Ultrastrong and Flexible Hybrid Hydrogels based on Solution Self-Assembly of Chitin Nanofibers in Gelatin Methacryloyl (GelMA).

We demonstrate ultrastrong and flexible hydrogels by self-assembling chitin nanofiber in the presence of gelatin methacryloyl. We tune the mechanical properties of the hydrogel with chitin nanofiber content and show proof-of-concept applications in engineering vascular tissue.

Transcatheter Replacement of Stenotic Aortic Valve Normalizes Cardiac-Coronary Interaction by Restoration of Systolic Coronary Flow Dynamics as Assessed by Wave Intensity Analysis.

BACKGROUND: Aortic valve stenosis (AS) can cause angina despite unobstructed coronary arteries, which may be related to increased compression of the intramural microcirculation, especially at the subendocardium. We assessed coronary wave intensity and phasic flow velocity patterns to unravel changes in cardiac-coronary interaction because of transcatheter aortic valve implantation (TAVI). METHODS AND RESULTS: Intracoronary pressure and flow velocity were measured at rest and maximal hyperemia in undiseased vessels in 15 patients with AS before and after TAVI and in 12 control patients. Coronary flow reserve, systolic and diastolic velocity time integrals, and the energies of forward (aorta-originating) and backward (microcirculatory-originating) coronary waves were determined. Coronary flow reserve was 2.8±0.2 (mean±SEM) in control and 1.8±0.1 in AS (P<0.005) and was not restored by TAVI. Compared with control, the resting backward expansion wave was 45% higher in AS. The peak of the systolic forward compression wave was delayed in AS, consistent with a delayed peak aortic pressure, which was partially restored after TAVI. The energy of forward waves doubled after TAVI, whereas the backward expansion wave increased by >30%. The increase in forward compression wave with TAVI was related to an increase in systolic velocity time integral. AS or TAVI did not alter diastolic velocity time integral. CONCLUSIONS: Reduced coronary forward wave energy and systolic velocity time integral imply a compromised systolic flow velocity with AS that is restored after TAVI, suggesting an acute relief of excess compression in systole that likely benefits subendocardial perfusion. Vasodilation is observed to be a major determinant of backward waves.

Impact of Aortic Valve Stenosis on Coronary Hemodynamics and the Instantaneous Effect of Transcatheter Aortic Valve Implantation.

BACKGROUND: Aortic valve stenosis (AS) induces compensatory alterations in left ventricular hemodynamics, leading to physiological and pathological alterations in coronary hemodynamics. Relief of AS by transcatheter aortic valve implantation (TAVI) decreases ventricular afterload and is expected to improve microvascular function immediately. We evaluated the effect of AS on coronary hemodynamics and the immediate effect of TAVI. METHODS AND RESULTS: Intracoronary pressure and flow velocity were simultaneously assessed at rest and at maximal hyperemia in an unobstructed coronary artery in 27 patients with AS before and immediately after TAVI and in 28 patients without AS. Baseline flow velocity was higher and baseline microvascular resistance was lower in patients with AS as compared with controls, which remained unaltered post-TAVI. In patients with AS, hyperemic flow velocity was significantly lower as compared with controls (44.5±14.5 versus 54.3±18.6 cm/s; P=0.04). Hyperemic microvascular resistance (expressed in mm Hg·cm·s(-1)) was 2.10±0.69 in patients with AS as compared with 1.80±0.60 in controls (P=0.096). Coronary flow velocity reserve in patients with AS was lower, 1.9±0.5 versus 2.7±0.7 in controls (P<0.001). Improvement in coronary hemodynamics after TAVI was most pronounced in patients without post-TAVI aortic regurgitation. In these patients (n=20), hyperemic flow velocity increased significantly from 46.24±15.47 pre-TAVI to 56.56±17.44 cm/s post-TAVI (P=0.003). Hyperemic microvascular resistance decreased from 2.03±0.71 to 1.66±0.45 (P=0.050). Coronary flow velocity reserve increased significantly from 1.9±0.4 to 2.2±0.6 (P=0.009). CONCLUSIONS: The vasodilatory reserve capacity of the coronary circulation is reduced in AS. TAVI induces an immediate decrease in hyperemic microvascular resistance and a concomitant increase in hyperemic flow velocity, resulting in immediate improvement in coronary vasodilatory reserve.

Wave speed in human coronary arteries is not influenced by microvascular vasodilation: implications for wave intensity analysis.

