Electrical Diuretics: Dorsal Root Ganglion Stimulation to Increase Diuresis.

BACKGROUND: Stimulation of diuresis is an essential component of heart failure treatment to reduce fluid overload. Over time, increasing doses of loop diuretics are required to achieve adequate urine output, and approximately 30% to 45% of patients develop diuretic resistance. We investigated the feasibility of affecting renal afferent sensory nerves by dorsal root ganglion neurostimulation as an alternative to medication to increase diuresis. MATERIALS AND METHODS: Acute volume overload with an elevated and stable pulmonary capillary wedge pressure (PCWP) was induced by infusion of isotonic fluid in swine (N = 7). In each experiment, diuresis and blood electrolyte levels were measured during cycles of up to two hours (baseline, stimulation, poststimulation) through bladder catheterization. Efficacy was tested using bilateral dorsal root ganglion (bDRG) stimulation at the T11 and/or T12 vertebral levels. RESULTS: An elevated, stable PCWP (15 ± 4 mm Hg, N = 7) was obtained after uploading. Under these conditions, average diuresis increased 20% to 205% compared with no stimulation. Side effects such as motor stimulation were mitigated by decreasing current or terminated spontaneously without intervention. There was no negative effect on acute kidney function because blood electrolyte concentrations remained stable. When stimulation was deactivated, urine output decreased significantly but did not return to baseline levels, suggesting a carry-over effect of up to two hours. CONCLUSIONS: Electrical stimulation (bDRG) at T11 and/or T12 increased diuresis in an acute volume overload model. Side effects caused by unintended (motor) stimulation could be eliminated by reducing the electrical current while sustaining increased diuresis.

The autonomic nervous system as a therapeutic target in heart failure: a scientific position statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology.

Despite improvements in medical therapy and device-based treatment, heart failure (HF) continues to impose enormous burdens on patients and health care systems worldwide. Alterations in autonomic nervous system (ANS) activity contribute to cardiac disease progression, and the recent development of invasive techniques and electrical stimulation devices has opened new avenues for specific targeting of the sympathetic and parasympathetic branches of the ANS. The Heart Failure Association of the European Society of Cardiology recently organized an expert workshop which brought together clinicians, trialists and basic scientists to discuss the ANS as a therapeutic target in HF. The questions addressed were: (i) What are the abnormalities of ANS in HF patients? (ii) What methods are available to measure autonomic dysfunction? (iii) What therapeutic interventions are available to target the ANS in patients with HF, and what are their specific strengths and weaknesses? (iv) What have we learned from previous ANS trials? (v) How should we proceed in the future?

Mapping for Acute Transvenous Phrenic Nerve Stimulation Study (MAPS Study).

BACKGROUND: Central sleep apnea syndrome, correlated with the occurrence of heart failure, is characterized by periods of insufficient ventilation during sleep. This acute study in 15 patients aims to map the venous system and determine if diaphragmatic movement can be achieved by phrenic nerve stimulation at various locations within the venous system. METHODS: Subjects underwent a scheduled catheter ablation procedure. During the procedural waiting time, one multielectrode electrophysiology catheter was subsequently placed at the superior and inferior vena cava and the junctions of the left jugular and left brachiocephalic vein and right jugular and right brachiocephalic vein, for phrenic nerve stimulation (1-2 seconds ON/2-3 seconds OFF, 40 Hz, pulse width 210 µs). Diaphragmatic movement was assessed manually and by a breathing mask. During a follow-up assessment between 2 and 4 weeks postprocedure, occurrence of adverse events was assessed. RESULTS: In all patients diaphragmatic movement was induced at one or more locations using a median threshold of at least 2 V and maximally 7.5 V (i.e., e 3.3 mA, 14.2 mA). The lowest median current to obtain diaphragmatic stimulation without discomfort was found for the right brachiocephalic vein (4.7 mA). In 12/15 patients diaphragmatic movement could be induced without any discomfort, but in three patients hiccups occurred. CONCLUSION: Diaphragmatic stimulation from the brachiocephalic and caval veins is feasible. Potential side effects should be eliminated by adapting the stimulation pattern. This information could be used to design a catheter, combining cardiac pacing with enhancing diaphragm movement during a sleep apnea episode.

Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study.

