Assessment of aortic stiffness by cardiovascular magnetic resonance following the treatment of severe aortic stenosis by TAVI and surgical AVR.

BACKGROUND: Aortic stiffness is increasingly used as an independent predictor of adverse cardiovascular outcomes. We sought to compare the impact of transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) upon aortic vascular function using cardiovascular magnetic resonance (CMR) measurements of aortic distensibility and pulse wave velocity (PWV). METHODS AND RESULTS: A 1.5 T CMR scan was performed pre-operatively and at 6 m post-intervention in 72 patients (32 TAVI, 40 SAVR; age 76 ± 8 years) with high-risk symptomatic severe aortic stenosis. Distensibility of the ascending and descending thoracic aorta and aortic pulse wave velocity were determined at both time points. TAVI and SAVR patients were comparable for gender, blood pressure and left ventricular ejection fraction. The TAVI group were older (81 ± 6.3 vs. 72.8 ± 7.0 years, p < 0.05) with a higher EuroSCORE II (5.7 ± 5.6 vs. 1.5 ± 1.0 %, p < 0.05). At 6 m, SAVR was associated with a significant decrease in distensibility of the ascending aorta (1.95 ± 1.15 vs. 1.57 ± 0.68 × 10(-3)mmHg(-1), p = 0.044) and of the descending thoracic aorta (3.05 ± 1.12 vs. 2.66 ± 1.00 × 10(-3)mmHg(-1), p = 0.018), with a significant increase in PWV (6.38 ± 4.47 vs. 11.01 ± 5.75 ms(-1), p = 0.001). Following TAVI, there was no change in distensibility of the ascending aorta (1.96 ± 1.51 vs. 1.72 ± 0.78 × 10(-3)mmHg(-1), p = 0.380), descending thoracic aorta (2.69 ± 1.79 vs. 2.21 ± 0.79 × 10(-3)mmHg(-1), p = 0.181) nor in PWV (8.69 ± 6.76 vs. 10.23 ± 7.88 ms(-1), p = 0.301) at 6 m. CONCLUSIONS: Treatment of symptomatic severe aortic stenosis by SAVR but not TAVI was associated with an increase in aortic stiffness at 6 months. Future work should focus on the prognostic implication of these findings to determine whether improved patient selection and outcomes can be achieved.

3.0T, time-resolved, 3D flow-sensitive MR in the thoracic aorta: Impact of k-t BLAST acceleration using 8- versus 32-channel coil arrays.

PURPOSE: To evaluate the performance of 4D flow MR in the thoracic aorta with 8- and 32-channel coil arrays using k-t BLAST and SENSE acceleration techniques and compare this to a conventional 2D SENSE approach. MATERIALS AND METHODS: Fifteen healthy subjects and eight patients underwent magnetic resonance imaging (MRI) at 3.0T using: 1) 2D SENSE phase contrast velocity mapping as the reference standard and 2) 4D-flow pulse sequences accelerated with SENSE and k-t BLAST, using both 8- and 32-channel coil arrays. Data processing was performed using GT Flow. Image quality of the magnitude images and pathline visualization were graded and mean scan times, flow, peak velocity, stroke volume, and image quality were compared between techniques. RESULTS: Mean scan times were significantly lower for 4D-flow sequences accelerated with k-t BLAST compared to SENSE (5.5 vs. 25.2 min; P < 0.01). 4D k-t BLAST acquisition had greater magnitude and pathline image quality than 4D SENSE acquisition for both 32-channel and 8-channel data (P < 0.001); both 4D SENSE and 4D k-t BLAST acquisitions had significantly greater image quality when 32 channels were utilized compared to 8 (P < 0.05). On Bland-Altman analysis, all 4D flow pulse sequences showed significant agreement with the 2D SENSE reference for peak velocity measurement (P > 0.05); the lowest bias being observed with the 4D 32 channel k-t BLAST sequence. There were no significant differences in measured flow, peak velocity, or stroke volume with any of the four investigated 4D acquisition techniques compared to reference technique values (P > 0.05). In patients, there were no significant differences in flow, peak velocity, or stroke volume measurements between 32-channel 4D k-t BLAST and the reference acquisition. CONCLUSION: 4D flow MR using k-t BLAST and 32 channel coils allows a reduction in total scan time while improving overall image quality compared to a standard 2D SENSE and 4D SENSE acquisitions. The use of 32 channels rather than 8 channels with the 4D k-t BLAST was also preferable in terms of image quality.

