Using a Mock Circulatory Loop as a Regulatory Science Tool to Simulate Different Heart Failure Conditions.

Mechanical circulatory support (MCS) device therapy is one of the primary treatment options for end-stage heart failure (HF), whereby a mechanical pump is integrated with the failing heart to maintain adequate tissue perfusion. The ISO 14708-5:2020 standard prescribes generic guidelines for nonclinical device evaluation and system performance testing of MCS devices using a mock circulatory loop (MCL). However, the utility of MCLs in premarket regulatory submissions of MCS devices is ambiguous, and the specific disease states that the device is intended to treat are not usually simulated. Hence, we aim to outline the potential of MCLs as a valuable regulatory science tool for characterizing MCS device systems by adequately representing target clinical-use HF conditions on the bench. Target pathophysiologic hemodynamics of HF conditions (i.e., cardiogenic shock (CS), left ventricular (LV) hypertrophy secondary to hypertension, and coronary artery disease), along with a healthy adult at rest and a healthy adult during exercise are provided as recommended test conditions. The conditions are characterized based on LV, aorta, and left atrium pressures using recommended cardiac hemodynamic indices such as systolic, diastolic, and mean arterial pressure, mean cardiac output (CO), cardiac cycle time, and systemic vascular resistance. This study is a first step toward standardizing MCLs to generate well-defined target HF conditions used to evaluate MCS devices.

Design of a "Lean" Case Report Form for Heart Failure Therapeutic Development.

The development of treatments for heart failure (HF) is challenged by burdensome clinical trials. Reducing the need for extensive data collection and increasing opportunities for data compatibility between trials may improve efficiency and reduce resource burden. The Heart Failure Collaboratory (HFC) multi-stakeholder consortium sought to create a lean case report form (CRF) for use in HF clinical trials evaluating cardiac devices. The HFC convened patients, clinicians, clinical researchers, the U.S. Food and Drug Administration (FDA), payers, industry partners, and statisticians to create a consensus core CRF. Eight recent clinical trial CRFs for the treatment of HF from 6 industry partners were analyzed. All CRF elements were systematically reviewed. Those elements deemed critical for data collection in HF clinical trials were used to construct the final, harmonized CRF. The original CRFs included 176 distinct data items covering demographics, vital signs, physical examination, medical history, laboratory and imaging testing, device therapy, medications, functional and quality of life assessment, and outcome events. The resulting, minimally inclusive CRF device contains 75 baseline data items and 6 events, with separate modular additions that can be used depending on the additional detail required for a particular intervention. The consensus electronic form is now freely available for use in clinical trials. Creation of a core CRF is important to improve clinical trial efficiency in HF device development in the United States. This living document intends to reduce clinical trial administrative burden, increase evidence integrity, and improve comparability of clinical data between trials.

A Mild Version of Danon Disease Caused by a Newly Recognized Mutation in the Lysosome-associated Membrane Protein-2 Gene.

We present the case of a patient with dilated cardiomyopathy caused by a novel mutation in the lysosome-associated membrane protein-2 (LAMP-2) gene. Patients with pathogenic mutations of this gene typically suffer from Danon disease - a condition that leads to cognitive decline, severe skeletal myopathy, and severe hypertrophic cardiomyopathy. Our patient's presentation and clinical course, however, is different and much less severe than other patients with this disease. He did not suffer from neurologic and musculoskeletal complications. He is also possibly the longest-known survivor of this disease without a heart transplant. This disease is unfamiliar to many physicians, and our case highlights the importance of an awareness of this disorder, particularly because of its implications for both the patient and his family.

Assessment of pulmonary arterial hypertension in patients with systemic sclerosis: comparison of noninvasive tests with results of right-heart catheterization.

