MMP-8 causes leftward shift in end-diastolic pressure-volume relationship and may explain the development of diastolic dysfunction in septic cardiomyopathy.

BACKGROUND: Septic cardiomyopathy (SCM) with diastolic dysfunction carries a poor prognosis, and the mechanisms underlying the development of diastolic dysfunction remain unclear. Matrix metalloproteinase-8 (MMP-8) is released from neutrophils and degrades collagen I. MMP-8 levels correlate with SCM severity. OBJECTIVES: We scrutinized, for the first time, the direct impact of MMP-8 on cardiac systolic and diastolic functions. METHODS: Isolated rat hearts were perfused with Krebs-Henseleit solution in a Langendorff setup with computer-controlled filling pressures of both ventricles at isovolumetric regime. The end-diastolic pressure (EDP) varied periodically between 3 and 20 mmHg. After baseline recordings, MMP-8 (100 µg/ml) was added to the perfusion. Short-axis views of both ventricles were continuously acquired by echocardiography. RESULTS: MMP-8 perfusion resulted in progressive decline in peak systolic pressures (Psys) in both ventricles, but without significant changes in their end-systolic pressure-area relationships (ESPARs). Counterintuitively, conspicuous leftward shifts of the end-diastolic pressure-area relationships (EDPARs) were observed in both ventricles. The LV end-diastolic area (EDA) decreased by 32.8±5.7%, (p=0.008), at EDP of 10.5±0.4 mmHg, when LV Psys dropped by 20%. The decline of Psys was primarily due to the decrease in EDA and restoring the baseline EDA by increasing EDP recovered 81.33 ± 5.87% of the pressure drops. CONCLUSION: Collagen I generates tensile (eccentric) stress, and its degradation by MMP-8 causes EDPVR leftward shift, resulting in diastolic and systolic dysfunctions. The diastolic dysfunction explains the clinically observed fluid unresponsiveness, while the decrease in EDV diminishes the systolic functions. MMP-8 can explain the development of SCM with diastolic dysfunction.

Novel Peripheral Perfusion Dynamics Indices for Detecting and Grading Arterial Stenosis.

PURPOSE: Peripheral artery disease causes severe morbidity, especially in diabetics and the elderly. There is a need for accurate noninvasive detection of peripheral arterial stenosis. The study has tested the hypothesis that arterial stenosis and the associated adaptation of the downstream circulation yield characteristic changes in the leg perfusion dynamics that enable early diagnosis, utilizing impedance plethysmography. METHODS: The arterial perfusion dynamic was derived from impedance plethysmography (IPG). Two degrees of arterial stenosis were emulated by inflating a blood-pressure cuff around the thigh to 45 and 90 mmHg, in healthy volunteers (n = 30). IPG signals were acquired continuously throughout the experiment. Ankle and brachial blood pressures were measured at the beginning of each experiment and at the end of each emulated stenosis phase. RESULTS: Thigh compressions did not affect the pulse-transit time, but prolonged the time to the peak perfusion wave. Segmentation of the perfusion upstroke into two phases, at the time point of maximum acceleration (MAT), revealed that arterial compression prolonged only the initial slow phase duration (SPd). The MAT and SPd were proportional to the emulated stenosis severity and detected the arterial stenosis with high sensitivity (> 93%) and specificity (100%). The SPd increased from 46.4 ± 21.2 ms at baseline to 75.4 ± 38.5 ms and 145 ± 39 ms under 45 mmHg and 90 mmHg compressions (p < 0.001), without affecting the pulse-transit time. CONCLUSIONS: The novel method and indices can identify and grade the emulated arterial stenosis with high accuracy and may assist in differentiating between focal arterial stenosis and widespread arterial hardening.

Extracorporeal acute cardiac pacing by high intensity focused ultrasound.

Ultrasound has been shown to produce Premature Ventricular Contractions (PVC's). Two clinical applications in which acute cardiac pacing by ultrasound may be valuable are: (1) preoperative patient screening in cardiac resynchronization therapy surgery; (2) Emergency life support, following an event of sudden death, caused by cardiac arrest. Yet, previously the demonstrated mean success rate of extra-systole induction by High Intensity Focused Ultrasound (HIFU) in rats is below 4.5% (Miller et al., 2011). This stands in contrast to previous work in rats using ultrasound (US) and ultrasound contrast agents (UCAs), where success rates of close to 100% were reported (Rota et al., 2006). Herein, bi-stage temporal sequences of accentuated negative pressure (rarefaction) and positive pressure HIFU transmission (insonation) patterns were applied to anaesthetized rats under real-time vital-signs monitoring and US imaging. This pattern of insonation first produces a gradual growth of dissolved gas cavities in tissue (cavitation) and then an ultrasonic impact. Results demonstrate sequences of successive successful HIFU pacing. Triggering insonation at different delays from the preceding ECG R-wave demonstrated successful HIFU pacing induction from mid ECG T-wave till the next ECG complex's PR interval. Spatially focusing the beam at different locations allows cumulative coverage of the whole left ventricle. Analysis of the acoustic wave patterns and temporal characteristics of paced PVCs is suggested to provide new insight into the mechanisms of HIFU cardiac pacing. Specifically, the observed HIFU pacing temporal success rate distribution suggests against sarcomere length modulation current being the dominant cellular level mechanism of HIFU cardiac pacing and may allow postulating that membrane deformation currents are dominant at the applied insonation conditions.