Aortic remodelling following the treatment and regression of hypertensive left ventricular hypertrophy: a cardiovascular magnetic resonance study.

BACKGROUND: Increased arterial stiffness independently predicts adverse prognosis. While different antihypertensive strategies produce different magnitudes of left ventricular hypertrophy (LVH) regression, there are no comparative data on how these strategies affect arterial stiffness. The aim was to determine the longitudinal change in aortic stiffness following the treatment of essential hypertension with two mechanistically different antihypertensive treatment strategies. METHODS AND RESULTS: Forty-two patients with essential hypertension and CMR confirmed with LVH were randomly assigned to antihypertensive regimes for 6 months. Treatment strategies were designed either to inhibit the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system (SNS) (valsartan and moxonidine, group VM) or to have neutral effect on these systems (bendroflumethiazide and amlodipine, group BA). Both treatment groups underwent identical baseline and a 6-month follow-up CMR and were compared with a healthy age-matched control group. Baseline aortic distensibility (AD) was lower in both hypertensive groups compared with controls (2.8 × 10(-3 )mmHg(-1) in group VM (p = 0.001) and 3.3 × 10(-3 )mmHg(-1) group BA (p = 0.039) compared with 4.5 × 10(-3 )mmHg(-1) in the control group). AD increased after antihypertensive therapy (VM: 2.8 × 10(-3 )mmHg(-1)-4.2 × 10(-3 )mmHg(-1) (p = 0.001); BA 3.3 × 10(-3 )mmHg(-1)-4.6 × 10(-3 )mmHg(-1) (p < 0.01)). In both treatment groups AD returned to a level comparable with the normal control group (p = 0.81) after 6 months. CONCLUSIONS: In patients with essential hypertension and LVH, AD was lower than in matched normal controls. Despite the opposing pharmacological mechanisms utilised across the treatment groups, the improvement in AD was similar, suggesting that blood pressure reduction per se may be more important than RAAS and SNS inhibition for the improvement of aortic remodelling.

Time-dependent interactions of the hypotensive effects of sildenafil citrate and sublingual glyceryl trinitrate.

AIM: To investigate the time course of the hypotensive interaction between sildenafil and glyceryl trinitrate (GTN). METHODS: Two double-blind, placebo-controlled, randomized, crossover studies were performed. Subjects were challenged with sublingual GTN 400 microg at different times after oral sildenafil 100 mg. After each GTN challenge frequent measures of blood pressure (BP) were made. In the first study GTN was given 1-48 h after sildenafil/placebo to 33 healthy men. In the second study GTN was given 1-8 h after sildenafil/placebo to 20 men with stable angina. RESULTS: In healthy men there was a greater mean maximum reduction in BP with sildenafil/GTN than with placebo/GTN only at 1 h. In angina patients, there was a greater mean maximum reduction in BP with sildenafil/GTN than with placebo/GTN for up to 8 h. The mean (95% confidence interval) differences in maximum systolic BP reduction (mmHg) at 1, 4, 6 and 8 h were -16 (-12, -21), -12 (-4, -20), -6 (1, -12) and -9 (-3, -15), all P < 0.05 except at 6 h (NS). At 6 and 8 h the interaction was not more than additive, and hypotensive symptoms did not occur. CONCLUSIONS: In men with angina there is an interaction on BP reduction between sildenafil and GTN for >or= 8 h after sildenafil administration, but this is no more than additive from 6 h. These data may be helpful to clinicians who are considering the use of GTN in patients presenting with angina who have received sildenafil within 24 h.

Contribution of the M3 muscarinic receptors to the vasodilator response to acetylcholine in the human forearm vascular bed.

