Impaired FMD (flow-mediated dilatation) has traditionally been recognized as an indirect marker of NO bioactivity, occurring in disease states such as DM (diabetes mellitus). Endothelium-dependent FMD is a homoeostatic response to short-term increases in local shear stress. Microvascular dysfunction in DM influences blood flow velocity patterns. We explored the determinants of the FMD response in relation to evoked DSS (diastolic shear stress) and forearm microcirculation haemodynamics by quantifying changes in Doppler flow velocity waveforms between groups. Forty patients with uncomplicated Type 1 DM and 32 controls underwent B-mode and Doppler ultrasound scanning to interrogate the brachial artery. Postischaemic Doppler velocity spectral envelopes were recorded and a wavelet-based time-frequency spectral analysis method was employed to track change in distal microcirculatory haemodynamics. No difference in baseline brachial artery diameter was evident between the groups (4.15 compared with 3.94 mm, P =0.23). FMD was significantly impaired in patients with Type 1 DM (3.95 compared with 7.75%, P <0.001). Endothelium-independent dilatation in response to GTN (glyceryl trinitrate) was also significantly impaired (12.07 compared with 18.77%, P <0.001). DSS (dyn/cm 2 ) was significantly reduced in the patient group (mean 20.19 compared with 29.5, P =0.001). Wavelet interrogation of postischaemic flow velocity waveforms identified significant differences between groups. In conclusion, DSS, microcirculatory function and endothelium-independent vasodilatation in response to GTN are important determinants that impact on the magnitude of FMD response and are impaired in patients with Type 1 DM. Impaired FMD response is multifactorial in origin and cannot be attributed solely to a diminished NO bioavailability.

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.

Risk factors for cardiovascular disease mediate their effects by altering the structure and function of wall and endothelial components of arterial blood vessels. A pathological change in the microcirculation plays a pivotal role in promoting end-organ dysfunction that not only predisposes to further organ damage, but also increases the risk for future macrovascular events. The microcirculation is recognized as the site where the earliest manifestations of cardiovascular disease, especially inflammatory responses, occur that may play a pivotal role in driving the atherosclerotic process in conduit vessels. Furthermore, the vast surface area of the endothelium compared with conduit vessels means that the vascular effects of endothelial dysfunction or activation will be most apparent in this section of the vasculature. Current techniques providing indices of vascular health focus on large arteries without providing insight into the structure and function of small vessels. Techniques capable of detecting microvascular damage and monitoring the response to therapeutic interventions, especially in vulnerable target organs of interest, may improve risk stratification and represent a valuable surrogate for future cardiovascular outcome.

Most traditional cardiovascular risk factors alter the structure and/or function of arteries. An assessment of arterial wall integrity could therefore allow accurate prediction of cardiovascular risk in individuals. The term ‘arterial stiffness’ denotes alterations in the mechanical properties of arteries, and much effort has focused on how best to measure this. Pulse pressure, pulse wave velocity, pulse waveform analysis, localized assessment of blood vessel mechanics and other methods have all been used. We review the methodology underlying each of these measures, and present an evidence-based critique of their relative merits and limitations. An overview is also given of the drug therapies that may prove useful in the treatment of patients with altered arterial mechanics.

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 μg 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 waveshape 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.

Ageing and disease states associated with an increase in cardiovascular events alter the physical characteristics of blood vessel walls and impair the pulsatile function of arteries. An accumulating body of evidence indicates that impaired pulsatile function of arteries provides important prognostic and therapeutic information beyond that provided by traditional blood pressure measurements. A variety of techniques are currently employed to evaluate the mechanical properties of arteries. All techniques have theoretical, technical and practical limitations that impact on their widespread application in the clinical setting and use as measurement tools to improve cardiovascular risk stratification. A detailed discussion of these issues forms the basis of this review.

Traditionally, nitric oxide-mediated alteration in blood vessel tone has been inferred from changes in flow in response to physical and pharmacological interventions using plethysmographic or ultrasonic techniques. We hypothesized that alteration in pulsatile arterial function may represent a more sensitive measure to detect and monitor nitric oxide-mediated modulation of arterial smooth muscle tone. Healthy male volunteers ( n = 15) had radial artery pressure pulse waveforms recorded using a calibrated tonometer device. A computer-based assessment of the diastolic pressure decay was employed to quantify changes in arterial waveform morphology in terms of altered pulsatile (arterial compliance) and steady-state (peripheral resistance) haemodynamics. N G -nitro- L -arginine methyl ester ( L -NAME), a stereospecific inhibitor of nitric oxide synthesis, was infused intravenously in incrementally increasing doses of 0.25, 0.5 and 0.75 mg/kg for 8 min each. Subjects then received either L -arginine or D -arginine (200 mg/kg over 15 min) intravenously in a blinded fashion. On a separate day, subjects had radial artery pressure pulse waveforms recorded before and after the sublingual administration of glyceryl trinitrate, an exogenous donor of nitric oxide. Cardiac output and heart rate decreased and mean arterial blood pressure increased significantly ( P < 0.01 for all) in response to the incremental intravenous infusion of L -NAME. Small artery compliance decreased, whereas systemic vascular resistance increased in response to nitric oxide synthesis inhibition ( P < 0.01 for both). The intravenous infusion of L -arginine restored the pulsatile and steady-state haemodynamic parameters to pre-treatment values, whereas D -arginine had no effect. Sublingual glyceryl trinitrate decreased systemic vascular resistance by 11%, whereas large artery- and small artery-compliance increased by 25% and 44% respectively. Pressure pulse contour analysis represents a sensitive and convenient technique capable of tracking changes in the pulsatile function of arteries accompanying nitric oxide-mediated alteration in arterial smooth muscle tone.