Hereditary transthyretin amyloidosis presenting with prominent autonomic dysfunction.

A 56-year-old man reported 2 years of slowly progressive exertional fatigue, presyncope, paraesthesia, generalised weakness and nocturnal bowel frequency. He had an abnormal Valsalva ratio and significant postural hypotension. Serum N-terminal pro-B-type natriuretic peptide and troponin T were elevated. Transthoracic echocardiogram identified thickening of the biventricular walls, interatrial septum and atrioventricular valve leaflets. Global longitudinal strain was reduced with relative apical sparing, suspicious for cardiac amyloidosis. Technetium-99m and 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy supported a diagnosis of transthyretin amyloidosis (ATTR). However, urinary Bence Jones protein (kappa) was identified despite a normal kappa/lambda light chain ratio and no serum paraprotein. Bone marrow and buccal biopsy provided histological confirmation of amyloid. The bone marrow had no evidence of plasma cell dyscrasia but positive TTR immunohistochemistry. The patient had a T60A genetic mutation for hereditary ATTR. Overlapping cardiac and autonomic symptoms prompt an amyloid workup, which then must distinguish AL amyloid from ATTR pathology.

Prevalence of patent foramen ovale in a consecutive cohort of 261 patients undergoing routine "coronary" 64-multi-detector cardiac computed tomography.

BACKGROUND: A patent foramen ovale (PFO) is strongly associated with cryptogenic stroke (CS), neurological and other phenomena. The reported prevalence of PFO varies according to the imaging technique used and population studied. PURPOSE: To measure prospectively, the prevalence of PFO in a cohort of consecutive patients attending for routine "coronary" CT angiography using standard, everyday coronary protocols including low-dose prospective ECG gated studies. METHODS: Standard coronary imaging protocols were used. PFOs were graded according to the classification of Williamson et al. RESULTS: 261 patients were studied. A PFO was identified in 22.6% (11.5% grade 1 (closed flap), 6.5% grade 2 (open flap) and 4.6% grade 3 (open flap with jet)). A further 6.1% had an atrial septal aneurysm. CONCLUSIONS: The prevalence of all grades of PFO (22.6%) and open flap PFO (11.1% = grade 2 and 3) with this technique compares with 24.3% by trans-oesophageal echocardiography (TOE) and 14.9% by saline contrast echocardiography (SCE). Further comparative studies are required but we believe an open flap PFO or ASA should be identified and recorded during cardiac CT. This approach may identify those at risk of cryptogenic stroke as well as avoid unnecessary tests in stroke patients.

Statins have beneficial effects on platelet free radical activity and intracellular distribution of GTPases in hyperlipidaemia.

In addition to lowering cholesterol, statins may alter endothelial release of the vasodilator NO and harmful superoxide free radicals. Statins also reduce cholesterol intermediates including isoprenoids. These are important for post-translational modification of substances including the GTPases Rho and Rac. By altering the membrane association of these molecules, statins affect intracellular positioning and hence activity of a multitude of substances. These include eNOS(endothelial NO synthase), which produces NO (inhibited by Rho), and NADPH oxidase, which produces superoxide (dependent on Rac). Statins may improve endothelial function by enhancing production of NO while decreasing superoxide production. A total of 40 hypercholesterolaemic patients were randomized to treatment with either atorvastatin or placebo; 20 normolipidaemic patients were also studied. Platelet nitrite, NO and superoxide were examined as was the cellular distribution of the GTPases Rho and Rac at baseline and after 8 weeks of treatment.Following atorvastatin therapy, platelet NO was increased (3.2 pmol/10(8) platelets) and superoxide output was attenuated [-3.4 pmol min(-1) (10(8) platelets)(-1)] when compared with placebo. The detection of both Rho and Rac was significantly reduced in the membranes of platelets, implying reduced activity. In conclusion, the results of the present study show altered NO/superoxide production following statin therapy. A potential mechanism for this is the change in the distribution of intracellular GTPases, which was considered to be secondary to decreases in isoprenoid intermediates, suggesting that the activity of the former had been affected by atorvastatin.

Nitric oxide modulation of ophthalmic artery blood flow velocity waveform morphology in healthy volunteers.

