Carlo R. Bartoli

Mechanisms of Inhaled Fine Particulate Air Pollution–induced Arterial Blood Pressure Changes

Background Epidemiologic studies suggest a positive association between fine particulate matter and arterial blood pressure, but the results have been inconsistent. Objectives We investigated the effect of ambient particles on systemic hemodynamics during a 5-hr exposure to concentrated ambient air particles (CAPs) or filtered air (FA) in conscious canines. Methods Thirteen dogs were repeatedly exposed via permanent tracheostomy to CAPs (358.1 ± 306.7 μg/m3, mean ± SD) or FA in a crossover protocol (55 CAPs days, 63 FA days). Femoral artery blood pressure was monitored continuously via implanted telemetry devices. We measured baroreceptor reflex sensitivity before and after exposure in a subset of these experiments (n = 10 dogs, 19 CAPs days, 20 FA days). In additional experiments, we administered α-adrenergic blockade before exposure (n = 8 dogs, 16 CAPs days, 15 FA days). Blood pressure, heart rate, rate–pressure product, and baroreceptor reflex sensitivity responses were compared using linear mixed-effects models. Results CAPs exposure increased systolic blood pressure (2.7 ± 1.0 mmHg, p = 0.006), diastolic blood pressure (4.1 ± 0.8 mmHg; p < 0.001), mean arterial pressure (3.7 ± 0.8 mmHg; p < 0.001), heart rate (1.6 ± 0.5 bpm; p < 0.001), and rate–pressure product (539 ± 110 bpm × mmHg; p < 0.001), and decreased pulse pressure (−1.7 ± 0.7 mmHg, p = 0.02). These changes were accompanied by a 20 ± 6 msec/mmHg (p = 0.005) increase in baroreceptor reflex sensitivity after CAPs versus FA. After α-adrenergic blockade, responses to CAPs and FA no longer differed significantly. Conclusions Controlled exposure to ambient particles elevates arterial blood pressure. Increased peripheral vascular resistance may mediate these changes, whereas increased baroreceptor reflex sensitivity may compensate for particle-induced alterations in blood pressure.

Effect of Ranolazine on Ventricular Vulnerability and Defibrillation Threshold in the Intact Porcine Heart

Introduction: Extensive in vitro studies and clinical evidence (MERLIN trial) indicate an antiarrhythmic potential of ranolazine, a novel antianginal agent. Programmed electrophysiologic testing was performed to quantify ranolazines effects on ventricular vulnerability and defibrillation thresholds and to gain insights into mechanisms.

Concentrated Ambient Particles Alter Myocardial Blood Flow During Acute Ischemia in Conscious Canines

Background Experimental and observational studies have demonstrated that short-term exposure to ambient particulate matter (PM) exacerbates myocardial ischemia. Objectives We conducted this study to investigate the effects of concentrated ambient particles (CAPs) on myocardial blood flow during myocardial ischemia in chronically instrumented conscious canines. Methods Eleven canines were instrumented with a balloon occluder around the left anterior descending coronary artery and catheters for determination of myocardial blood flow using fluorescent microspheres. Telemetric electrocardiographic and blood pressure monitoring was available for four of these animals. After recovery, we exposed animals by inhalation to 5 hr of either filtered air or CAPs (mean concentration ± SD, 349.0 ± 282.6 μg/m3) in a crossover protocol. We determined myocardial blood flow during a 5-min coronary artery occlusion immediately after each exposure. Data were analyzed using mixed models for repeated measures. The primary analysis was based on four canines that completed the protocol. Results CAPs exposure decreased total myocardial blood flow during coronary artery occlusion by 0.12 mL/min/g (p < 0.001) and was accompanied by a 13% (p < 0.001) increase in coronary vascular resistance. Rate–pressure product, an index of myocardial oxygen demand, did not differ by exposure (p = 0.90). CAPs effects on myocardial blood flow were significantly more pronounced in myocardium within or near the ischemic zone versus more remote myocardium (p interaction < 0.001). Conclusions These results suggest that PM exacerbates myocardial ischemia by increased coronary vascular resistance and decreased myocardial perfusion. Further studies are needed to elucidate the mechanism of these effects.

Mechanistic pathway(s) of acquired von willebrand syndrome with a continuous-flow ventricular assist device: in vitro findings.