INTRODUCTION: Vagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia. METHODS: We performed a randomized double-blind sham-controlled study in healthy male volunteers. A stimulation catheter was inserted in the left internal jugular vein at spinal level C5-C7, adjacent to the vagus nerve. In the tVNS group (n = 10), stimulation was continuously performed for 30 minutes (0-10 V, 1 ms, 20 Hz), starting 10 minutes before intravenous administration of 2 ng kg(-1) Escherichia coli lipopolysaccharide (LPS). Sham-instrumented subjects (n = 10) received no electrical stimulation. RESULTS: No serious adverse events occurred throughout the study. In the tVNS group, stimulation of the vagus nerve was achieved as indicated by laryngeal vibration. Endotoxemia resulted in fever, flu-like symptoms, and hemodynamic changes that were unaffected by tVNS. Furthermore, plasma levels of inflammatory cytokines increased sharply during endotoxemia, but responses were similar between groups. Finally, cytokine production by leukocytes stimulated with LPS ex vivo, as well as neutrophil phagocytosis capacity, were not influenced by tVNS. CONCLUSIONS: tVNS is feasible and safe, but does not modulate the innate immune response in humans in vivo during experimental human endotoxemia. TRIAL REGISTRATION: Clinicaltrials.gov NCT01944228. Registered 12 September 2013.

Increase of ventricular interval during atrial fibrillation by atrioventricular node vagal stimulation: chronic clinical atrioventricular-nodal stimulation download study.

BACKGROUND: Patients with a high ventricular rate during atrial fibrillation (AF) are at increased risk of receiving inappropriate implantable cardioverter defibrillator shocks. The objective was to demonstrate the feasibility of high frequency atrioventricular-nodal stimulation (AVNS) to reduce the ventricular rate during AF to prevent inappropriate implantable cardioverter defibrillator shocks. METHODS AND RESULTS: Patients with a new atrial lead placement as part of a cardiac resynchronization therapy and defibrillator implant and a history of paroxysmal or persistent AF were eligible. If proper atrial lead position was confirmed, AVNS software was uploaded to the cardiac resynchronization therapy device, tested, and optimized. AVNS was delivered via a right atrial pacing lead positioned in the posterior right atrium. Software allowed initiation of high frequency bursts triggered on rapidly conducted AF. Importantly, the efficacy was evaluated during spontaneous AF episodes between 1 and 6 months after implant. Forty-four patients were enrolled in 4 centers. Successful atrial lead placement occurred in 74%. Median implant time of the AVNS lead was 37 minutes. In 26 (81%) patients, manual AVNS tests increased the ventricular interval by >25%. Between 1 and 6 months, automatic AVNS activations occurred in 4 patients with rapidly conducted AF, and in 3 patients, AVNS slowed the ventricular rate out of the implantable cardioverter defibrillator shock zone. No adverse events were associated with the AVNS software. CONCLUSIONS: The present study demonstrated the feasibility of implementation of AVNS in a cardiac resynchronization therapy and defibrillator system. AVNS increased ventricular interval >25% in 81% of patients. AVNS did not influence the safety profile of the cardiac resynchronization therapy and defibrillator system. CLINICAL TRIAL REGISTRATION: clinicaltrials.gov; Unique Identifier: NCT01095952.

Selectivity for specific cardiovascular effects of vagal nerve stimulation with a multi-contact electrode cuff.

The cardiovascular system can be influenced by electrically stimulating the vagal nerve. Selectivity for specific cardiac fibers may be limited when stimulating at the cervical level. Our objective was to increase effectiveness and selectivity for cardiovascular effects of vagal nerve stimulation by using local bipolar stimulation in one nerve cross section using a multi-contact cuff instead of less localized stimulation using a tripolar ring electrode. Both types of cuff electrodes were compared with respect to their relative effects on R-R interval (RRI), P-Q interval (PQI), left ventricular contractility (LVC), and left ventricular pressure (P(LV)) in seven pigs. Stimulation using the optimal bipolar configuration on the multi-contact cuff significantly affected RRI, PQI, LVC, and P(LV), whereas stimulation with the ring electrode only significantly affected RRI and PQI. The cardiovascular parameters that could be significantly influenced varied between the bipolar configurations. These novel findings may be relevant for optimizing electrode configurations for clinical cardiac applications of vagal nerve stimulation.

Stimulation of the intra-cardiac vagal nerves innervating the AV-node to control ventricular rate during AF: specificity, parameter optimization and chronic use up to 3 months.

