Loss Of Pulsatility Research Articles

Optimal timing of heart transplantation in patients with an implantable left ventricular assist device.

Heart transplantation (HTPL) has been established as the gold-standard surgical treatment for end-stage heart failure. However, the use of a left ventricular assist device (LVAD) as a bridge to HTPL has been increasing due to the limited availability of HTPL donors. Currently, more than half of HTPL patients have a durable LVAD. Advances in LVAD technology have provided many benefits for patients on the waiting list for HTPL. Despite their advantages, LVADs also have limitations such as loss of pulsatility, thromboembolism, bleeding, and infection. In this narrative review, the benefits and shortcomings of LVADs as a bridge to HTPL are summarized, and the available literature evaluating the optimal timing of HTPL after LVAD implantation is reviewed. Because only a few studies have been published on this issue in the current era of third-generation LVADs, future studies are needed to draw a definite conclusion.

Loss of pulsatility with continuous-flow left ventricular assist devices and the significance of the arterial endothelium in von-Willebrand factor production and degradation.

Patients on continuous flow ventricular assist devices (CF-VADs) are at high risk for the development of Acquired von-Willebrand Syndrome (AVWS) and non-surgical bleeding. von Willebrand Factor (vWF) plays an essential role in maintaining hemostasis via platelet binding to the damaged endothelium to facilitate coagulation. In CF-VAD patients, degradation of vWF into low MW multimers that are inefficient in facilitating coagulation occurs and has been primarily attributed to the supraphysiological shear stress associated with the CF-VAD impeller. In this review, we evaluate information from the literature regarding the unraveling behavior of surface-immobilized vWF under pulsatile and continuous flow pertaining to: (A) the process of arterial endothelial vWF production and release into circulation, (B) the critical shear stress required to unravel surface bound versus soluble vWF which leads to degradation, and (C) the role of pulsatility in on the production and degradation of vWF. Taken together, these data suggests that the loss of pulsatility and its impact on arterial endothelial cells plays an important role in the production, release, unraveling, and proteolytic degradation of vWF into low MW multimers, contributing to the development of AVWS. Restoration of pulsatility can potentially mitigate this issue by preventing AVWS and minimizing the risk of non-surgical bleeding.

Lymphoedema conditions disrupt endothelial barrier function in vitro.

Lymphatic vessel contractions generate net antegrade pulsatile lymph flow. By contrast, impaired lymphatic vessels are often associated with lymphoedema and altered lymph flow. The effect of lymphoedema on the lymph flow field and endothelium is not completely known. Here, we characterized the lymphatic flow field of a platelet-specific receptor C-type lectin-like receptor 2 (CLEC2) deficient lymphoedema mouse model. In regions of lymphoedema, collecting vessels were significantly distended, vessel contractility was greatly diminished and pulsatile lymph flow was replaced by quasi-steady flow. In vitro exposure of human dermal lymphatic endothelial cells (LECs) to lymphoedema-like quasi-steady flow conditions increased intercellular gap formation and permeability in comparison to normal pulsatile lymph flow. In the absence of flow, LECs exposed to steady pressure (SP) increased intercellular gap formation in contrast with pulsatile pressure (PP). The absence of pulsatility in steady fluid flow and SP conditions without flow-induced upregulation of myosin light chain (MLCs) regulatory subunits 9 and 12B mRNA expression and phosphorylation of MLCs, in contrast with pulsatile flow and PP without flow. These studies reveal that the loss of pulsatility, which can occur with lymphoedema, causes LEC contraction and an increase in intercellular gap formation mediated by MLC phosphorylation.

B-4 | Clinical Outcomes of Patients with Transient Loss of Pulsatility During Hemodynamically Supported High Risk PCI

B-4 | Clinical Outcomes of Patients with Transient Loss of Pulsatility During Hemodynamically Supported High Risk PCI

Effect of pulsatility on shear-induced extensional behavior of Von Willebrand factor.