In patients with a ventricular assist device (VAD), diminished high-molecular-weight von Willebrand factor (vWF) multimers may contribute to a bleeding diathesis. The mechanistic pathway(s) of vWF degradation and the role of ADAMTS-13, the vWF-cleaving metalloproteinase, are unknown. The objective of this study was to investigate the molecular mechanisms of VAD-induced vWF impairment in an in vitro system.Simple, mock circulatory loops (n = 4) were developed with a clinically approved, paracorporeal continuous-flow VAD. The loops were primed with anticoagulated, whole bovine blood (750 ml). The VAD was operated at constant blood flow and pressure. Blood samples were drawn at baseline and hourly for 6 hours. vWF multimers and ADAMTS-13 protein were quantified by agarose and polyacrylamide gel electrophoresis with immunoblotting. Plasma platelet factor 4 (PF4), a marker of platelet activation, was quantified via ELISA.Within 120 minutes, high-molecular-weight vWF multimers decreased, and low-molecular-weight multimers increased. Multiple low-molecular-weight vWF fragments emerged (~140, 176, 225, and 310 kDa). Total plasma ADAMTS-13 increased by 13 ± 3% (p < 0.05). Plasma PF4 increased by 21 ± 7% (p = 0.05).During VAD support, vWF degradation occurred quickly. Multiple mechanisms were responsible and included vWF cleavage by ADAMTS-13 (140 and 176 kDa fragments), and what may have been mechanical demolition of endogenous plasma vWF (225 kDa fragments) and nascent vWF (225 and 310 kDa fragments) from platelets. A modest increase in plasma ADAMTS-13 from activated platelets may have contributed to this process but was not the major mechanism. Mechanical demolition was likely the dominant process and warrants further evaluation.

Hemodynamic Support With a Microaxial Percutaneous Left Ventricular Assist Device (Impella) Protects Against Acute Kidney Injury in Patients Undergoing High-Risk Percutaneous Coronary InterventionNovelty and Significance

Rationale: Acute kidney injury (AKI) is common during high-risk percutaneous coronary intervention (PCI), particularly in those with severely reduced left ventricular ejection fraction. The impact of partial hemodynamic support with a microaxial percutaneous left ventricular assist device (pLVAD) on renal function after high-risk PCI remains unknown. Objective: We tested the hypothesis that partial hemodynamic support with the Impella 2.5 microaxial pLVAD during high-risk PCI protected against AKI. Methods and Results: In this retrospective, single-center study, we analyzed data from 230 patients (115 consecutive pLVAD-supported and 115 unsupported matched-controls) undergoing high-risk PCI with ejection fraction ⩽35%. The primary outcome was incidence of in-hospital AKI according to AKI network criteria. Logistic regression analysis determined the predictors of AKI. Overall, 5.2% (6) of pLVAD-supported patients versus 27.8% (32) of unsupported control patients developed AKI (P<0.001). Similarly, 0.9% (1) versus 6.1% (7) required postprocedural hemodialysis (P<0.05). Microaxial pLVAD support during high-risk PCI was independently associated with a significant reduction in AKI (adjusted odds ratio, 0.13; 95% confidence intervals, 0.09–0.31; P<0.001). Despite preexisting CKD or a lower ejection fraction, pLVAD support protection against AKI persisted (adjusted odds ratio, 0.63; 95% confidence intervals, 0.25–0.83; P=0.04 and adjusted odds ratio, 0.16; 95% confidence intervals, 0.12–0.28; P<0.001, respectively). Conclusions: Impella 2.5 (pLVAD) support protected against AKI during high-risk PCI. This renal protective effect persisted despite the presence of underlying CKD and decreasing ejection fraction.

Left ventricular volume unloading with axial and centrifugal rotary blood pumps.