Wave intensity analysis and wave separation are powerful tools for interrogating coronary, myocardial and microvascular physiology. Wave speed is integral to these calculations and is usually estimated by the single-point technique (SPc), a feasible but as yet unvalidated approach in coronary vessels. We aimed to directly measure wave speed in human coronary arteries and assess the impact of adenosine and nitrate administration. In 14 patients, the transit time Δt between two pressure signals was measured in angiographically normal coronary arteries using a microcatheter equipped with two high-fidelity pressure sensors located Δs = 5 cm apart. Simultaneously, intracoronary pressure and flow velocity were measured with a dual-sensor wire to derive SPc. Actual wave speed was calculated as DNc = Δs/Δt. Hemodynamic signals were recorded at baseline and during adenosine-induced hyperemia, before and after nitroglycerin administration. The energy of separated wave intensity components was assessed using SPc and DNc. At baseline, DNc equaled SPc (15.9 ± 1.8 vs. 16.6 ± 1.5 m/s). Adenosine-induced hyperemia lowered SPc by 40 % (p < 0.005), while DNc remained unchanged, leading to marked differences in respective separated wave energies. Nitroglycerin did not affect DNc, whereas SPc transiently fell to 12.0 ± 1.2 m/s (p < 0.02). Human coronary wave speed is reliably estimated by SPc under resting conditions but not during adenosine-induced vasodilation. Since coronary wave speed is unaffected by microvascular dilation, the SPc estimate at rest can serve as surrogate for separating wave intensity signals obtained during hyperemia, thus greatly extending the scope of WIA to study coronary physiology in humans.

Dynamic damping of the aortic pressure trace during hyperemia: the impact on fractional flow reserve measurement.

We report on two cases that illustrate an important caveat in the measurement of fractional flow reserve (FFR) in coronary arteries. To obtain accurate FFR measurements, two fundamental requirements must be fulfilled. One is to minimize microvascular resistance; the other is that there is no damping of the proximal aortic pressure trace. A problem with either of these requirements can be a source of serious error in the measurement of FFR. In each case we present here, despite a good aortic pressure trace at the start of the procedure, there is dynamic damping of the pressure trace during hyperemia, secondary to axial migration of the guiding catheter into the left main stem (LMS). In both cases, a normal aortic pressure trace (Pa) is present at baseline. After intracoronary adenosine injection, there was a fall in both mean Pa and distal coronary pressure (Pd) concomitant with damping of Pa, evidenced by loss of the dicrotic notch and ventricularization of the pressure trace. The resultant FFR value is underestimated. As hyperemia wears off, both pressure traces return to normal with good articulation of the dicrotic notch. When the procedure was repeated taking care to ensure that the guide did not move into the LMS during hyperemia, the Pa trace remained stable following intracoronary adenosine, while mean Pd decreased as before. In both cases, hemodynamically significant lesions were demonstrated that had been masked by the artifactual drop in Pa during the first attempt.

Does the instantaneous wave-free ratio approximate the fractional flow reserve?

OBJECTIVES: This study sought to examine the clinical performance of and theoretical basis for the instantaneous wave-free ratio (iFR) approximation to the fractional flow reserve (FFR). BACKGROUND: Recent work has proposed iFR as a vasodilation-free alternative to FFR for making mechanical revascularization decisions. Its fundamental basis is the assumption that diastolic resting myocardial resistance equals mean hyperemic resistance. METHODS: Pressure-only and combined pressure-flow clinical data from several centers were studied both empirically and by using pressure-flow physiology. A Monte Carlo simulation was performed by repeatedly selecting random parameters as if drawing from a cohort of hypothetical patients, using the reported ranges of these physiologic variables. RESULTS: We aggregated observations of 1,129 patients, including 120 with combined pressure-flow data. Separately, we performed 1,000 Monte Carlo simulations. Clinical data showed that iFR was +0.09 higher than FFR on average, with ±0.17 limits of agreement. Diastolic resting resistance was 2.5 ± 1.0 times higher than mean hyperemic resistance in patients. Without invoking wave mechanics, classic pressure-flow physiology explained clinical observations well, with a coefficient of determination of >0.9. Nearly identical scatter of iFR versus FFR was seen between simulation and patient observations, thereby supporting our model. CONCLUSIONS: iFR provides both a biased estimate of FFR, on average, and an uncertain estimate of FFR in individual cases. Diastolic resting myocardial resistance does not equal mean hyperemic resistance, thereby contravening the most basic condition on which iFR depends. Fundamental relationships of coronary pressure and flow explain the iFR approximation without invoking wave mechanics.

Synergistic adaptations to exercise in the systemic and coronary circulations that underlie the warm-up angina phenomenon.