BACKGROUND: Stimulation of the intra-cardiac vagal nerves innervating the AV-node (AVNS) is a promising approach to slow down ventricular rate (VR) during atrial fibrillation (AF). Our purpose was to demonstrate that effects on R-R-interval during stable AF can be maintained for several months once optimized and that AVNS affects specifically the nerves innervating the AV-node. METHODS: Our study included both an acute and chronic phase. Fifteen goats were implanted with a pacemaker connected to an atrial and ventricular lead and a neurostimulator connected to an atrial lead placed at a certain septal site, to induce an AV prolongation. In the chronic experiments (n = 9), after assessment of optimal AVNS parameters, the effect of continuous AVNS on VR was studied during stable AF for up to 3 months. The mechanism of AVNS was studied using atropine and esmolol. Next, the effects of AVNS during the atrial refractory period on electrophysiological and hemodynamic parameters were investigated acutely (n = 7). RESULTS: The maximal effect was found at a stimulation frequency of 40 Hz, and increased with increasing pulse width (at lower voltages) and increasing voltage. After 0, 1, and 3 months of AVNS during stable AF, AVNS decreased average VR, respectively, 55% (n = 9), 48% (n = 8), and 28% (n = 6). The AVNS effect appeared to be dominantly parasympathetic. AVNS did not influence (1) the sinus node, (2) the refractory period of the atrial, ventricular tissue, and His and (3) hemodynamic parameters. CONCLUSION: AVNS is efficient in reducing ventricular rate for at least 3 months using optimized parameters and specifically affects the parasympathetic nerves innervating the AV-node.

Electrical modalities beyond pacing for the treatment of heart failure.

In this review, we report on electrical modalities, which do not fit the definition of pacemaker, but increase cardiac performance either by direct application to the heart (e.g., post-extrasystolic potentiation or non-excitatory stimulation) or indirectly through activation of the nervous system (e.g., vagal or sympathetic activation). The physiological background of the possible mechanisms of these electrical modalities and their potential application to treat heart failure are discussed.

An indirect component in the evoked compound action potential of the vagal nerve.

The vagal nerve plays a vital role in the regulation of the cardiovascular system. It not only regulates the heart but also sends sensory information from the heart back to the brain. We hypothesize that the evoked vagal nerve compound action potential contains components that are indirect via the brain stem or coming via the neural network on the heart. In an experimental study of 15 pigs, we identified four components in the evoked compound action potentials. The fourth component was found to be an indirect component, which came from the periphery. The latency of the indirect component increased when heart rate and contractility were decreased by burst stimulation (P = 0.01; n = 7). When heart rate and contractility were increased by dobutamine administration, the latency of the indirect component decreased (P = 0.01; n = 9). This showed that the latency of the indirect component of the evoked compound action potentials may relate to the state of the cardiovascular system.

Vagal tone augmentation to the atrioventricular node in humans: efficacy and safety of burst endocardial stimulation.

BACKGROUND: Control of atrioventricular (AV) nodal conduction by endocardial stimulation of efferent AV nodal vagal fibers [atrioventricular nodal vagal stimulation (AVNS)] is a promising approach for long-term device-based modulation of ventricular rate during atrial fibrillation (AF). However, few data on the efficacy of AVNS delivered as high-frequency stimulus packages (burst AVNS) in humans are available. OBJECTIVE: The purpose of this study was to determine whether burst AVNS can to modulate AV nodal conduction during AF and whether burst AVNS delivered during sinus rhythm (SR) in the effective atrial refractory period allows safe implantation of a permanent lead in a position suitable for AVNS. METHODS: Twenty patients (10 in SR and 10 in AF) who were candidates for dual-chamber pacemaker implantation for sick sinus syndrome were enrolled in the study. The posteroseptal right atrium was mapped to identify a location at which burst AVNS would achieve AV nodal conduction modulation (lengthening of PR interval in SR and reduction of ventricular rate in AF). Subsequently, a lead was screwed in at that site and burst stimulation (pulse rate 50 Hz, burst duration 180 ms) was delivered at different burst rates, pulse durations, and amplitudes. RESULTS: In all SR patients, PR-interval prolongation was evoked at 90 and 120 bursts/minute with pulse durations < or =1 ms. Specifically, the mean voltages required to obtain PR-interval prolongation and advanced AV block were 4.3 +/- 2.2 V and 5.4 +/- 1.8 V (at 90 bursts/minute and 1 ms), respectively. Similarly, ventricular rate reduction was obtained in all AF patients, starting from 90 bursts/minute and 0.5-ms pulse duration (at 5.4 +/- 1.8 V). Ventricular arrhythmias were never induced during AVNS. CONCLUSION: Endocardial right atrial burst AVNS reduces ventricular rate during AF. Burst AVNS delivered during SR in the effective atrial refractory period allows optimization of lead positioning for AVNS.