Axial (AX) and centrifugal (CFG) rotary blood pumps have gained clinical acceptance for the treatment of advanced heart failure. Differences between AX and CFG designs and mechanism of blood flow delivery may offer clinical advantages. In this study, pump characteristics, and acute physiologic responses during support with AX (HeartMate II) and CFG (HVAD) left ventricular assist devices (LVAD) were investigated in mock loop and chronic ischemic heart failure bovine models. In the mock loop model, pump performance was characterized over a range of pump speeds (HeartMate II: 7,000–11,000 rpm, HVAD: 2,000–3,600 rpm) and fluid viscosities (2.7 cP, 3.2 cP, 3.7 cP). In the ischemic heart failure bovine model, hemodynamics, echocardiography, and end-organ perfusion were investigated. CFG LVAD had a flatter HQ curve, required less power, and had a more linear flow estimation relation than AX LVAD. The flow estimation error for the AX LVAD (±0.9 L/min at 2.7 cP, ±0.7 L/min at 3.2 cP, ±0.8 L/min at 3.7 cP) was higher than the CFG LVAD (±0.5 L/min at 2.7 cP, ±0.2 L/min at 3.2 cP, ±0.5 L/min at 3.7 cP). No differences in acute hemodynamics, echocardiography, or end-organ perfusion between AX and CFG LVAD over a wide range of support were statistically discernible. These findings suggest no pronounced acute differences in LV volume unloading between AX and CFG LVAD.

Technique for Implantation of Chronic Indwelling Aortic Access Catheters

Introduction For chronic, repeated cardiovascular studies in trained, conscious dogs, we describe a technique for implantation of an arterial vascular access catheter in the aorta. In comparison to previous techniques, our technique enables arterial catheter implantation without interrupting the systemic circulation or compromising peripheral arterial flow, requires only a single penetration of the aortic wall, and results in a catheter facing downstream in the aorta. The catheter is usable for both arterial blood sampling and intra-arterial injection of pharmacologic agents. Methods After thoracotomy, two purse-string sutures were set in the aortic wall at the catheter entry-site. A Debakey–Satinsky vena cava clamp was used to partially clamp and isolate a 3-cm portion of aorta surrounding the pursestring sutures. The catheter was prepared by inserting a 0.35 mm guide wire, curve tip end first, into a 7 French silicone Access Technologies catheter. This caused a slight bend at the tip of the catheter, which later facilitated entry into the aorta and prevented damage to the intima of the aortic wall. Catheters were tunneled from the thorax to the nape of the neck, attached to a subcutaneous vascular access port (VAP), and buried in the fascia. Catheters were locked with 2 mL heparinized saline (20 IU/mL). With this technique, we implanted 16 aortic vascular access catheters in 16 dogs. Results Of the 16 animals, 8 are being maintained for long-term study, 7 were sacrificed for histopathological examination, and 1 died due to improper catheter implantation without the aid of the curved-tip guide-wire technique. VAPs have remained bidirectionally patent in all long-term animals (n = 8) ongoing for 7.5 ± 1.4 months (mean ± SEM), with an ongoing maximum of 14 months. In these long-term animals, VAPs were used 5.88 ± 1.34 times. Postmortem examinations were performed on short-term animals (n = 8) sacrificed at 2.85 ± 1.29 months. The catheters have remained bidirectionally patent in all but the one animal that died. In the short-term animals, the 7 patent VAPs were used 12.71 ± 1.64 times. Histopathological examination of hematoxylin and eosin (H&E) slides from the catheter entry site revealed only minimal chronic inflammation. No evidence of tissue overgrowth around any of the intravascular segments of these silicone catheters was noted in any animal. Conclusions Thus, this dependable subcutaneous arterial access system provides a means for examining acute and long-term effects of environmental and pathophysiological influences in conscious dogs. These catheters have remained bidirectionally patent ongoing for more than 1 year and allowed infusion of agents and withdrawal of central arterial blood samples.

Long-term pericardial catheterization is associated with minimum foreign-body response.