Patients with continuous flow ventricular assist devices (CF-VADs) are at high risk for non-surgical bleeding, speculated to associate with the loss of pulsatility following CF-VAD placement. It has been hypothesized that continuous shear stress causes elongation and increased enzymatic degradation of von Willebrand Factor (vWF), a key player in thrombus formation at sites of vascular damage. However, the role of loss of pulsatility on the unravelling behavior of vWF has not been widely explored. vWF molecules were immobilized on the surface of microfluidic devices and subjected to various pulsatile flow profiles, including continuous flow and pulsatile flow of different magnitudes, dQ/dt (i.e., first derivative of flow rate) of pulsatility and pulse frequencies to mimic in vivo shear flow environments with and without CF-VAD support. VWF elongation was observed using total internal reflection fluorescence (TIRF) microscopy. Besides, the vWF level is measured from the patients' blood sample before and after CF-VAD implantation from a clinical perspective. To our knowledge, this work is the first in providing direct, visual observation of single vWF molecule extension under controlled-pulsatile shear flow. Unravelling of vWF (total sample size n~200 molecules) is significantly reduced under pulsatile flow (p<0.01) compared to continuous flow. An increase in the magnitude of pulsatility further reduces unravelling lengths, while lower frequency of pulsatility (20 vs. 60 pulses per min) does not have a major effect on the maximum or minimum unravelling lengths. Evaluation of CF-VAD patient blood samples (n=13) demonstrates that vWF levels decreased by ~40% following CF-VAD placement (p<0.01), which correlates to single-molecule observations from a clinical point of view. Pulsatile flow reduces unfolding of vWF compared to continuous flow and a lower pulse frequency of 20 pulses/minute yielded comparable vWF unfolding to 60 pulses/minute. These findings could shed light on non-surgical bleeding associated with the loss of pulsatility following CF-VAD placement.

Is PTSD-Phenotype Associated with HPA-Axis Sensitivity? Feedback Inhibition and Other Modulating Factors of Glucocorticoid Signaling Dynamics

Previously, we found that basal corticosterone pulsatility significantly impacts the vulnerability for developing post-traumatic stress disorder (PTSD). Rats that exhibited PTSD-phenotype were characterized by blunted basal corticosterone pulsatility amplitude and a blunted corticosterone response to a stressor. This study sought to identify the mechanisms underlining both the loss of pulsatility and differences in downstream responses. Serial blood samples were collected manually via jugular vein cannula at 10-min intervals to evaluate suppression of corticosterone following methylprednisolone administration. The rats were exposed to predator scent stress (PSS) after 24 h, and behavioral responses were assessed 7 days post-exposure for retrospective classification into behavioral response groups. Brains were harvested for measurements of the glucocorticoid receptor, mineralocorticoid receptor, FK506-binding protein-51 and arginine vasopressin in specific brain regions to assess changes in hypothalamus–pituitary–adrenal axis (HPA) regulating factors. Methylprednisolone produced greater suppression of corticosterone in the PTSD-phenotype group. During the suppression, the PTSD-phenotype rats showed a significantly more pronounced pulsatile activity. In addition, the PTSD-phenotype group showed distinct changes in the ventral and dorsal CA1, dentate gyrus as well as in the paraventricular nucleus and supra-optic nucleus. These results demonstrate a pre-trauma vulnerability state that is characterized by an over-reactivity of the HPA and changes in its regulating factors.

Uncoupling of cerebral blood flow and brain oxygen saturation under non-pulsatile flow conditions