Atrioventricular (AV) node vagal stimulation by transvenous permanent lead implantation to modulate AV node function: safety and feasibility in humans.

BACKGROUND: Atrioventricular (AV) node vagal stimulation (AVNVS) has recently emerged as a novel approach to controlling AV dromotropic function. Animal studies have demonstrated that selective epicardial AVNVS is effective in controlling ventricular rate (VR) acutely and in the long term. Endocardial AVNVS has been shown to significantly reduce VR acutely during atrial fibrillation (AF) in humans. However, no data are available on its long-term reproducibility. OBJECTIVES: The purpose of this study was to demonstrate that the posteroseptal right atrium is a suitable site for permanent pacing and allows AVNVS in humans both acutely and during follow-up. METHODS: In 12 candidates for implantable cardioverter-defibrillator with a history of AF, the atrial lead was implanted in the posteroseptal right atrium, where advanced AV block was achieved during temporary high-frequency stimulation (HFS). On implantation and 3-month follow-up examination, HFS was delivered through the permanent lead to demonstrate the possibility to gradually slow the VR until complete AV block. RESULTS: On implantation, VR during AF was gradually slowed until complete AV block, which was elicited at 4.3 V (0.2 ms, 50 Hz). After 3 months, this effect remained reproducible. No significant change in pacing thresholds was observed after 3 months. We observed one dislodgment and one microdislodgement of atrial leads. CONCLUSIONS: Our study demonstrates, for the first time in humans, that selective placement of the atrial lead yields electrical characteristics suitable for permanent pacing and enables VR to be significantly reduced under HFS. These results, which were reproducible during follow-up, provide data for the development of device-based control of VR during AF.

Post-operative atrial fibrillation management by selective epicardial vagal fat pad stimulation.

PURPOSE: Post-operative atrial fibrillation (POAF) is a common complication after cardiac surgery and often leads to poorly tolerated fast ventricular rates. Negative dromotropic drugs are not always effective and may not be well tolerated in heart failure patients. Aim of this study is to verify if high-frequency stimulation of the right inferior fat pad (RIFPS) allows an effective decrease in ventricular rate (VR) during POAF. METHODS: We enrolled 32 consecutive patients submitted to bypass; during surgery, a temporary heart wire was implanted in a site where RIFPS evoked a functional AV block. During POAF, RIFPS was delivered from the heart wire to decrease VR. RESULTS: Intra-operative RIFPS evoked complete AV block in 29 patients (91%). Fourteen patients (44%) developed POAF (mean VR 127 +/- 12 bpm). In these patients, RIFPS achieved a 25% reduction of VR and complete AV block with 6.0 +/- 1.9 and 7.5 +/- 1.8 V (duration 0.2 ms, frequency 50 Hz), respectively. CONCLUSION: Epicardial RIFPS represents an effective and feasible technique to decrease VR during POAF.

Reduction of atrial fibrillation burden by atrial overdrive pacing: experience with an improved algorithm to reduce early recurrences of atrial fibrillation.

AIMS: Two independent studies have revealed a potential limitation of post-mode switch overdrive pacing (PMOP), which is its delayed start. METHODS AND RESULTS: We conducted a prospective, randomized, single blind, crossover design study (the post-long pause overdrive pacing study) to test the efficacy of an improved version of PMOP (PMOP(enhanced)). A total of 45 patients were enrolled, of whom 41 were analysed. The median number of atrial tachycardia/atrial fibrillation (AT/AF) episodes per day (1.38 vs. 1.19), the median number of early recurrences of atrial fibrillation (ERAF) per day (0.56 vs. 0.51), and the median AT/AF burden (time per day spent in AT/AF) (2.47 vs. 2.51 h) were not significantly different during the control and active study periods. Based on the median number of episodes per week recorded 90 days prior to enrollment, the patients were stratified by the median and then split into two groups, Group A (lower 2-Quartiles) and Group B (upper 2-Quartiles). The median AT/AF burden was significantly lower in Group B during the active study period (3.71 vs. 1.71 h, P = 0.02).The median number of AT/AF episodes per day and the median number of ERAF per day in Group B showed a trend towards reduction when the algorithm was turned on (3.79 vs. 2.44 and 2.77 vs. 1.86, respectively). In contrast, in Group A we did not demonstrate any difference in AT/AF frequency, ERAF frequency, or burden. CONCLUSION: The main finding of this study is that temporary overdrive pacing at 90 bpm for 10 min starting just prior to device-classified AT/AF termination does not show a positive effect on the overall study population. However, when enabled in patients who suffer from a high percentage of ERAF, a significant reduction in the AT/AF burden could be demonstrated. Based on these findings, further prospective studies on a more targeted patient population are needed to confirm our results.

