Valvular regurgitation flow jet assessment using in vitro 4D flow MRI: Implication for mitral regurgitation.

PURPOSE: The purpose of this study was to evaluate the accuracy of four-dimensional (4D) flow MRI for direct assessment of peak velocity, flow volume, and momentum of a mitral regurgitation (MR) flow jets using an in vitro pulsatile jet flow phantom. We systematically investigated the impact of spatial resolution and quantification location along the jet on flow quantities with Doppler ultrasound as a reference for peak velocity. METHODS: Four-dimensional flow MRI data of a pulsatile jet through a circular, elliptical, and 3D-printed patient-specific MR orifice model was acquired with varying spatial resolution (1.5-5 mm isotropic voxel). Flow rate and momentum of the jet were quantified at various axial distances (x = 0-50 mm) and integrated over time to calculate Voljet and MTIjet . In vivo assessment of Voljet and MTIjet was performed on 3 MR patients. RESULTS: Peak velocities were comparable to Doppler ultrasound (3% error, 1.5 mm voxel), but underestimated with decreasing spatial resolution (-40% error, 5 mm voxel). Voljet was similar to regurgitant volume (RVol) within 5 mm, and then increased linearly with the axial distance (19%/cm) because of flow entrainment. MTIjet remained steady throughout the jet (2%/cm) as theoretically predicted. Four and 9 voxels across the jet were required to measure flow volume and momentum-time-integral within 10% error, respectively. CONCLUSION: Four-dimensional flow MRI detected accurate peak velocity, flow rate, and momentum for in vitro MR-mimicking flow jets. Spatial resolution significantly impacted flow quantitation, which otherwise followed predictions of flow entrainment and momentum conservation. This study provides important preliminary information for accurate in vivo MR assessment using 4D flow MRI.

Sodium nitrate alleviates functional muscle ischaemia in patients with Becker muscular dystrophy.

Becker muscular dystrophy (BMD) is a progressive X-linked muscle wasting disease for which there is no treatment. BMD is caused by in-frame mutations in the gene encoding dystrophin, a structural cytoskeletal protein that also targets other proteins to the sarcolemma. Among these is neuronal nitric oxide synthase mu (nNOSµ), which requires specific spectrin-like repeats (SR16/17) in dystrophin's rod domain and the adaptor protein α-syntrophin for sarcolemmal targeting. When healthy skeletal muscle is exercised, sarcolemmal nNOSµ-derived nitric oxide (NO) attenuates α-adrenergic vasoconstriction, thus optimizing perfusion. In the mdx mouse model of dystrophinopathy, this protective mechanism (functional sympatholysis) is defective, resulting in functional muscle ischaemia. Treatment with a NO-donating non-steroidal anti-inflammatory drug (NSAID) alleviates this ischaemia and improves the murine dystrophic phenotype. In the present study, we report that, in 13 men with BMD, sympatholysis is defective mainly in patients whose mutations disrupt sarcolemmal targeting of nNOSµ, with the vasoconstrictor response measured as a decrease in muscle oxygenation (near infrared spectroscopy) to reflex sympathetic activation. Then, in a single-arm, open-label trial in 11 BMD patients and a double-blind, placebo-controlled cross-over trial in six patients, we show that acute treatment with oral sodium nitrate, an inorganic NO donor without a NSIAD moiety, restores sympatholysis and improves post-exercise hyperaemia (Doppler ultrasound). By contrast, sodium nitrate improves neither sympatholysis, nor hyperaemia in healthy controls. Thus, a simple NO donor recapitulates the vasoregulatory actions of sarcolemmal nNOS in BMD patients, and constitutes a putative novel therapy for this disease.

Microbubble-Facilitated Ultrasound Catheter Ablation Causes Microvascular Damage and Fibrosis.

High-intensity ultrasound (US) ablation produces deeper myocardial lesions than radiofrequency ablation. The presence of intravascular microbubble (MB) contrast agents enhances pulsed-wave US ablation via cavitation-related histotripsy, potentially facilitating ablation in persistently perfused/conducting myocardium. US ablation catheters were developed and tested in the presence of MBs using ex vivo and in vivo models. High-frame-rate videomicroscopy and US imaging of gel phantom models confirmed MB destruction by inertial cavitation. MB-facilitated US ablation in an ex vivo perfused myocardium model generated shallow (2 mm) lesions and, in an in vivo murine hindlimb model, reduced perfusion by 42% with perivascular hemorrhage and inflammation, but no myonecrosis.

