Lung-to-Heart Nano-in-Micro Peptide Promotes Cardiac Recovery in a Pig Model of Chronic Heart Failure.

BACKGROUND: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. OBJECTIVES: In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. METHODS: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. RESULTS: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. CONCLUSIONS: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart.

Differential pressure in shunt therapy: investigation of position-dependent intraperitoneal pressure in a porcine model.

OBJECT: The differential pressure between the intracranial and intraperitoneal cavities is essential for ventriculoperitoneal shunting. A determination of the pressure in both cavities is decisive for selecting the appropriate valve type and opening pressure. The intraperitoneal pressure (IPP)-in contrast to the intracranial pressure-still remains controversial with regard to its normal level and position dependency. METHODS: The authors used 6 female pigs for the experiments. Two transdermal telemetric pressure sensors (cranial and caudal) were implanted intraperitoneally with a craniocaudal distance of 30 cm. Direct IPP measurements were supplemented with noninvasive IPP measurements (intragastral and intravesical). The IPP was measured with the pigs in the supine (0°), 30°, 60°, and vertical (90°) body positions. After the pigs were euthanized, CT was used to determine the intraperitoneal probe position. RESULTS: With pigs in the supine position, the mean (± SD) IPP was 10.0 ± 3.5 cm H2O in a mean vertical distance of 4.5 ± 2.8 cm to the highest level of the peritoneum. The difference between the mean IPP of the cranially and the caudally implanted probes (Δ IPP) increased according to position, from 5.5 cm H2O in the 0° position to 11.5 cm H2O in the 30° position, 18.3 cm H2O in the 60° position, and 25.6 cm H2O in the vertical body position. The vertical distance between the probe tips (cranially implanted over caudally implanted) increased 3.4, 11.2, 19.3, and 22.3 cm for each of the 4 body positions, respectively. The mean difference between the Δ IPP and the vertical distance between both probe tips over all body positions was 1.7 cm H2O. CONCLUSIONS: The IPP is subject to the position-dependent hydrostatic force. Normal IPP is able to reduce the differential pressure in patients with ventriculoperitoneal shunts.