Endocardial transcatheter stimulation of the AV nodal fat pad: stabilization of rapid ventricular rate response during atrial fibrillation in left ventricular failure.

INTRODUCTION: Recent acute studies demonstrated that atrioventricular (AV) node vagal stimulation during atrial fibrillation (AF) decreases the mean ventricular rate, thus improving hemodynamics. METHODS AND RESULTS: We report a case of a woman with acute heart failure (HF), chronic AF with untreatable ventricular rapid response, in severe hypotensive state due to a cardiogenic shock. The patient underwent left ventricular (LV) pacemaker implantation and received 50 Hz AV node stimulation, delivered through a posteroseptal atrial lead, thus allowing a 100% pacing. Hemodynamics improvements allowed carvedilol titration; the rate was below 85 bpm after 4 days, then the atrial lead was removed. CONCLUSIONS: This novel strategy may allow controlling the rapid AV response in patients undergoing pacemaker implantation.

Risk stratification after myocardial infarction: a new method of determining the neural component of the baroreflex is potentially more discriminative in distinguishing patients at high and low risk for arrhythmias.

AIMS: We hypothesize that the neural component (NC) of the baroreflex sensitivity (BRS) is a better risk stratifier for ventricular tachycardia/fibrillation (VT/VF) than conventional BRS itself, because it is both independent of vessel wall stiffness and can be measured non-invasively. METHODS AND RESULTS: NC was determined by correlating spontaneous carotid artery diameter variations with R-R interval variations using spectral analyses. In consecutive outpatient populations with chronic coronary artery disease the ability of the NC to distinguish post-myocardial infarction (MI) patients at risk for VT/VF (post-MI(HIGH RISK)) from post-MI less prone to arrhythmias (post-MI(LOW RISK)) was compared with the pressure-derived BRS(phenyl) and BRS(spectral) method. Ninety-six patients, i.e. 28 post-MI(LOW RISK), 28 post-MI(HIGH RISK) [a LVEF(left ventricular ejection fraction) <30% and/or history of VT/VF] and 40 healthy controls were enrolled. With NC, rather than with BRS methods, median values for post-MI(HIGH RISK) were smaller than for post-MI(LOW RISK) patients (NC, P = 0.03; BRS(spectral), P = 0.35; BRS(phenyl), P = 0.63). Variability of R-R interval (LF = 0.04-0.15 Hz) was significantly larger in the control group than in the post-MI(HIGH RISK) and post-MI(LOW RISK) group (P < 0.01 and P < 0.01). To separate post-MI(HIGH RISK) from post-MI(LOW RISK) patients, a linear combination of age and the logarithm of the NC measurement was constructed as a risk index. By optimizing the intercept of this line, an optimal sensitivity and specificity pair was determined. The sum of optimal specificity and sensitivity was higher for NC (155) than for BRS(spectral) (133) and BRS(phenyl) method (132). With all methods, values for post-MI patients were significantly smaller than for controls. CONCLUSION: NC may be superior to conventional BRS measures in identifying post-MI patients at high risk for VT/VF.

Reduction of atrial tachyarrhythmia episodes during the overdrive pacing period using the post-mode switch overdrive pacing (PMOP) algorithm.

