Edward Barin

Effects of Isosorbide Mononitrate and AII Inhibition on Pulse Wave Reflection in Hypertension

Abstract—The aortic pulse wave contour in isolated systolic hypertension often shows a prominent reflection peak, which combines with the incident wave arising from cardiac ejection so as to widen pulse pressure. We investigated the effects of an extended-release nitrate preparation and of 2 angiotensin II (AII) inhibitors (an AII receptor antagonist and an ACE inhibitor) on the aortic pulse wave contour and systemic blood pressure in hypertensive subjects with high augmentation index caused by exaggerated pulse wave reflection. Two double-blind, randomized, placebo-controlled crossover studies were carried out in a total of 16 elderly patients with systolic hypertension resistant to conventional antihypertensive therapy. In 1 study, pharmacodynamic responses to single doses of placebo, isosorbide mononitrate, eprosartan, and captopril were determined; in the other, single-dose isosorbide mononitrate and placebo were compared in subjects treated with AII inhibitors at baseline. Blood pressure was measured by sphygmomanometry and pulse wave components by applanation tonometry at the radial artery. All 3 agents were shown to decrease brachial systolic blood pressure, aortic systolic blood pressure, and aortic pulse pressure. Qualitative effects on the aortic pulse wave contour differed: augmentation index was not significantly altered by either captopril or eprosartan but was decreased (P <0.0001) by ≈50% of the placebo value with isosorbide mononitrate in both study groups. We propose that isosorbide mononitrate corrected the magnified wave reflection in systolic hypertension of these elderly patients by an effect that was distinct from that exercised by either acute or chronic AII inhibition.

Long-Term Effectiveness of Extended-Release Nitrate for the Treatment of Systolic Hypertension

Isosorbide mononitrate (ISMN) is effective in the short-term for decreasing systolic blood pressure, pulse pressure, and pulse wave reflection in patients with systolic hypertension. To determine whether tolerance negates the efficacy of this nitrate in the long-term, a placebo-controlled study was performed in which ISMN was withdrawn briefly in a group of patients (n=16) who had received extended-release ISMN 60 to 120 mg once daily for 16 to 109 months. Blood pressure and wave reflection were determined by 24-hour ambulatory recorder and tonometer, respectively. During a 4-hour delay of the regular morning dose of ISMN, mean systolic blood pressure was higher than with the regular ISMN dosing schedule (P<0.0001). The maximum placebo-active difference was 16±4 mm Hg. The corresponding difference in augmentation index (a measure of pulse wave reflection) corrected for heart rate was 25±4% (P<0.001). The difference in pulse pressure was 13±3 mm Hg (P<0.001). There was no significant difference in diastolic blood pressure. For a subgroup (n=12) in which the effects of a single ISMN dose had been determined at the initiation of regular ISMN therapy, the mean change in augmentation index was of similar magnitude to that observed in their initial study. Thus, tolerance does not seriously diminish the antihypertensive efficacy of ISMN used as adjunct therapy in the chronic treatment of systolic hypertension. This agent lowers systolic blood pressure sufficiently to achieve therapeutic goal in some patients refractory to conventional treatment regimens.

A mobile rehabilitation application for the remote monitoring of cardiac patients after a heart attack or a coronary bypass surgery

This paper describes a personalised rehabilitation application using a smart phone (PDA) and wireless (bio) sensors. It instructs and motivates patients to follow their exercise programme and keeps track of their progress. It also monitors the relevant biosignals and provides immediate feedback to the patient. Sensors transmit data to the mobile phone where it is analysed locally and the data can also be instantaneously transmitted to a healthcare centre for remote monitoring by a health professional. The rehabilitation application is personalised for each cardiac patient and provides tailored advice (e.g. exercise more, slow down). A trial with a rehabilitation centre is in progress in which we investigate whether the personalised rehabilitation application improves the success of the rehabilitation programme in terms of patient compliance with recommended life style changes (such as increase physical activity or lose weight) and whether use of the system brings peace of mind to cardiac patients.

Trial Results of a Novel Cardiac Rhythm Management System Using Smart Phones and Wireless ECG Sensors

This paper discusses the trial results of a personalised Cardiac Rhythm Management (CRM) system using a smart phone (PDA) and a wireless ECG sensor. The system is used in a trial to record and diagnose abnormal cardiac arrhythmias. This novel approach uses standard mobile phones, off-the-shelf ECG sensors and personalised feedback to the patient when compared to a conventional clinical Holter and event monitor systems. The preliminary results are discussed of an ongoing trial conducted with the Royal North Shore Hospital in Sydney Australia. The results indicate the viability of the system for commercial purposes.

Heart Rate Dependency of Large Artery Stiffness

Carotid-femoral pulse wave velocity (cfPWV) quantifies large artery stiffness, it is used in hemodynamic research and is considered a useful cardiovascular clinical marker. cfPWV is blood pressure (BP) dependent. Intrinsic heart rate (HR) dependency of cfPWV is unknown because increasing HR is commonly accompanied by increasing BP. This study aims to quantify cfPWV dependency on acute, sympathovagal-independent changes in HR, independent of BP. Individuals (n=52, age 40–93 years, 11 female) with in situ cardiac pacemakers or cardioverter defibrillators were paced at 60, 70, 80, 90, and 100 bpm. BP and cfPWV were measured at each HR. Both cfPWV (mean [95% CI], 0.31 [0.26–0.37] m/s per 10 bpm; P<0.001) and central aortic diastolic pressure (3.78 [3.40–4.17] mm Hg/10 bpm; P<0.001) increased with HR. The HR effect on cfPWV was isolated by correcting the BP effects by 3 different methods: (1) statistically, by a linear mixed model; (2) mathematically, using an exponential relationship between BP and cross-sectional lumen area; and (3) using measured BP dependency of cfPWV derived from changes in BP induced by orthostatic changes (seated and supine) in a subset of subjects (n=17). The BP-independent effects of HR on cfPWV were quantified as 0.20 [0.11–0.28] m/s per 10 bpm (P<0.001, method 1), 0.16 [0.11–0.22] m/s per 10 bpm (P<0.001, method 2), and 0.16 [0.11–0.21] m/s per 10 bpm (P<0.001, method 3). With a mean HR dependency in the range of 0.16 to 0.20 m/s per 10 bpm, cfPWV may be considered to have minimal physiologically relevant changes for small changes in HR, but larger differences in HR must be considered as contributing to significant differences in cfPWV.

