Background Older patients with severe aortic stenosis (AS) are increasingly identified as having cardiac amyloidosis (CA). It is unknown whether concomitant AS-CA has worse outcomes or results in futility of transcatheter aortic valve replacement (TAVR). Objectives This study identified clinical characteristics and outcomes of AS-CA compared with lone AS. Methods Patients who were referred for TAVR at 3 international sites underwent blinded research core laboratory 99m technetium-3,3-diphosphono-1,2-propanodicarboxylic acid (DPD) bone scintigraphy (Perugini grade 0: negative; grades 1 to 3: increasingly positive) before intervention. Transthyretin-CA (ATTR) was diagnosed by DPD and absence of a clonal immunoglobulin, and light-chain CA (AL) was diagnosed via tissue biopsy. National registries captured all-cause mortality. Results A total of 407 patients (age 83.4 ± 6.5 years; 49.8% men) were recruited. DPD was positive in 48 patients (11.8%; grade 1: 3.9% [n = 16]; grade 2/3: 7.9% [n = 32]). AL was diagnosed in 1 patient with grade 1. Patients with grade 2/3 had worse functional capacity, biomarkers (N-terminal pro-brain natriuretic peptide and/or high-sensitivity troponin T), and biventricular remodeling. A clinical score (RAISE) that used left ventricular remodeling (hypertrophy/diastolic dysfunction), age, injury (high-sensitivity troponin T), systemic involvement, and electrical abnormalities (right bundle branch block/low voltages) was developed to predict the presence of AS-CA (area under the curve: 0.86; 95% confidence interval: 0.78 to 0.94; p < 0.001). Decisions by the heart team (DPD-blinded) resulted in TAVR (333 [81.6%]), surgical AVR (10 [2.5%]), or medical management (65 [15.9%]). After a median of 1.7 years, 23% of patients died. One-year mortality was worse in all patients with AS-CA (grade: 1 to 3) than those with lone AS (24.5% vs. 13.9%; p = 0.05). TAVR improved survival versus medical management; AS-CA survival post-TAVR did not differ from lone AS (p = 0.36). Conclusions Concomitant pathology of AS-CA is common in older patients with AS and can be predicted clinically. AS-CA has worse clinical presentation and a trend toward worse prognosis, unless treated. Therefore, TAVR should not be withheld in AS-CA.

Aims Cardiac amyloidosis is common in elderly patients with aortic stenosis (AS) referred for transcatheter aortic valve implantation (TAVI). We hypothesized that patients with dual aortic stenosis and cardiac amyloid pathology (AS-amyloid) would have different baseline characteristics, periprocedural and mortality outcomes. Methods and results Patients aged ≥75 with severe AS referred for TAVI at two sites underwent blinded bone scintigraphy prior to intervention (Perugini Grade 0 negative, 1–3 increasingly positive). Baseline assessment included echocardiography, electrocardiogram (ECG), blood tests, 6-min walk test, and health questionnaire, with periprocedural complications and mortality follow-up. Two hundred patients were recruited (aged 85 ± 5 years, 50% male). AS-amyloid was found in 26 (13%): 8 Grade 1, 18 Grade 2. AS-amyloid patients were older (88 ± 5 vs. 85 ± 5 years, P = 0.001), with reduced quality of life (EQ-5D-5L 50 vs. 65, P = 0.04). Left ventricular wall thickness was higher (14 mm vs. 13 mm, P = 0.02), ECG voltages lower (Sokolow–Lyon 1.9 ± 0.7 vs. 2.5 ± 0.9 mV, P = 0.03) with lower voltage/mass ratio (0.017 vs. 0.025 mV/g/m2, P = 0.03). High-sensitivity troponin T and N-terminal pro-brain natriuretic peptide were higher (41 vs. 21 ng/L, P &lt; 0.001; 3702 vs. 1254 ng/L, P = 0.001). Gender, comorbidities, 6-min walk distance, AS severity, prevalence of disproportionate hypertrophy, and post-TAVI complication rates (38% vs. 35%, P = 0.82) were the same. At a median follow-up of 19 (10–27) months, there was no mortality difference (P = 0.71). Transcatheter aortic valve implantation significantly improved outcome in the overall population (P &lt; 0.001) and in those with AS-amyloid (P = 0.03). Conclusions AS-amyloid is common and differs from lone AS. Transcatheter aortic valve implantation significantly improved outcome in AS-amyloid, while periprocedural complications and mortality were similar to lone AS, suggesting that TAVI should not be denied to patients with AS-amyloid.

