The role of cardiac magnetic resonance imaging in the assessment of heart failure with preserved ejection fraction.

Heart failure (HF) is a major cause of morbidity and mortality worldwide. Current classifications of HF categorize patients with a left ventricular ejection fraction of 50% or greater as HF with preserved ejection fraction or HFpEF. Echocardiography is the first line imaging modality in assessing diastolic function given its practicality, low cost and the utilization of Doppler imaging. However, the last decade has seen cardiac magnetic resonance (CMR) emerge as a valuable test for the sometimes challenging diagnosis of HFpEF. The unique ability of CMR for myocardial tissue characterization coupled with high resolution imaging provides additional information to echocardiography that may help in phenotyping HFpEF and provide prognostication for patients with HF. The precision and accuracy of CMR underlies its use in clinical trials for the assessment of novel and repurposed drugs in HFpEF. Importantly, CMR has powerful diagnostic utility in differentiating acquired and inherited heart muscle diseases presenting as HFpEF such as Fabry disease and amyloidosis with specific treatment options to reverse or halt disease progression. This state of the art review will outline established CMR techniques such as transmitral velocities and strain imaging of the left ventricle and left atrium in assessing diastolic function and their clinical application to HFpEF. Furthermore, it will include a discussion on novel methods and future developments such as stress CMR and MR spectroscopy to assess myocardial energetics, which show promise in unraveling the mechanisms behind HFpEF that may provide targets for much needed therapeutic interventions.

Comparison of exercise testing and CMR measured myocardial perfusion reserve for predicting outcome in asymptomatic aortic stenosis: the PRognostic Importance of MIcrovascular Dysfunction in Aortic Stenosis (PRIMID AS) Study.

AIMS: To assess cardiovascular magnetic resonance (CMR) measured myocardial perfusion reserve (MPR) and exercise testing in asymptomatic patients with moderate-severe AS. METHODS AND RESULTS: Multi-centre, prospective, observational study, with blinded analysis of CMR data. Patients underwent adenosine stress CMR, symptom-limited exercise testing (ETT) and echocardiography and were followed up for 12-30 months. The primary outcome was a composite of: typical AS symptoms necessitating referral for AVR, cardiovascular death and major adverse cardiovascular events. 174 patients were recruited: mean age 66.2 ± 13.34 years, 76% male, peak velocity 3.86 ± 0.56 m/s and aortic valve area index 0.57 ± 0.14 cm2/m2. A primary outcome occurred in 47 (27%) patients over a median follow-up of 374 (IQR 351-498) days. The mean MPR in those with and without a primary outcome was 2.06 ± 0.65 and 2.34 ± 0.70 (P = 0.022), while the incidence of a symptom-limited ETT was 45.7% and 27.0% (P = 0.020), respectively. MPR showed moderate association with outcome area under curve (AUC) = 0.61 (0.52-0.71, P = 0.020), as did exercise testing (AUC = 0.59 (0.51-0.68, P = 0.027), with no significant difference between the two. CONCLUSIONS: MPR was associated with symptom-onset in initially asymptomatic patients with AS, but with moderate accuracy and was not superior to symptom-limited exercise testing. ClinicalTrials.gov (NCT01658345).

Differences in performance of five types of aortic valve prostheses: haemodynamic assessment by dobutamine stress echocardiography.

BACKGROUND: In patients being considered for aortic valve replacement, there remains controversy over which design or tissue offers the best performance. We aimed to evaluate in a single study the haemodynamic performances of five different widely used aortic valve prostheses: stentless porcine xenograft (Elan), stentless bovine pericardium (Pericarbon Freedom), stented porcine xenograft (Aspire), stented bovine pericardium (More) and mechanical (Ultracor). We also compared them with normal aortic valves and stenosed valves of variable severity. METHODS AND RESULTS: Preoperative echocardiography and dobutamine stress echocardiography at 1 year postoperatively were undertaken in 106 patients (n=18-24 from each group). Stentless bioprostheses, whether porcine or bovine, displayed superior haemodynamics across nearly all echocardiographic parameters: lower gradients, larger effective orifice area, higher dimensionless severity index (DSI) and lower resistance, when compared with stented or mechanical prostheses. Comparing both stented designs, bovine tissue performed the worst at rest, but with stress, there was no difference. The stress performances of the stentless bioprostheses were similar to the mildly stenosed native aortic valve, whereas the performances of the stented and mechanical prostheses resembled that of native valves with mild-to-moderate stenoses. Haemodynamic differences, however, did not translate into differences in left ventricular mass reduction at 1 year. CONCLUSIONS: Stentless bioprostheses displayed haemodynamics superior to stented or mechanical prostheses and had the closest performance to a normal, native aortic valve. Stress DSI data, least reliant on variable annulus/valve sizes and flow rates, provided the best haemodynamic discrimination.