AIMS: Acetylcholine (ACh) is a muscarinic agonist that causes receptor-mediated, endothelium-dependent vasodilatation in the forearm vasculature. Previous indirect evidence suggests this effect may be mediated by muscarinic M(3) receptors. Darifenacin is a recently developed antimuscarinic drug with greater M(3) selectivity, and our main objective was to investigate whether darifenacin affects dose-dependent vasodilatation to ACh in the forearm circulation. METHODS: Healthy subjects were enrolled in two studies designed to assess the effects of atropine and darifenacin on the forearm blood flow (FBF) response to ACh. RESULTS: In both studies ACh caused similar dose-dependent vasodilation in the forearm vasculature. In study I (5 subjects), the FBF response to ACh was largely attenuated by pretreatment with the nonselective muscarinic antagonist atropine. In study II (10 subjects), oral administration of darifenacin 15 mg for 1 week significantly reduced the FBF dose-dependent response to ACh 20 microg min(-1) (mean difference from placebo 5.8 [95% confidence interval (CI) 3.1, 8.7] ml min(-1) per 100 ml of forearm volume, P < 0.001) and to ACh 60 microg min(-1)[mean difference from placebo 5.9 (95% CI 3.1, 8.7) ml min(-1) per 100 ml of forearm volume, P < 0.001]. After darifenacin, the AUC of change in FBF from baseline was reduced by almost 50% compared with placebo. CONCLUSIONS: These results suggest that, in the forearm vasculature, muscarinic M(3) receptors play a major role in ACh-induced endothelium-mediated vasodilatation.

The impact of prognosis without treatment on doctors' and patients' resource allocation decisions and its relevance to new drug recommendation processes.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The dominant health economic units upon which new treatment funding decisions are made are the incremental cost per life year gained (LYG) or the cost per quality-adjusted life year (QALY) gained. Neither of these units modifies the amount of health gained, by the amount of health patients would have had if they had not been given the treatment under consideration, which may unfairly undervalue the treatments for poor prognosis conditions. How certain patients make decisions about their own treatment has previously been explored, but not how they, or doctors, would allocate hypothetical resource within a healthcare system given information on disease-treatment scenarios' prognoses with and without treatment. WHAT THIS STUDY ADDS: Information on prognosis without treatment is used within the resource allocation strategies of many doctors and most patients. Individuals use this information in a variety of different ways and a single dominant strategy for quantitative modification of health units is not apparent. Information on prognosis without treatment, or prognosis with standard treatment, is available from the control arm of randomized controlled clinical trials and should be used qualitatively to facilitate decision-making around the second inflexion point on cost per QALY/LYG acceptability curves. AIMS: Health economic assessments increasingly contribute to funding decisions on new treatments. Treatments for many poor prognosis conditions perform badly in such assessments because of high costs and modest effects on survival. We aimed to determine whether underlying shortness of prognosis should also be considered as a modifier in such assessments. METHODS: Two hundred and eighty-three doctors and 201 oncology patients were asked to allocate treatment resource between hypothetical patients with unspecified life-shortening diseases. The prognoses with and without treatment were varied such that consistent use of one of four potential allocation strategies could be deduced: life years gained (LYGs) - which did not incorporate prognosis without treatment information; percentage increase in life years (PILY); life expectancy with treatment (LEWT) or immediate risk of death (IRD). RESULTS: Random choices were rare; 47% and 64% of doctors and patients, respectively, used prognosis without treatment in their strategies; while 50% and 32%, respectively, used pure LYG-based strategies. Ranking orders were LYG > PILY > IRD > LEWT (doctors) and LEWT > LYG > IRD > PILY (patients). When LYG information alone could not be used, 76% of doctors prioritized shorter prognoses, compared with 45% of patients. CONCLUSIONS: Information on prognosis without treatment is used within the resource allocation strategies of many doctors and most patients, and should be considered as a qualitative modifier during the health economic assessments of new treatments for life-shortening diseases. A single dominant strategy incorporating this information for any quantitative modification of health units is not apparent.

Echocardiographic Screening for Pulmonary Hypertension in Congenital Heart Disease: JACC Review Topic of the Week.

