter the lipid profile in biological males, these changes are not reflected in changes in systemic arterial compliance. Changes in arterial compliance may not be central to the beneficial effects of oestrogen on vascular function, at least in males.

The effect of age on vascular compliance in man: which are the appropriate measures?

Vascular compliance declines rapidly with age and measures of arterial compliance may help understanding of the aging process. Of the different measures of vascular compliance, those more closely related to chronological age need to be identified. These measures may help in the estimation of 'biological age'. We measured pulse wave velocity as the carotid-finger interval, carotid-toe interval and QKD interval (time between the Q wave and the arrival of the diastolic Korotkoff sound (K) over the brachial artery in diastoly (D)); central aortic compliance (CAC) and SV/PP (the stroke volume divided by pulse pressure in the brachial artery). Thirty-six volunteers were studied (30 men), ages 20 to 84, mean 49 years, to give the relationship of these measurements with age. CAC, the QKD interval and the carotid-toe interval were most closely related to age (r = - 0.51, -0.60 and -0.58 respectively). After adjustment for age, the only measure related to blood pressure was the carotid-finger interval; b for diastolic blood pressure = -0.83 (P = 0.01), the higher the pressure the shorter the interval. Measurements of CAC, QKD interval and carotid-toe interval may be employed to assess the impact of age on vascular compliance. Measures of peripheral vascular compliance, such as the carotid-finger interval, may prove useful in assessing the relationship between blood pressure and vascular compliance.