Quantitative analysis of the arterial pressure pulse waveform recorded by applanation tonometry of the radial artery can track NO (nitric oxide)-mediated modulation of arterial smooth muscle tone. The changes in pressure pulse waveform morphology result from pulse wave reflection arising predominantly from smaller arteries and arterioles. Employing Doppler ultrasound to record the spectral flow velocity waveform in the ophthalmic artery, we studied the effects of NO modulation on waveforms recorded in the proximity of the terminal ocular microcirculatory bed. In healthy young men (n=10; age 18-26 years), recordings were made at baseline, following 300 mug of sublingual GTN (glyceryl trinitrate) and during the intravenous infusion of 0.25 and 0.5 mg/kg of L-NAME (N(G)-nitro-L-arginine methyl ester). Peaks (P1, P2 and P3) and nodes (N1, N2 and N3) on the arterial flow velocity waveform were identified during the cardiac cycle and employed to quantify wave shape change in response to the haemodynamic actions of the pharmacological interventions. The administration of GTN resulted in a significant (P<0.05) increase in heart rate without significant alteration in blood pressure. At the doses employed, L-NAME did not significantly alter systemic haemodynamics. With the exception of peak Doppler systolic velocity, all other peaks and nodes decreased significantly in response to GTN (P<0.05 for all points compared with baseline). In response to the administration of L-NAME, all peaks and nodes decreased significantly (P<0.05 for all points compared with baseline). The resistive index, a ratio calculated from the peak and trough flow velocities employed to assess change in flow resistance, increased significantly in response to GTN (0.77 at baseline compared with 0.85; P<0.05). Quantification of changes in the flow velocity spectral waveform during the cardiac cycle sensitively identified NO modulation of smooth muscle tone prior to alteration in systemic haemodynamics. Focusing on the resistive index, which identifies isolated points on the waveform describing the excursions of flow, may provide misleading information in relation to the haemodynamic effects of drug interventions.

NAD(P)H-dependent superoxide production in platelets: the role of angiotensin II and protein kinase C.

OBJECTIVES: Vascular NAD(P)H oxidase represents a major source for excessive superoxide production in hypertension. Angiotensin II (AngII) can activate NAD(P)H oxidase via the angiotensin II type 1 (AT1) receptor and protein kinase C (PKC). Platelets possess AT1 receptors and all the components of the NAD(P)H oxidase system. We employed this tissue model to explore mechanisms involved in AngII-mediated superoxide production. DESIGN AND METHODS: Platelet suspensions from hypertensive patients' blood were activated with AngII or phorbol 12-myristate 13-acetate (PMA). Inhibitors of NAD(P)H oxidase, PKC, and the AT1 receptor were employed to study their effects on superoxide production. RESULTS: Superoxide production was stimulated by AngII and PMA and attenuated by AT1 receptor antagonists (mean percentage reduction 80.2%, P<0.01) and inhibitors of PKC (mean reduction 94.8%, P<0.001) and NAD(P)H oxidase (mean reduction 100%, P< 0.001). CONCLUSIONS: AngII stimulates platelet superoxide production through activation of vascular NAD(P)H oxidase via the AT1 receptor and PKC.

Increased superoxide production in hypertensive patients with diabetes mellitus: role of nitric oxide synthase.

BACKGROUND: Hypertension and diabetes are important independent risk factors for increased oxidative stress and increased cardiovascular risk. The combination of hypertension and diabetes results in a dramatic increase in cardiovascular risk. Enhanced oxidative stress in hypertension and diabetes is linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O(2)(*-)), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, NO synthase III (NOS III) can also produce O(2)(*-). We studied platelet superoxide production in patients with hypertension alone and in patients with coexistent diabetes mellitus, investigating the contribution of NOS III uncoupling to platelet superoxide production. METHODS AND RESULTS: Gel-filtered platelets were obtained and were stimulated with Phorbol 12-myristate 13-acetate, and O(2)(*-) production was detected using lucigenin-enhanced chemiluminescence. Superoxide production was significantly higher in patients with diabetes and hypertension (6.4 +/- 1.6 pmol/min/10(8) platelets) than in patients with hypertension (1.6 +/- 0.6 pmol/min/10(8) platelets) (P < .04). After incorporation of N(omega)-nitro-l-arginine methyl ester (L-NAME, 1 mmol/L), O(2)(*-) detection increased in 40% of patients with diabetes and hypertension and in 87% of patients with hypertension. This expected response results from L-NAME inhibition of NO production preventing NO scavenging of O(2)(*-). A reduction in O(2)(*-) production in response to L-NAME occurred in the remaining patients and indicates O(2)(*-) production by the uncoupled NOS III enzyme. CONCLUSIONS: This study provides first published evidence that NOS III can reside in the uncoupled state in patients with hypertension and, to a greater extent, in patients with coexisting hypertension and diabetes, and that it contributes significantly to increased superoxide production in these disease states.