BACKGROUND: The mechanisms of reduced angina on second exertion in patients with coronary arterial disease, also known as the warm-up angina phenomenon, are poorly understood. Adaptations within the coronary and systemic circulations have been suggested but never demonstrated in vivo. In this study we measured central and coronary hemodynamics during serial exercise. METHODS AND RESULTS: Sixteen patients (15 male, 61±4.3 years) with a positive exercise ECG and exertional angina completed the protocol. During cardiac catheterization via radial access, they performed 2 consecutive exertions (Ex1, Ex2) using a supine cycle ergometer. Throughout exertions, distal coronary pressure and flow velocity were recorded in the culprit vessel using a dual sensor wire while central aortic pressure was recorded using a second wire. Patients achieved a similar workload in Ex2 but with less ischemia than in Ex1 (P<0.01). A 33% decline in aortic pressure augmentation in Ex2 (P<0.0001) coincided with a reduction in tension time index, a major determinant of left ventricular afterload (P<0.001). Coronary stenosis resistance was unchanged. A sustained reduction in coronary microvascular resistance resulted in augmented coronary flow velocity on second exertion (both P<0.001). These changes were accompanied by a 21% increase in the energy of the early diastolic coronary backward-traveling expansion, or suction, wave on second exercise (P<0.05), indicating improved microvascular conductance and enhanced left ventricular relaxation. CONCLUSIONS: On repeat exercise in patients with effort angina, synergistic changes in the systemic and coronary circulations combine to improve vascular-ventricular coupling and enhance myocardial perfusion, thereby potentially contributing to the warm-up angina phenomenon.

Coronary wave intensity during the Valsalva manoeuvre in humans reflects altered intramural vessel compression responsible for extravascular resistance.

Our aim was to investigate the effect of altered cardiac-coronary interaction during the Valsalva manoeuvre (VM) on coronary wave intensity and the response of coronary microvascular resistance. In 13 patients, left ventricular (P(LV)) and aortic pressure were measured during catheterization, together with intracoronary pressure and blood flow velocity (U) via a dual-sensor guide wire advanced into an angiographically normal coronary artery. Signals were analysed for the following phases of VM: baseline (B1), onset of strain (S1), sustained strain (S2), onset of release (R1), maximal response during recovery (R2), and baseline after VM. The immediate effects of VM were most evident from diastolic P(LV) (LVDP), which increased from 11.0 ± 2.3 to 36.4 ± 2.7 mmHg between B1 and S1 and fell from 28.3 ± 3.4 to 8.3 ± 1.9 mmHg between S2 and R1. Wave intensities and rate pressure product (RPP) were only minimally affected at these transient phases, but coronary wave energies decreased by about 50% and RPP by 38% from S1 to S2, together with a 30% depression of LVdP/dt. All signals were restored to baseline values during the recovery. U did not vary significantly throughout the VM. Despite the depressed cardiac performance during VM strain, microvascular resistance, calculated with LVDP as backpressure, decreased by 31% from B1 to S2, whereas an increase via metabolically induced vasoconstriction was expected. Since coronary U remained essentially constant despite the marked reduction in oxygen consumption, microvascular vasoconstriction must have been compensated by a decrease in the contraction-mediated impediment on coronary blood flow, as confirmed by the reduced coronary wave energies.

Coronary pressure-flow relations as basis for the understanding of coronary physiology.

Recent technological advancements in the area of intracoronary physiology, as well as non-invasive contrast perfusion imaging, allow to make clinical decisions with respect to percutaneous coronary interventions and to identify microcirculatory coronary pathophysiology. The basic characteristics of coronary hemodynamics, as described by pressure-flow relations in the normal and diseased heart, need to be understood for a proper interpretation of these physiological measurements. Especially the hyperemic coronary pressure-flow relation, as well as the influence of cardiac function on it, bears great clinical significance. The interaction of a coronary stenosis with the coronary pressure-flow relation can be understood from the stenosis pressure drop-flow velocity relationship. Based on these relationships the clinically applied concepts of coronary flow velocity reserve, fractional flow reserve, stenosis resistance and microvascular resistance are discussed. Attention is further paid to the heterogeneous nature of myocardial perfusion, the vulnerability of the subendocardium and the role of collateral flow on hyperemic coronary pressure-flow relations. This article is part of a Special Issue entitled "Coronary Blood Flow".

Effect of the Valsalva maneuver on cardiac-coronary interaction assessed by wave intensity analysis.

The Valsalva maneuver (VM) provokes strong changes in the cardiovascular system and is therefore well suited to study the cardiac-coronary interaction in humans. In 12 patients undergoing catheterization we simultaneously recorded aortic pressure, left ventricular pressure, and intracoronary pressure (Pd) and flow velocity (U) while the patients were performing a VM. Coronary wave intensity was calculated (dI = dP*dU) at characteristic phases of the VM and related to hemodynamic parameters of left ventricular (LV) performance. During the strain, blood pressure increased transiently followed by a significant decrease (p < 0.001) at maximum strain. Changes in mean LV pressure followed the same pattern, while LV end-diastolic pressure increased to almost 40 mmHg (p < 0.001), with a 30% reduction in LV dP/dt (p < 0.005). Coronary flow velocity remained fairly constant throughout the VM. All hemodynamic values returned to the baseline at conclusion of the maneuver. Coronary wave intensity was strongly reduced during the strain and was related to the depression in LV performance. Wave intensity analysis clearly revealed the inherent features of cardiac-coronary interaction.