Pivotal role for endothelial tetrahydrobiopterin in pulmonary hypertension.

BACKGROUND: Pulmonary hypertension is a fatal disease characterized by vasoconstriction and vascular remodeling. Loss of endothelial nitric oxide bioavailability is implicated in pulmonary hypertension pathogenesis. Recent evidence suggests that the cofactor tetrahydrobiopterin (BH4) is an important regulator of nitric oxide synthase enzymatic function. METHODS AND RESULTS: In the hph-1 mouse with deficient BH4 biosynthesis, BH4 deficiency caused pulmonary hypertension, even in normoxic conditions, and greatly increased susceptibility to hypoxia-induced pulmonary hypertension. In contrast, augmented BH4 synthesis in the endothelium, by targeted transgenic overexpression of GTP-cyclohydrolase I (GCH), prevented hypoxia-induced pulmonary hypertension. Furthermore, specific augmentation of endothelial BH4 in hph-1 mice by crossing with GCH transgenic mice rescued pulmonary hypertension induced by systemic BH4 deficiency. Lung BH4 availability controlled pulmonary vascular tone, right ventricular hypertrophy, and vascular structural remodeling in a dose-dependent manner in both normoxia and hypoxia. Furthermore, BH4 availability had striking effects on the immediate vasoconstriction response to acute hypoxia. These effects of BH4 were mediated through the regulation of nitric oxide compared with superoxide synthesis by endothelial nitric oxide synthase. CONCLUSIONS: Endothelial BH4 availability is essential for maintaining pulmonary vascular homeostasis, is a critical mediator in the pathogenesis of pulmonary hypertension, and is a novel therapeutic target.

Congenic mapping and genotyping of the tetrahydrobiopterin-deficient hph-1 mouse.

The hph-1 ENU-mutant mouse provides a model of tetrahydrobiopterin deficiency for studying hyperphenylalaninaemia, dopa-response dystonia, and vascular dysfunction. We have successively localized the hph-1 mutation to a congenic interval of 1.6-2.8 Mb, containing the GCH gene encoding GTP cyclohydrolase I (GTP-CH I). We used these data to establish a PCR method for genotyping wild type, hph-1 and heterozygote mice, and found that heterozygote animals have partial tetrahydrobiopterin deficiency. These new findings will extend the utility of the hph-1 mouse in studies of GTP-CH I deficiency.

EPR quantification of vascular nitric oxide production in genetically modified mouse models.

With increasing use of genetically modified mice to study endothelial nitric oxide (NO) biology, methods for reliable quantification of vascular NO production by mouse tissues are crucial. We describe a technique based on electron paramagnetic resonance (EPR) spectroscopy, using colloid iron (II) diethyldithiocarbamate [Fe(DETC)2], to trap NO. A signal was seen from C57BL/6 mice aortas incubated with Fe(DETC)2, that increased 4.7-fold on stimulation with calcium ionophore A23187 [3.45+/-0.13 vs 0.73+/-0.13au (arbitrary units)]. The signal increased linearly with incubation time (r(2) = 0.93), but was abolished by addition of N(G)-nitro-l-arginine methyl ester (L-NAME) or endothelial removal. Stimulated aortas from eNOS knockout mice had virtually undetectable signals (0.14+/-0.06 vs 3.17+/-0.21 au in littermate controls). However, the signal was doubled from mice with transgenic eNOS overexpression (7.17+/-0.76 vs 3.37+/-0.43 au in littermate controls). We conclude that EPR is a useful tool for direct NO quantification in mouse vessels.