Introduction Non-pulsatile blood flow has been associated with altered microcirculatory perfusion. Soon after loss of pulsatility a marked heterogenous flow profile in the very small vessels ensues that is coupled with impaired oxygen extraction [1]. We investigated if changes in cerebral blood flow during non-pulsatile perfusion would affect brain tissue oxygenation assessed by near-infrared spectroscopy. Methods After approval by the local ethics committee thirty-two patients were included in this trial. They were studied during general anaesthesia, and stable hemodynamic conditions. Cerebral blood flow velocity in the middle cerebral artery was measured during non-pulsatile flow in the course of cardiac surgery on total extracorporeal bypass and again postoperatively on the intensive care unit during pulsatile flow. We modified cerebral blood flow by changing arterial partial pressures of carbon dioxide between 30, 40 and 50 mmHg. This was conducted either by a change of sweep gas flow at the heart lung machine or by changing respiratory rate at the respirator. In addition to flow measurements patients' regional brain oxygenation was determined. Relative changes in blood flow velocity were plotted against relative changes in regional brain saturation for both flow conditions and compared using Pearson's correlation. A p-value Results Absolute cerebral blood flow velocity was slightly higher during non-pulsatile flow when serum hemoglobin was diluted. Relative changes in cerebral blood flow velocity and regional brain oxygenation were tightly coupled independent of the flow condition. R-values for non-pulsatile and pulsatile blood flow were 0.724 and 0.796, respectively. However, during non-pulsatile flow the slope of the regression line was less steep as compared with pulsatile flow (P Discussion Despite greater cerebral perfusion during hypercapnia and non-pulsatile flow there was no equivalent rise in cerebral oxygenation. Assuming similar cerebral oxygen delivery this finding could be explained by impaired brain oxygen extraction in the high flow range while partial pressure of carbon dioxide was elevated. In contrast, during hypocapnia, when cerebral blood flow was decreased to a greater extent as during pulsatile flow, the concomitant desaturation was less pronounced. Both findings are in line with shunting on the microcirculatory level, whereby hyperperfused vessels coexist with vessels lacking adequate flow. These findings substantiate that loss of pulsatility seems to negatively affect nutritive tissue perfusion. Raised neurological morbidity in patients supported with non-pulsatile extracorporeal cardiac assist devices could potentially be attributable to the observed perfusion deficit [2].

Islet Hypersensitivity to Glucose Is Associated With Disrupted Oscillations and Increased Impact of Proinflammatory Cytokines in Islets From Diabetes-Prone Male Mice.

Pulsatile insulin release is the primary means of blood glucose regulation. The loss of pulsatility is thought to be an early marker and possible factor in developing type 2 diabetes. Another early adaptation in islet function to compensate for obesity is increased glucose sensitivity (left shift) associated with increased basal insulin release. We provide evidence that oscillatory disruptions may be linked with overcompensation (glucose hypersensitivity) in islets from diabetes-prone mice. We isolated islets from male 4- to 5-week-old (prediabetic) and 10- to 12-week-old (diabetic) leptin-receptor-deficient (db/db) mice and age-matched heterozygous controls. After an overnight incubation in media with 11 mM glucose, we measured islet intracellular calcium in 5, 8, 11, or 15 mM glucose. Islets from heterozygous 10- to 12-week-old mice were quiescent in 5 mM glucose and displayed oscillations with increasing amplitude and/or duration in 8, 11, and 15 mM glucose, respectively. Islets from diabetic 10- to 12-week-old mice, in contrast, showed robust oscillations in 5 mM glucose that declined with increasing glucose. Similar trends were observed at 4-5-weeks of age. A progressive left shift in maximal insulin release was also observed in islets as db/db mice aged. Reducing glucokinase activity with 1 mM D-mannoheptulose restored oscillations in 11 mM glucose. Finally, overnight low-dose cytokine exposure negatively impacted oscillations preferentially in high glucose in diabetic islets compared with heterozygous controls. Our findings suggest the following: 1) islets from frankly diabetic mice can produce oscillations, 2) elevated sensitivity to glucose prevents diabetic mouse islets from producing oscillations in normal postprandial (11-15 mM glucose) conditions, and 3) hypersensitivity to glucose may magnify stress effects from inflammation or other sources.