Background We assessed the contribution of endothelium-derived hyperpolarizing factors (EDHFs) to resting and agonist-stimulated vasodilator tone in health and disease. Tetraethylammonium chloride (TEA) was employed to inhibit K+Ca channel activation and fluconazole to inhibit cytochrome P450 2C9-mediated epoxyeicosatrienoic acid synthesis. We hypothesized that 1) EDHFs contribute to resting vascular tone by K+Ca channel activation and epoxyeicosatrienoic acid release, and 2) EDHFs compensate for reduced nitric oxide bioavailability at rest and with endothelium-dependent vasodilators. Methods and Results In 103 healthy subjects and 71 non-hypertensive subjects with multiple risk factors, resting forearm blood flow (FBF) was measured using venous occlusion plethysmography before and after intra-arterial infusions of NG-monomethyl-L-arginine (L-NMMA), TEA, fluconazole, and their combination. The effects of these antagonists on resting FBF, and on bradykinin- and acetylcholine-mediated vasodilation was studied. Resting FBF decreased with TEA and L-NMMA in all subjects (P<0.001), however, the vasoconstrictor response to L-NMMA was greater (p=0.04) and to TEA lower (p=0.04) in healthy subjects compared to those with risk factors. Fluconazole decreased resting FBF in all subjects and addition of TEA further reduced FBF after fluconazole, suggesting that cytochrome P450 metabolites and other hyperpolarizing factor(s) activate K+Ca channels. Both L-NMMA and TEA attenuated bradykinin-mediated vasodilation in healthy and hypercholesterolemic subjects (P<0.001). In contrast, acetylcholine-mediated vasodilation remained unchanged with TEA in healthy subjects, but was significantly attenuated in hypercholesterolemia (P<0.04). Conclusions Firstly, EDHFs by activating TEA inhibitable K+Ca channels together with NO contribute to resting microvascular dilator tone. The contribution of K+Ca channel activation compared to NO is greater in those with multiple risk factors compared to healthy subjects. Second, activation of K+Ca channels is only partly through epoxyeicosatrienoic acid release, indicating presence of other hyperpolarizing mechanisms. Third, bradykinin, but not acetylcholine stimulates K+Ca channel-mediated vasodilation in healthy subjects, whereas in hypercholesterolemia, K+Ca channel-mediated vasodilation compensates for the reduced NO activity. Thus, enhanced EDHF activity in conditions of NO deficiency contributes to maintenance of resting and agonist-stimulated vasodilation. Clinical Trial Registration Information: http://clinicaltrials.gov/, Identifier: NCT00166166

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Endothelial function refers to a multitude of physiological processes that maintain healthy homeostasis of the vascular wall. Exposure of the endothelium to cardiac risk factors results in endothelial dysfunction and is associated with an alteration in the balance of vasoactive substances produced by endothelial cells. These include a reduction in nitric oxide (NO), an increase in generation of potential vasoconstrictor substances and a potential compensatory increase in other mediators of vasodilation. The latter has been surmised from data demonstrating persistent endothelium-dependent vasodilatation despite complete inhibition of NO and prostaglandins. This remaining non-NO, non-prostaglandin mediated endothelium-dependent vasodilator response has been attributed to endothelium-derived hyperpolarizing factor/s (EDHF). Endothelial hyperpolarization is likely due to several factors that appear to be site and species specific. Experimental studies suggest that the contribution of the EDHFs increase as the vessel size decreases, with a predominance of EDHF activity in the resistance vessels, and a compensatory up-regulation of hyperpolarization in states characterized by reduced NO availability. Since endothelial dysfunction is a precursor for atherosclerosis development and its magnitude is a reflection of future risk, then the mechanisms underlying endothelial dysfunction need to be fully understood, so that adequate therapeutic interventions can be designed.