BACKGROUND: Early recurrences within 10 minutes after termination of an atrial tachyarrhythmia, such as atrial tachycardia (AT), atrial flutter, or atrial fibrillation (AF) episodes, account for a large part of paroxysmal AT/AF episodes. It is unclear whether these arrhythmias can be suppressed by overdrive pacing. OBJECTIVE: We set out to prove that overdrive pacing is effective in preventing early recurrences of AT/AF. METHODS: This AT500 (DDDRP device, Bakken Research Center Medtronic, Maastricht, The Netherlands) post-mode switch overdrive pacing (PMOP) study is a randomized controlled trial designed to test the efficacy of overdrive pacing on the suppression of early recurring AT/AF episodes. With the PMOP feature, overdrive pacing is activated 12 ventricular beats after device-confirmed termination of an AT/AF episode with a programmed duration and rate. If at least four episodes of 1 minute in duration occurred within the run-in period of 1 month, patients were randomized to one of the three settings (PMOP off and PMOP 10 minutes at 90 bpm or 120 bpm) for 2 months. At 2 and 4 months, patients were crossed over to another arm. At 6 months, all patients were programmed with PMOP on at 90 bpm for 30 minutes. RESULTS: We enrolled 122 and randomized 50 patients. Sixty percent of all stored AT/AF episodes occurred within 10 minutes after a previous episode; 31% occurred after device-determined termination and before the device reached the overdrive rate (17-27 ventricular beats after termination), and 29% of the episodes occurred while the device was pacing at the programmed overdrive rate. Thirty-seven percent of the average percentage of episodes during the overdrive period was prevented by the randomized settings of PMOP 90 bpm/10 min (P = .01, paired t-test, n = 39) and 120 bpm/10 min (P = .03, n = 35). In addition, for the nonrandomized setting of PMOP 90 bpm/30 min, the average number of episodes during the overdrive period was significantly smaller than the percentage of episodes occurring during the corresponding off period of 30 minutes (P = .05, n = 33). No significant differences in burden and episodes were found between the PMOP settings and the corresponding off periods. CONCLUSIONS: This is the first randomized controlled clinical trial to prove that overdrive pacing is effective in preventing early recurrences of AT/AF. However, shortcomings of the PMOP algorithm, such as late activation, need further improvement.

Neural activity of the cardiac baroreflex decreases with age in normotensive and hypertensive subjects.

OBJECTIVES: Baroreflex control of the heart rate is impaired in hypertensive subjects and decreases with age. The decrease in cardiac baroreflex sensitivity (BRS) is often ascribed to decreased distension of the pressure-sensing arterial wall segments. However, alterations in the sensing and processing of neural signals may be involved as well. DESIGN: Conventionally, both vessel wall stiffness and the sensing and neural processing of the baroreflex are incorporated in the measure of pressure-derived BRS. We introduce stretch-derived BRS, which only considers the sensing and neural components of the baroreflex. METHODS: To determine stretch-derived BRS in a non-invasive manner, we measured the spontaneously occurring low-frequency variations (range, 0.06-0.12 Hz) in the carotid artery diameter and the corresponding R-R interval fluctuations, and determined the associated transfer function. The stretch-derived BRS in a group of age-matched (age range, 25-72 years) normotensive (n = 20) and hypertensive (n = 21) subjects was compared. RESULTS: In both subject groups the stretch-derived BRS decreased significantly with age. Moreover, the stretch-derived BRS of both groups was only different below 50 years of age. CONCLUSIONS: The analysis of low-frequency fluctuations in the carotid artery diameter demonstrates that aging as well as hypertension are associated with impaired neural control of the baroreflex. Beyond 50 years of age the effect of hypertension cannot be distinguished from the effect of aging.

In patients with pseudoxanthoma elasticum a thicker and more elastic carotid artery is associated with elastin fragmentation and proteoglycans accumulation.

Skin biopsies in patients with pseudoxanthoma elasticum (PXE) show elastic fiber fragmentation and calcium and proteoglycans accumulation. Assuming such changes to be present in the artery wall as well, we studied the influence of such alterations on function and structure of the human common carotid artery (CCA). Indeed, elastin fragmentation and increased calcium and proteoglycans content were present in the arteries of the two PXE patients examined. Internal diameter, distension and intima-media thickness (IMT) in the CCA of PXE patients (n = 19) and controls (n = 39) were determined by ultrasound (US). Pulse pressure was assessed in the brachial artery. The distensibility and compliance coefficients as well as the Young's modulus were calculated. Diameter and pulse pressure were not significantly different in PXE patients and controls. The distensibility and compliance coefficients were significantly greater in older PXE patients than in older controls. The distensibility coefficient decreased with age in both PXE patients and in controls. Unlike in controls, the compliance coefficient did not decrease and the Young's modulus barely increased with age in PXE patients. IMT was significantly greater at both younger and older ages and the Young's modulus was significantly smaller at older ages in PXE patients than in controls. The carotid artery is thicker and more elastic in PXE patients than in control subjects; differences are most pronounced at older ages. These alterations might be explained by the elastin fragmentation and proteoglycans accumulation as observed in these patients.