Peripheral blood and bone marrow changes after treatment with ATRA and G-CSF in AML, APL and blast crisis following Vaquez's disease.

The aim of the present study was to better understand the possibility of utilizing growth factors of the myelomonocytic line in acute leukemias. The study is an examination of morphological changes and marker behavior in peripheral and bone marrow cells in AML and APL during treatment both with all-transretinoic acid (ATRA) alone and in association with chemotherapy and G-CSF. The same treatment was carried out in a patient who had been diagnosed with Vaquez's disease 15 years earlier and currently presented a bone marrow and peripheral picture of AML (80% myeloblasts) with thrombocytopenia. We observed that treatment with ATRA, alone or in association with chemotherapy, was followed by a remission of AML and especially of APL, with amelioration of the general condition of the patients. The addition of G-CSF to ATRA at the end of chemotherapy, during consequent pancytopenia, produced a rapid increase in mature peripheral granulocytes and an apparent medullary complete remission, which was more prolonged in APL than in AML; there was no increase in peripheral blasts. Discontinuation of G-CSF was followed by a relapse in the patient with AML. A patient with Vaquez's disease, in remission for 15 years and presenting a progressive increase in bone marrow and peripheral myeloblasts, did not have a positive response to the administration of ATRA; however, the association of G-CSF to ATRA was followed by a complete remission. The morphological changes observed in bone marrow and peripheral granulocytes (with changes in the main cellular markers: CD11b, CD13, CD14, CD15, CD34) seemed to express progressive modification of the single elements towards differentiation, with progressive bone marrow reduction and peripheral disappearance of blasts. The data agree with the changes observed in in vitro blasts cultured in the presence of ATRA and G-CSF.

[Systemic lupus erythematosus (SLE) today]. / Il lupus eritematoso sistemico (LES) oggi.

SLE is a complex systemic disease which probably has a multifactorial genesis. The basis alteration takes the form of a severe immunoregulation disorders. From an epidemiological point of view, there are no certain links with country of origin or race; knowledge of the disease's etiology is equally limited. Clinical symptoms are widely variable according to the prevalent organ or apparatus pathology. The symptomatology of SLE is in fact highly polymorphous thus making it complex and sometimes difficult to diagnose. From a prognostic point of view, over recent years the future of these patients has appeared brighter than in the past. The current therapeutic approach uses a number of measures which can be used in combination or sequentially. It is precisely this varying combination of therapies that has led to a marked prolongation of survival and long disease-free periods.

In vitro binding of 125I-HCG to the rat ovary from birth to puberty.

Neither homogenates nor frozen ovarian sections of rats aged 1, 5 and 7 days demonstrated specific binding of 125I-HCG. However, from day 10 to day 35, the homogenates could bind specifically, with an equilibrium association constant in the range of 0.9-2.7 x 10(10) M-1. The binding capacity increased from 5.8 fmol/mg tissue at day 10 to 15.7 fmol/mg tissue at day 35. As revealed by autoradiograpy, the frozen ovarian sections from 10-day-old rats showed 125I-HCG binding localized over the interstitial and thecal tissues and, in the older age groups, also in the granulosa cells of follicles larger than 500 micrometers in diameter. These results indicate that LH/HCG receptors appear in the rat ovary at the beginning of the second postnatal week, and that the interstitial cells are the main site of action of LH before puberty.

Autoradiographic localization of binding sites for follicle stimulating hormone (FSH) in the boar testis.

The tubular localization of binding sites for 125I-FSH is demonstrated in vitro by the autoradiography on frozen sections of boar-testis. The uniform distribution of silver grains throughout the seminiferous epithelium suggests the presence of receptors for FSH also in the adluminal compartment. Similar results have been obtained using rat testis.

A histochemical approach to the study of human chorionic gonadotrophin receptors in the rat testis.

Standard suspensions of interstitial cells in PBS were exposed to the action of various fixatives, solvents (clearing agents), temperatures and U. V. light, in order to establish the effects of such chemical and physical agents on the HCG receptors. After exposure to the various agents, the interstitial cells were incubated with [125I]HCG for 2 h at 37 degrees C. To check the specificity of the reaction, competitive tests were performed with added excess non-iodinated HCG. Only formaldehyde fixation for short periods of time, preserved satisfactorily the specific binding activity of the receptors. A different degree of thermolability of the receptors was demonstrated, in relation to 37, 45, 54 and 60 degrees C, while freezing in liquid nitrogen had no effect on the receptors binding activity. After the binding reaction, solvents had a significant solubilizing effect on the HCG-receptor complexes. U. V. light had no significant damaging effect on the receptors. The application of the results for a histochemical approach to the study of the HCG receptors is discussed.