CAP remains uncommon but the prevalence is increasing. CAP is associated with significant short- and long-term mortality, particularly when there is haemodynamic compromise necessitating pericardiocentesis. Covered stents are a valuable tool but they are associated with a high risk of stent thrombosis.

Objectives The purpose of this study was to validate computed tomography measured ECV (ECV CT ) as part of routine evaluation for the detection of cardiac amyloid in patients with aortic stenosis (AS)-amyloid. Background AS-amyloid affects 1 in 7 elderly patients referred for transcatheter aortic valve replacement (TAVR). Bone scintigraphy with exclusion of a plasma cell dyscrasia can diagnose transthyretin-related cardiac amyloid noninvasively, for which novel treatments are emerging. Amyloid interstitial expansion increases the myocardial extracellular volume (ECV). Methods Patients with severe AS underwent bone scintigraphy (Perugini grade 0, negative; Perugini grades 1 to 3, increasingly positive) and routine TAVR evaluation CT imaging with ECV CT using 3- and 5-min post-contrast acquisitions. Twenty non-AS control patients also had ECV CT performed using the 5-min post-contrast acquisition. Results A total of 109 patients (43% male; mean age 86 ± 5 years) with severe AS and 20 control subjects were recruited. Sixteen (15%) had AS-amyloid on bone scintigraphy (grade 1, n = 5; grade 2, n = 11). ECV CT was 32 ± 3%, 34 ± 4%, and 43 ± 6% in Perugini grades 0, 1, and 2, respectively (p < 0.001 for trend) with control subjects lower than lone AS (28 ± 2%; p < 0.001). ECV CT accuracy for AS-amyloid detection versus lone AS was 0.87 (0.95 for 99m Tc-3,3-diphosphono-1,2-propanodicarboxylic acid Perugini grade 2 only), outperforming conventional electrocardiogram and echocardiography parameters. One composite parameter, the voltage/mass ratio, had utility (similar AUC of 0.87 for any cardiac amyloid detection), although in one-third of patients, this could not be calculated due to bundle branch block or ventricular paced rhythm. Conclusions ECV CT during routine CT TAVR evaluation can reliably detect AS-amyloid, and the measured ECV CT tracks the degree of infiltration. Another measure of interstitial expansion, the voltage/mass ratio, also performed well.

Objectives Abnormalities in nitric oxide (NO) bioavailability have been reported in African Americans. Whether there are differences in endothelium-derived hyperpolarizing factor (EDHF) in addition to NO between African Americans and whites, and how these affect physiologic vasodilation remains unknown. We hypothesized that the bioavailability of vascular NO and EDHF, at rest and with pharmacologic and physiologic vasodilation, varies between white and African Americans. Approach and Results In 74 white and 86 African American subjects without known cardiovascular disease risk factors, forearm blood flow (FBF) was measured using plethysmography at rest and during inhibition of NO with NG-monomethyl-L-arginine (L-NMMA) and/or of K+Ca channels (EDHF) with tetraethylammonium (TEA). The reduction in resting FBF was greater with L-NMMA (p=0.019) and similar with TEA in whites compared to African Americans. Vasodilation with bradykinin, acetylcholine, and sodium nitroprusside was lower in African Americans compared to whites (all p<0.0001). Inhibition with L-NMMA was greater in whites compared to African Americans with bradykinin, acetylcholine, and exercise. Inhibition with TEA was lower in African Americans with bradykinin, but greater during exercise and with acetylcholine. Conclusions The contribution to both resting and stimulus-mediated vasodilator tone of NO is greater in whites compared to African Americans. EDHF partly compensates for the reduced NO release in exercise and acetylcholine-mediated vasodilation in African Americans. Preserved EDHF but reduced NO bioavailability and sensitivity characterizes the vasculature in healthy African Americans.