Echocardiography is the mainstay in screening for pulmonary hypertension (PH). International guidelines suggest echocardiographic parameters for suspecting PH, but these may not apply to many adults with congenital heart disease (ACHD). PH is relatively common in ACHD patients and can significantly affect their exercise capacity, quality of life, and prognosis. Identification of patients who have developed PH and who may benefit from further investigations (including cardiac catheterization) and treatment is thus extremely important. A systematic review and survey of experts from the United Kingdom and Ireland were performed to assess current knowledge and practice on echocardiographic screening for PH in ACHD. This paper presents the findings of the review and expert statements on the optimal approaches when using echocardiography to assess ACHD patients for PH, with particular focus on major subgroups: patients with right ventricular outflow tract obstruction, patients with systemic right ventricles, patients with unrepaired univentricular circulation, and patients with tetralogy of Fallot with pulmonary atresia.

Stimulated tissue plasminogen activator release as a marker of endothelial function in humans.

The initiation, modulation, and resolution of thrombus associated with eroded or unstable coronary plaques are critically dependent on the efficacy of endogenous fibrinolysis. This is dependent on the cellular function of the surrounding endothelium and vascular wall. In particular, the acute release of tissue plasminogen activator from the endothelium makes an important contribution to the defense against intravascular thrombosis. Here, we describe the rationale and methodology for, and clinical relevance of, assessing acute endothelial tissue plasminogen activator release in humans. The investigation of endothelial fibrinolytic function has the potential to provide major new insights into the pathophysiology of cardiovascular disease, and to shape future therapeutic interventions.

Endothelial function and dysfunction. Part I: Methodological issues for assessment in the different vascular beds: a statement by the Working Group on Endothelin and Endothelial Factors of the European Society of Hypertension.

An enormous number of studies in the last two decades have been devoted to investigating the role of the endothelium in cardiovascular diseases. Nonetheless, the optimal methodology for investigating the multifaceted aspects of endothelial dysfunction is still under debate. Biochemical markers, molecular genetic tests and invasive and non-invasive tools with and without pharmacological and physiological stimuli have been introduced. Furthermore newer pharmacological tools have been proposed. However, the application of these methodologies should fulfil a number of requirements in order to provide conclusive answers in this area of research. Thus, the most relevant methodological issues in the research on endothelial function and dysfunction are summarized in this paper.

Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working Group on Endothelins and Endothelial Factors of the European Society of Hypertension.

Dysfunction of the vascular endothelium is a hallmark of most conditions that are associated with atherosclerosis and is therefore held to be an early feature in atherogenesis. However, the mechanisms by which endothelial dysfunction occurs in smoking, dyslipidaemia, hyperhomocysteinaemia, diabetes mellitus, arterial hypertension, cerebrovascular diseases, coronary artery disease and heart failure are complex and heterogeneous. Recent data indicate that endothelial dysfunction is often associated with erectile dysfunction, which can precede and predict cardiovascular disease in men. This paper will provide a concise overview of the mechanisms causing endothelial dysfunction in the different cardiovascular risk factors and disease conditions, and of the impact of the intervention measures and treatments.

Noninvasive assessment of arterial stiffness and risk of atherosclerotic events.

Investigation of arterial stiffness, especially of the large arteries, has gathered pace in recent years with the development of readily available noninvasive assessment techniques. These include the measurement of pulse wave velocity, the use of ultrasound to relate the change in diameter or area of an artery to distending pressure, and analysis of arterial waveforms obtained by applanation tonometry. Here, we describe each of these techniques and their limitations and discuss how the measured parameters relate to established cardiovascular risk factors and clinical outcome. We also consider which techniques might be most appropriate for wider clinical application. Finally, the effects of current and future cardiovascular drugs on arterial stiffness are also discussed, as is the relationship between arterial elasticity and endothelial function.

No adverse hemodynamic interaction between sildenafil and red wine.