Augmentation of Tissue Perfusion in Patients With Peripheral Artery Disease Using Microbubble Cavitation.

OBJECTIVES: The authors investigated ideal acoustic conditions on a clinical scanner custom-programmed for ultrasound (US) cavitation-mediated flow augmentation in preclinical models. We then applied these conditions in a first-in-human study to test the hypothesis that contrast US can increase limb perfusion in normal subjects and patients with peripheral artery disease (PAD). BACKGROUND: US-induced cavitation of microbubble contrast agents augments tissue perfusion by convective shear and secondary purinergic signaling that mediates release of endogenous vasodilators. METHODS: In mice, unilateral exposure of the proximal hindlimb to therapeutic US (1.3 MHz, mechanical index 1.3) was performed for 10 min after intravenous injection of lipid microbubbles. US varied according to line density (17, 37, 65 lines) and pulse duration. Microvascular perfusion was evaluated by US perfusion imaging, and in vivo adenosine triphosphate (ATP) release was assessed using in vivo optical imaging. Optimal parameters were then used in healthy volunteers and patients with PAD where calf US alone or in combination with intravenous microbubble contrast infusion was performed for 10 min. RESULTS: In mice, flow was augmented in the US-exposed limb for all acoustic conditions. Only at the lowest line density was there a stepwise increase in perfusion for longer (40-cycle) versus shorter (5-cycle) pulse duration. For higher line densities, blood flow consistently increased by 3-fold to 4-fold in the US-exposed limb irrespective of pulse duration. High line density and long pulse duration resulted in the greatest release of ATP in the cavitation zone. Application of these optimized conditions in humans together with intravenous contrast increased calf muscle blood flow by >2-fold in both healthy subjects and patients with PAD, whereas US alone had no effect. CONCLUSIONS: US of microbubbles when using optimized acoustic environments can increase perfusion in limb skeletal muscle, raising the possibility of a therapy for patients with PAD. (Augmentation of Limb Perfusion With Contrast Ultrasound; NCT03195556).

Limb Perfusion During Exercise Assessed by Contrast Ultrasound Varies According to Symptom Severity in Patients with Peripheral Artery Disease.

BACKGROUND: In patients with peripheral artery disease (PAD), the severity of symptoms correlates poorly with ankle-brachial index (ABI). The aim of this study was to test the hypothesis that limb perfusion assessed using contrast-enhanced ultrasound (CEU) during contractile exercise varies according to functional class in patients with PAD, particularly those with ABIs in the 0.4 to 0.6 range whose symptoms vary widely. METHODS: Bilateral quantitative CEU perfusion imaging of the calf was performed in normal control subjects (n = 10) and patients with PAD who had at least one limb with a moderately reduced ABI (0.4-0.6; n = 17). Imaging was performed at rest and immediately after 30 sec of modest periodic (0.3-Hz) plantar flexion (10 W). RESULTS: In patients with PAD, Rutherford symptom classification for each limb varied widely, including in limbs with ABIs of 0.4 to 0.6 (n = 6 with mild or no symptoms, n = 14 with moderate to severe symptoms). CEU perfusion imaging parameters at rest were similar between control subjects and patients with PAD irrespective of ABI. In normal control subjects, limb flow increased on average by > 20-fold after only 30 sec of moderate exercise. In patients with PAD, muscle exercise perfusion for all limbs was reduced compared with control subjects and decreased according to the severity of ABI reduction, primarily from reduced microvascular flux rate. Even limbs with ABIs > 0.9 in patients with PAD had lower exercise perfusion than in control subjects (P = .03). In subjects with PAD, exercise perfusion was lower in those with moderate to severe versus mild symptoms when analyzed for all limbs (median, 30 IU/sec [interquartile range (IQR), 21-52 IU/sec] vs 84 IU/sec [IQR, 36-177 IU/sec]; P = .01) and limbs with ABIs of 0.4 to 0.6 (median, 26 IU/sec [IQR, 14-41 IU/sec] vs 54 IU/sec [IQR, 31-105 IU/sec]; P = .05). CONCLUSIONS: In patients with PAD, CEU exercise perfusion imaging detects differences in limb muscle perfusion that are likely to be responsible for differences in symptom severity and can detect the flow abnormalities from microvascular dysfunction even in limbs with normal ABIs.