OBJECTIVE: Pulmonary hypertension (PH) is an ominous complication in patients with scleroderma (systemic sclerosis, SSc). We compared noninvasive assessment of PH with pulmonary artery (PA) pressures obtained by right-heart catheterization (RHC). METHODS: Forty-nine patients with SSc were evaluated for suspected PH based on clinical findings, progressive dyspnea, and pulmonary function tests (PFT). PH was defined as mean PA pressure > or = 25 mm Hg, or > or = 30 mm Hg after exercise, with normal pulmonary capillary wedge pressure (PCW). Doppler echocardiography (echo) and cardiac magnetic resonance imaging (MRI) were performed within 4 hours of RHC, and the predictive accuracy of the tests was compared. RESULTS: RHC identified 24/49 (49%) patients with PH. The noninvasive cutpoints were: estimated right ventricular systolic pressure > 47 mm Hg by echo; diameter of the main PA > 28 mm by MRI; and the ratio of forced vital capacity to diffusion capacity (%FVC/%DLCO) > 2.0 by PFT. Echo classified 38 subjects correctly (14/24 with and 24/25 without PH; sensitivity 58%, specificity 96%). The area under receiver-operating characteristic curve (AUC) was 0.84 for echo. MRI measurement of PA diameter had a sensitivity of 68% and specificity 71% (AUC 0.78). PFT evaluation had a sensitivity of 71% and specificity of 72% (AUC 0.76). CONCLUSION: In evaluation of SSc with suspected PH, echo appeared to be the most useful among the noninvasive tests, mainly due to the high specificity, high positive predictive value, and highest AUC. However, due to the low sensitivity of noninvasive testing, RHC should remain the gold standard.

Free-breathing delayed hyperenhanced imaging of the myocardium: a clinical application of real-time navigator echo imaging.

PURPOSE: To compare a free-breathing (FB) acquisition with the current standard of breath-holding (BH) in a clinical setting using identical two-dimensional MR pulse sequences for imaging of myocardial delayed hyperenhancement. MATERIALS AND METHODS: Two-dimensional gadolinium-enhanced images were acquired using FB and BH techniques in 18 subjects to evaluate delayed enhancement of myocardial infarction. The FB acquisition used a navigator echo to monitor the position of the right hemidiaphragm for respiratory gating and correction. Visual analysis using a 16-segment model, quantitative signal difference to noise ratios, and percent left ventricle (LV) viability measurements for the two acquisition types were statistically compared. RESULTS: An excellent agreement between two-dimensional BH and two-dimensional FB acquisitions was found. In one patient, a nontransmural infarct was seen only in the FB images. There were no statistically significant differences in the number of infarcted segments or the measured signal difference to noise ratios (SDNR) between the two methods. Linear regression and Bland Altman analysis of the percentage LV viable myocardium yielded a good fit and narrow limits of agreement. CONCLUSION: An FB navigator echo acquisition can be effectively used in the setting of myocardial delay hyperenhanced imaging. Image quality is similar or superior to that of BH imaging.

A novel nonobstructive intravascular MRI coil: in vivo imaging of experimental atherosclerosis.

OBJECTIVE: MRI is being used to characterize the composition of atherosclerotic plaques. However, the resolution achievable using surface radiofrequency coils is limited by the signal to noise ratio. We studied the utility of a new intravascular (IV) MRI probe for high-resolution in vivo imaging of atherosclerotic lesions. METHODS AND RESULTS: Balloon-injured Watanabe heritable hyperlipidemic rabbits served as the experimental model of atherosclerosis. The newly developed IV MRI probe is 1.3 mm in diameter and can be positioned over a guidewire. MRI was performed with both an external phased-array coil and the IV MR coil. MR observations were correlated with histopathology. After MRI, the animals were killed and analysis of agreement between MR and histopathology was performed. The IV MR coil allows aortic images to be obtained with 156x156 micro m(2) in-plane resolution versus 352x352 micro m(2) when used with the external phased-array coil. No significant motion artifacts were noted, despite the continuation of arterial blood flow during image acquisition around the IV probe. The different components of the atherosclerotic lesions (lipid core and fibrous cap) were easily identified. There was an excellent agreement between MRI with the IV coil and histopathology by simple linear regression for both the mean wall thickness (r=0.88, slope 0.82, P<0.0001) and vessel wall area (r=0.86, slope 1.08, P<0.0001). CONCLUSIONS: The new nonobstructive design for this intravascular coil provides great promise for additional work in high-resolution MRI characterization of atherosclerotic plaques in vivo. The ability to position the probe with a guidewire allows its placement under fluoroscopic or MRI guidance, whereas its size is compatible with human coronary arteries.