OBJECTIVE: Our objective was to investigate the hemodynamic interaction between sildenafil and red wine. Sildenafil citrate (Viagra), a phosphodiesterase type 5 inhibitor, is an effective treatment for male erectile dysfunction that potentiates nitric oxide-mediated vasodilation. Alcohol is a commonly used recreational substance with complex vascular effects, which may, in part, be mediated by nitric oxide. Thus there is potential for an adverse hemodynamic interaction. METHODS: Eight healthy men received either 100 mg sildenafil, alcohol (750 mL red wine, 13.5% by volume), or the combination, in a 4-way, double placebo-controlled, randomized crossover study. Blood pressure, heart rate, and cardiac index were measured every 15 minutes up to 180 minutes. RESULTS: Results are expressed as mean +/- SEM. Red wine increased cardiac index (by 15% +/- 8%, P = .04) and heart rate (by 27% +/- 5%, P < .0001). Mean arterial pressure initially increased by approximately 5% and then fell by a maximum of approximately 7%. Sildenafil reduced peripheral vascular resistance (by 24% +/- 8%, P = .03) and mean arterial pressure (by 7% +/- 3%, P = .03) with no effect on cardiac index or heart rate. CONCLUSIONS: There is no clinically important hemodynamic interaction between sildenafil and alcohol (red wine).

Clinical potential of combined organic nitrate and phosphodiesterase type 5 inhibitor in treatment-resistant hypertension.

NO donor drugs (eg, isosorbide mononitrate; ISMN) and phosphodiesterase 5 inhibitors (eg, sildenafil) have antihypertensive properties, and the combination can markedly reduce blood pressure (BP). The objective of this "proof-of-concept" study was to investigate the effect on BP of a combination of single oral doses of sildenafil (50 mg) and ISMN (10 mg) in patients with treatment-resistant hypertension. Six subjects with treatment-resistant hypertension were included, and their usual antihypertensive medication was continued during the study. Sildenafil alone, ISMN alone, and the combination all reduced brachial and central aortic BPs compared with placebo. The combination of sildenafil and ISMN produced the largest fall in BP (maximum brachial BP reduction of 26/18 mm Hg compared with placebo), without producing significant adverse effects. ISMN, alone and in combination with sildenafil, also reduced arterial wave reflection and central BP. In summary, in patients with treatment-resistant hypertension maintained on their usual antihypertensive treatment, sildenafil given alone and ISMN given alone both acutely reduced BP. There was additional BP reduction when these drugs were given in combination. In this therapeutically challenging group of patients, the combination of an NO donor drug and a phosphodiesterase 5 inhibitor may represent an effective treatment. Longer studies in larger numbers of patients are now justified.

Effect of regular phosphodiesterase type 5 inhibition in hypertension.

There are no published controlled clinical trials of regular phosphodiesterase type 5 inhibitor therapy as a long-term treatment of hypertension. In a randomized, double-blind, 2-way crossover study, 25 otherwise untreated hypertensive subjects were administered 50 mg of sildenafil or matched placebo 3 times daily for 16 days, and the effects on ambulatory blood pressure (BP), clinic BP, arterial wave reflection, carotid-femoral pulse wave velocity, and brachial artery flow-mediated dilatation were assessed. Three subjects were withdrawn because of adverse effects, and the data from the remaining 22 subjects were analyzed. Sildenafil reduced ambulatory BP (mean [SE] change from baseline for average daytime BP: systolic -8 [2] mm Hg versus 2 [2] mm Hg with placebo, P<0.01; diastolic -6 [1] mm Hg versus 0 [1] mm Hg, P<0.01) and clinic BP (change from baseline to 1 hour after drug administration on day 16: systolic -5 [2] mm Hg versus 4 [2] mm Hg, P<0.01; diastolic -5 [1] mm Hg versus 2 [2] mm Hg, P<0.01). Compared with baseline, sildenafil, but not placebo, reduced arterial wave reflection both acutely and after chronic treatment, but the chronic change in arterial wave reflection was not statistically different from the chronic change with placebo. Sildenafil did not affect pulse wave velocity or flow-mediated dilatation. The main adverse effects of sildenafil, which were generally transient and rated as mild or moderate in severity, were dyspepsia, headache, and myalgia. In conclusion, regular sildenafil constitutes effective antihypertensive therapy. Further studies are warranted to evaluate the role of longer-acting phosphodiesterase type 5 inhibitors as antihypertensive agents in clinical practice.