Objectives: The goals of this study were to assess the feasibility and to characterize the foreign‐body response of a long‐term catheter in the pericardium. Background: Long‐term access to the normal pericardial space provides opportunities for diagnostic sampling and therapeutic intervention. Methods: After thoracotomy, in 7 anesthetized canines, the pericardium was opened and a 5 French silicone vascular access catheter was advanced 10 cm into the pericardial sac toward the apex of the heart. A hydraulic coronary balloon occluder was implanted (N = 6). Pericardium was sealed with Prolene suture. Catheters were tunneled to the nape of the neck, attached to a subcutaneous vascular access port, and buried in the fascia. Animals underwent multiple experimental coronary artery occlusions across months. At sacrifice, we assessed the histopathological response of pericardium and epicardium to chronically indwelling silicone catheters. Results: Post‐mortem examinations were performed at 213 days post‐operatively (mean, range = 96–413, N = 6), with one animal maintained for longer‐term study. At sacrifice, all catheters were bidirectionally patent and completely mobile in the pericardium without evidence of tissue overgrowth around the intrapericardial segment. Adhesion tissue was found only at the site of catheter entry through the pericardium. Microscopic histopathological examination at catheter entry site, surrounding pericardium, and myocardium revealed minimum chronic inflammation. Conclusions: This subcutaneous system provides dependable, chronic access to the normal pericardial space for drug delivery and sampling. The presence of a chronic silicone catheter in the pericardium does not precipitate clinically significant pathologic changes even after repeated ischemic events.

Hemodynamic changes and retrograde flow in LVAD failure.

In the event of left ventricular assist device (LVAD) failure, we hypothesized that rotary blood pumps will experience significant retrograde flow and induce adverse physiologic responses. Catastrophic LVAD failure was investigated in computer simulation with pulsatile, axial, and centrifugal LVAD, mock flow loop with pulsatile (PVAD) and centrifugal (ROTAFLOW), and healthy and chronic ischemic heart failure bovine models with pulsatile (PVAD), axial (HeartMate II), and centrifugal (HVAD) pumps. Simulated conditions were LVAD “off” with outflow graft clamped (baseline), LVAD “off” with outflow graft unclamped (LVAD failure), and LVAD “on” (5 L/min). Hemodynamics (aortic and ventricular blood pressures, LVAD flow, and left ventricular volume), echocardiography (cardiac volumes), and end-organ perfusion (regional blood flow microspheres) were measured and analyzed. Retrograde flow was observed with axial and centrifugal rotary pumps during LVAD failure in computer simulation (axial = -3.4 L/min, centrifugal = -2.8 L/min), mock circulation (pulsatile = -0.1 L/min, centrifugal = -2.7 L/min), healthy (pulsatile = -1.2 ± 0.3 L/min, axial = -2.2 ± 0.2 L/min, centrifugal = -1.9 ± 0.3 L/min), and ischemic heart failure (centrifugal = 2.2 ± 0.7 L/min) bovine models for all test conditions (p < 0.05). Differences between axial and centrifugal LVAD were statistically indiscernible. Retrograde flow increased ventricular end-systolic and end-diastolic volumes and workload, and decreased myocardial and end-organ perfusion during LVAD failure compared with baseline, LVAD support, and pulsatile LVAD failure.

Blood Flow in the Foreign-Body Capsules Surrounding Surgically Implanted Subcutaneous Devices

BACKGROUNDnSurgically implanted devices initiate inflammatory mechanisms and wound healing events and result in the formation of a thick fibrotic capsule that surrounds the device. To investigate the foreign-body response to devices of clinically relevant size, we used microspheres to determine regional blood flow patterns in the foreign-body capsule (FBC) and surrounding subcutaneous tissue after device implantation.nnnMATERIALS AND METHODSnIn 10 canines, we implanted 40 subcutaneous devices (polysulfone n = 20, silicone-coated n = 10, titanium n = 10). Via thoracotomy, animals were instrumented with left atrial and aortic vascular access catheters for serial microsphere injections and reference blood sampling. Regional blood flow was repeatedly determined in the FBC, subcutaneous fascia surrounding the FBC, and subcutaneous fascia distal to the surgical site up to 19 wk after device implantation (n = 55 determinations).nnnRESULTSnCompared with normal blood flow in subcutaneous fascia distal to the surgical site, blood flow increased in FBCs surrounding each device material (polysulfone P = 0.0035, silicone-coated P < 0.0001, titanium P < 0.0001). Additionally, blood flow increased in the subcutaneous fascia within half a centimeter of fibrous capsules encasing polysulfone (P = 0.0081) but not silicone (P = 0.3706) or titanium (P = 0.8160) devices. The time-course of measured blood flow changes within FBCs were similar for polysulfone and silicone but not for titanium.nnnCONCLUSIONSnSurgically implanted subcutaneous devices of clinically relevant size elicit increases in blood flow in the FBC as well as surrounding fascia. Device material may influence regional blood flow patterns.