Beneficial aspects of real time flow measurements for the management of acute right ventricular heart failure following continuous flow ventricular assist device implantation

BackgroundOptimal management of acute right heart failure following the implantation of a left ventricular assist device requires a reliable estimation of left ventricular preload and contractility. This is possible by real-time pump blood flow measurements.Clinical caseWe performed implantation of a continuous flow left ventricular assist device in a 66 years old female patient with an end-stage heart failure on the grounds of a dilated cardiomyopathy. Real-time pump blood flow was directly measured by an ultrasonic flow probe placed around the outflow graft.DiagnosisThe progressive decline of real time flow and the loss of pulsatility were associated with an increase of central venous pressure, inotropic therapy and progressive renal failure suggesting the presence of an acute right heart failure. Diagnosis was validated by echocardiography and thermodilution measurements.TreatmentTemporary mechanical circulatory support of the right ventricle was successfully performed. Real time flow measurement proved to be a useful tool for the diagnosis and ultimately for the management of right heart failure including the weaning from extracorporeal membrane oxygenation.

The influence of acute hypothermia on renal function of anaesthetized euthermic and acclimatized rats.

Acute hypothermia has a major impact on cardiovascular control and renal function, but the extent to which these can be correlated with and influenced by changes in the altered pattern of sympathetic outflow to the kidneys is unclear. Moreover, it is unknown whether these responses to acute hypothermia are altered by chronic cold exposure and this study aimed to examine these factors. Renal function and renal sympathetic nerve activity (RSNA) were measured in male Wistar rats, euthermic (control) or acclimatized (exposed to progressively lower environmental temperature and photoperiod over 8 weeks), anaesthetized with chloralose/urethane. Reduction of core temperature (Tc) to 25 degrees C caused approximately 40% reduction in heart rate (HR), approximately 10% fall in mean arterial blood pressure (MABP), and decreased glomerular filtration rate (GFR) by approximately 50% and approximately 5% in euthermic and acclimatized rats, respectively. At 25 degrees C, urine flow increased some two-fold and absolute and fractional sodium excretions by 4- to 6-fold in the euthermic rats and to a lesser extent in the cold acclimatized rats, while basal levels of fluid excretion were higher in the acclimatized rats. A loss of pulsatility in the RSNA signal with cooling was seen in both groups. One of the factors contributing to modest hypotension during acute hypothermia is a reduction in RSNA. There was a progressive fall in the proportion of RSNA power at HR frequency with cooling of 20% in euthermic and 80% in acclimatized rats. All variables were restored to basal levels on rewarming in both groups of rats. We conclude that natriuresis and diuresis in euthermic rats during hypothermia is a consequence of a reduction in nephron reabsorption, reduced urine osmolality and possibly altered patterning of RSNA. In acclimatized rats, the response was modified by altered renal haemodynamics and/or hormonal influences induced by chronic cold exposure to minimize the hypothermic stress on renal function.

Acetabular blood flow during Bernese periacetabular osteotomy: an intraoperative study using laser Doppler flowmetry

Background: The blood flow to the acetabular fragment is of some concern in juxtaarticular pelvic osteotomies used for the treatment of hip dysplasia. No direct measurements have determined the effect of the Bernese periacetabular osteotomy (PAO) on acetabular perfusion. Methods: Acetabular perfusion was measured by means of laser Doppler flowmetry in 10 patients undergoing a PAO for symptomatic acetabular dysplasia. During the surgical procedure, the intraosseous high energy laser Doppler reliably depicts dynamic changes of small vessel blood flow. Measurements were performed after defined surgical steps to obtain sequential information on the blood perfusion of the acetabular fragment. Results: After complete separation of the acetabular fragment, nine out of 10 patients had pulsatile signals, but the blood flow (BF) significantly decreased by 77%. Corrective positioning of the fragment induced no further drop of the BF signal but a loss of pulsatility in six patients. After a recovery period of about 30 min following preliminary fixation of the fragment, reestablishment of the pulsatile signal and an increase of the BF signal was seen. At termination of the surgical procedure, five out of eight patients, who could be followed throughout the whole procedure, showed a clear pulsatile signal in the supraacetabular area. Bleeding of the supraacetabular cancellous surface could be observed in all acetabula. Conclusion: Despite careful preservation of soft tissues during the surgical procedure, a significant reduction of the blood flow in the supraacetabular region has been observed. Nevertheless, a pulsatile signal in more than 60% of the fragments after fragment correction and an increasing signal during the recovery period showed ongoing blood perfusion indicating reversible changes in the measured supraacetabular area. All osteotomies healed within eight weeks without showing signs of necrosis during a minimum follow up of 1 year.