Impaired endothelium-dependent and -independent vasodilation in elderly patients with chronic heart failure.

BACKGROUND: Impaired endothelium-dependent and independent vasodilator responses in chronic heart failure (CHF) have been well described. Previous studies involved younger patients and omitted medications prior to study. AIMS: We explored if new therapeutic interventions would restore vasodilator responses in typical patients with chronic heart failure. METHODS AND RESULTS: 24 patients and 15 controls were recruited, patients were maintained on their usual medications. Forearm blood flow responses were measured by venous occlusion plethysmography in response to incremental doses of sodium nitroprusside (SNP) (6, 9 and 12 nmol/min), acetylcholine (ACH) (120, 180 and 240 nmol/min), angiotensin II (AII) (1, 10 and 100 nmol/min) and N(g)-Nitro-L-arginine methyl ester (L-NAME) (1, 2 and 4 nmol/min) infused into the non-dominant brachial artery. FBF responses to SNP were impaired in patients compared with controls (13.7(9.9,17.4) vs. 24.8(18.6,30.9)) arbitrary units, P<0.001). Similarly FBF responses to ACH were reduced in patients compared with controls (7.5(4.2,10.9) vs. 24.8(16.4,33.2)) arbitrary units, P<0.001. Decreased FBF was noted in response to AII and L-NAME but was significant only for AII and did not differ between groups. CONCLUSIONS: In elderly patients with CHF, endothelium-dependent and independent vasodilator responses were blunted compared with controls. Defects in nitric oxide bioavailability and smooth muscle responsiveness are not reversed by modern medical management of the heart failure syndrome.

Vascular abnormalities in hypertension: cause, effect, or therapeutic target?

Alteration in the physical properties of arterial blood vessels act as the substrate for end-organ damage and the occurrence of vascular events in hypertension. Structural and functional alteration in the microcirculation represents a prevalent and characteristic abnormality described in the earliest stages of hypertension. In addition to lowering arterial pressure, the importance of reversing structural abnormalities and restoring endothelial function has recently been emphasized. The normalization of microvascular function does not always correlate with blood pressure reduction and might depend on the class of antihypertensive agent employed. Because altered resistance vessel structure and function is a recognized hallmark of hypertension, institution of drug therapy that corrects the associated pathogenic vascular abnormalities is a rational, if unproven, clinical goal.

Functional consequences of endothelial nitric oxide synthase uncoupling in congestive cardiac failure.

BACKGROUND: Impaired endothelium-mediated vasodilatation (EMVD) in congestive cardiac failure (CCF) has been linked to decreased nitric oxide (NO) bioavailability because of its interaction with vascular superoxide (O2*-), derived predominantly from NAD(P)H-dependent oxidases. When uncoupled from essential cofactors, endothelial nitric oxide synthase (eNOS) produces O2*-. We studied the functional consequences of eNOS uncoupling in relation to EMVD in patients with CCF. METHODS AND RESULTS: We employed the platelet as a compartmentalized ex-vivo model to examine O2*- and NO production. When eNOS is functioning normally, incorporation of Nomega-Nitro-L-Arginine methyl ester (L-NAME, 1 mmol/L), results in increased O2*- detection, as inhibition of NO production prevents NO scavenging of O2*-. This was observed in controls and 9 of the CCF patients, in whom O2*- detection increased by 63% and 101%, respectively. In the remaining 9 CCF patients, incorporation of L-NAME reduced O2*- production by 39%, indicating O2*- production by eNOS uncoupling. Detection of platelet-derived NO was significantly greater in eNOS-coupled platelets compared with the uncoupled group (2.8+/-1.4 versus 0.9+/-0.4 pmol/108 platelets, P=0.04). Endothelium-dependent and -independent vasodilator responses to acetylcholine and sodium nitroprusside recorded using venous occlusion plethysmography were significantly impaired in patients exhibiting eNOS uncoupling. CONCLUSIONS: This study provides first evidence that platelet eNOS can become uncoupled in human CCF. Impaired endothelium-dependent and -independent vasodilator responses and diminished platelet-derived NO production occurred in association with enzyme uncoupling.