Nocturia as an Unrecognized Symptom of Uncontrolled Hypertension in Black Men Aged 35 to 49 Years.

Background Hypertension is assumed to be asymptomatic. Yet, clinically significant nocturia (≥2 nightly voids) constitutes a putative symptom of uncontrolled hypertension. Black men with hypertension may be prone to nocturia because of blunted nocturnal blood pressure ( BP ) dipping, diuretic drug use for hypertension, and comorbidity that predisposes to nocturia. Here, we test the hypothesis that nocturia is a common and potentially reversible symptom of uncontrolled hypertension in black men. Methods and Results We determined the strength of association between nocturia (≥2 nightly voids) and high BP (≥135/85 mm Hg) by conducting in-person health interviews and measuring BP with an automated monitor in a large community-based sample of black men in their barbershops. Because nocturia is prevalent and steeply age-dependent after age 50 years, we studied men aged 35 to 49 years. Among 1673 black men (mean age, 43±4 years [ SD ]), those with hypertension were 56% more likely than men with normotension to have nocturia after adjustment for diabetes mellitus and sleep apnea (adjusted odds ratio, 1.56; 95% CI , 1.25-1.94 [ P<0.0001]). Nocturia prevalence varied by hypertension status, ranging from 24% in men with normotension to 49% in men whose hypertension was medically treated but uncontrolled. Men with untreated hypertension were 39% more likely than men with normotension to report nocturia ( P=0.02), whereas men whose hypertension was treated and controlled were no more likely than men with normotension to report nocturia ( P=0.69). Conclusions Uncontrolled hypertension was an independent determinant of clinically important nocturia in a large cross-sectional community-based study of non-Hispanic black men aged 35 to 49 years. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unqiue identifier: NCT 02321618.

Acute Effect of Hookah Smoking on the Human Coronary Microcirculation.

Hookah (water pipe) smoking is a major new understudied epidemic affecting youth. Because burning charcoal is used to heat the tobacco product, hookah smoke delivers not only nicotine but also large amounts of charcoal combustion products, including carbon-rich nanoparticles that constitute putative coronary vasoconstrictor stimuli and carbon monoxide, a known coronary vasodilator. We used myocardial contrast echocardiography perfusion imaging with intravenous lipid shelled microbubbles in young adult hookah smokers to determine the net effect of smoking hookah on myocardial blood flow. In 9 hookah smokers (age 27 ± 5 years, mean ± SD), we measured myocardial blood flow velocity (ß), myocardial blood volume (A), myocardial blood flow (A × ß) as well as myocardial oxygen consumption (MVO2) before and immediately after 30 minutes of ad lib hookah smoking. Myocardial blood flow did not decrease with hookah smoking but rather increased acutely (88 ± 10 to 120 ± 19 a.u./s, mean ± SE, p = 0.02), matching a mild increase in MVO2 (6.5 ± 0.3 to 7.6 ± 0.4 ml·minute(-1), p <0.001). This was manifested primarily by increased myocardial blood flow velocity (0.7 ± 0.1 to 0.9 ± 0.1 second(-1), p = 0.01) with unchanged myocardial blood volume (133 ± 7 to 137 ± 7 a.u., p = ns), the same pattern of coronary microvascular response seen with a low-dose ß-adrenergic agonist. Indeed, with hookah, the increased MVO2 was accompanied by decreased heart rate variability, an indirect index of adrenergic overactivity, and eliminated by ß-adrenergic blockade (i.v. propranolol). In conclusion, nanoparticle-enriched hookah smoke either is not an acute coronary vasoconstrictor stimulus or its vasoconstrictor effect is too weak to overcome the physiologic dilation of coronary microvessels matching mild cardiac ß-adrenergic stimulation.