Effect of pulse frequency and amplitude of D-Trp6-luteinizing hormone-releasing hormone on the pulsatile secretion of prolactin and LH

This work analyzes the effect of the pulse amplitude and frequency of a potent LHRH analog, D-Trp6-LHRH, in a perfusion system of isolated rat pituitary cells. To this purpose, we studied the LH and PRL secretion in different conditions: basal secretion, secretion after increasing concentrations of D-Trp6-LHRL (0.001, 0.01, 0.1 and 1 nM) secretion in function of the pulses frequency (2,3, and 4 pulses per h) and amplitude (0.1, 1 and 10 nM). The principal findings were: 1. The basal LH and PRL secretions was pulsatile; 2. The stimulation of LH by the analog was not dose-dependent; 3. When more than 2 pulses per h were administered, a rapid desensitization of gonadotroph to release LH (at 20-30 min) occurred; 4. There was a loss of pulsatility of PRL secretion with an increase in the pulse frequency and amplitude of the D-Trp6-LHRH, which was produced parallelly to the desensitization of the gonadotroph to release LH. In summary, these findings suggest that a rapid loss of pulsatility of the PRL when the D-Trp6-LHRH pulse frequency and amplitude is increased might be due to the early desensitization of the gonadotroph to the analog.

Non-insulin dependent diabetes mellitus: defects in insulin secretion.

NIDDM is a heterogeneous disorder, characterized by defects in insulin secretion as well as in insulin action. Several pathophysiological mechanisms are involved in the development of disturbances in insulin secretion. One of the histological features of islets of NIDDM patients is the deposition of amyloid-like material. Accumulation of amyloid over many years can lead to slowly progressive disruption of islet architecture and possibly to some of the abnormalities in insulin secretion, as found in NIDDM patients. Loss of pulsatility is the earliest detectable abnormality of insulin secretion in the disease, either as a specific early defect or as a disturbance caused by minimally elevated blood glucose levels. Although it has been shown that maximum insulin release is decreased by 50% in NIDDM, the B-cell sensitivity to glucose appears to be normal. Coregulatory factors such as prostaglandins do not play a major role in the derangements of insulin secretion in NIDDM. An imbalance between stimulatory and inhibitory endorphins, or in sympathetic tone may be of more importance. Hyperglycaemia by itself has a deleterious effect on insulin release, and may perpetuate the disturbances of insulin secretion.

Detection of occult colonic ischemia during aortic procedures: use of an intraoperative photoplethysmographic technique.

A photoplethysmographic technique was used in 30 consecutive patients who had abdominal aortic reconstruction to assess colonic viability intraoperatively. A sterile pulse oximeter probe was used to measure arterial pulsatility and transcolonic oxygen saturation (TCOS) in the proximal, midportion, and distal sigmoid colon before and after the reconstruction. No attempt at inferior mesenteric revascularization was made, irrespective of the photoplethysmographic results. The status of the colon was assessed between the third and sixth postoperative day by a colonoscopist unaware of the intraoperative data. Before the reconstructive procedure photoplethysmography displayed pulsatile flow in all patients with a mean TCOS of 95% +/- 0.4%. After reconstruction, 28 patients (93%) demonstrated unchanged pulsatility with mean TCOS of 94% +/- 0.4%. Despite ligation of a patent inferior mesenteric artery in 10 of these patients, all 28 had normal colonoscopic examinations. By contrast, two patients (6.7%) had a loss of photoplethysmographic pulsatility with unmeasurable TCOS. Both of these patients had ligation of an initially patent inferior mesenteric artery and demonstrated evidence of ischemic mucosal changes at colonoscopy. Intraoperative colonic photoplethysmography represents an easily performed, accurate method for predicting colonic viability. A loss of pulsatility suggests inadequate postreconstructive colonic perfusion and mandates revascularization of the inferior mesenteric artery.