Interactions of L-arginine, isosorbide mononitrate, and angiotensin II inhibitors on arterial pulse wave

BACKGROUND Deficiency of nitric oxide (NO) production has been implicated in the pathogenesis of increased pulse wave reflection associated with systolic hypertension. We investigated the effects on systolic blood pressure (BP) and pulse wave contour of two nitrate donors, isosorbide mononitrate (ISMN) and L-arginine. METHODS The subjects were 14 elderly patients chronically treated with antihypertensive agents. In seven of the subjects, agents causing angiotensin II (AII) inhibition (angiotensin-converting enzyme [ACE] inhibitor or AT(1) receptor antagonist, or both) were used. Study entry required systolic BP of 150 to 200 mm Hg, and aortic pulse wave augmentation more than 15 mm Hg. Pharmacodynamic responses to ISMN, L-arginine, and ISMN plus L-arginine, were assessed in double-blind crossover studies by standard sphygmomanometry and applanation tonometry. RESULTS Peripheral systolic BP, aortic systolic BP, and the aortic augmentation index were decreased (P <.001) by ISMN, irrespective of AII inhibition. L-arginine enhanced these effects (P <.001) in the subjects without AII inhibition, but not in those receiving AII inhibitors. Given without ISMN or AII inhibitors, L-arginine decreased peripheral systolic BP, but to a lesser extent than ISMN. CONCLUSIONS L-arginine has potential value as an adjunct to ISMN in combination with antihypertensive therapy in elderly patients with systolic hypertension. However, when given with single-dose ISMN, its vasodilator activity may overlap with that of AII inhibitors. Future studies of L-arginine in conjunction with chronic continuous ISMN dosing are warranted.

Effects of pacing modality on noninvasive assessment of heart rate dependency of indices of large artery function

Studies investigating the relationship between heart rate (HR) and arterial stiffness or wave reflections have commonly induced HR changes through in situ cardiac pacing. Although pacing produces consistent HR changes, hemodynamics can be different with different pacing modalities. Whether the differences affect the HR relationship with arterial stiffness or wave reflections is unknown. In the present study, 48 subjects [mean age, 78 ± 10 (SD), 9 women] with in situ cardiac pacemakers were paced at 60, 70, 80, 90, and 100 beats per min under atrial, atrioventricular, or ventricular pacing. At each paced HR, brachial cuff-based pulse wave analysis was used to determine central hemodynamic parameters, including ejection duration (ED) and augmentation index (AIx). Wave separation analysis was used to determine wave reflection magnitude (RM) and reflection index (RI). Arterial stiffness was assessed by carotid-femoral pulse wave velocity (cfPWV). Pacing modality was found to have significant effects on the HR relationship with ED (P = 0.01), central aortic pulse pressure (P = 0.01), augmentation pressure (P < 0.0001), and magnitudes of both forward and reflected waves (P = 0.05 and P = 0.003, respectively), but not cfPWV (P = 0.57) or AIx (P = 0.38). However, at a fixed HR, significant differences in pulse pressure amplification (P < 0.001), AIx (P < 0.0001), RM (P = 0.03), and RI (P = 0.03) were observed with different pacing modalities. These results demonstrate that although the HR relationships with arterial stiffness and systolic loading as measured by cfPWV and AIx were unaffected by pacing modality, it should still be taken into account for studies in which mixed pacing modalities are present, in particular, for wave reflection studies.

Feasibility trial of a novel mobile cardiac rehabilitation application

A trial with a cardiac rehabilitation centre is in progress where we test a novel cardiac rehab application using a standard mobile phone and wireless sensors. The goal is to obtain insight how remote monitoring compares to conventional rehabilitation methods in terms of adherence to cardiac rehabilitation programmes. In this trial we seek feedback from patients and health professionals regarding usability and practicability of the software and hardware used and we investigate whether the use of the novel mobile rehabilitation application provides clinically meaningful reassurance to patients during their cardiac rehabilitation. The trial also investigates whether physical and psychological measures improve using the system. This paper describes the mobile cardiac rehabilitation application as well as the setup of the trial.

Systolic time intervals assessed from analysis of the carotid pressure waveform

OBJECTIVE The timing of mechanical cardiac events is usually evaluated by conventional echocardiography as an index of cardiac systolic function and predictor of cardiovascular outcomes. We aimed to measure the systolic time intervals, namely the isovolumetric contraction time (ICT) and pre-ejection period (PEP), by arterial tonometry. APPROACH Sixty-two healthy volunteers (age 47  ±  17 years) and 42 patients with heart failure and reduced ejection fraction were enrolled (age 66  ±  14 years). Pulse waves were recorded at the carotid artery by arterial tonometry together with simultaneous aortic transvalvular flow by Doppler-echocardiography, synchronized by electrocardiographic gating. The ICT was determined from the time delay between the electrical R wave and the carotid pressure waveform, after adjustment for the pulse transit time from the aortic valve to the carotid artery site, estimated by an algorithm based on the carotid-femoral pulse wave velocity. The PEP was evaluated by adding the electrical QR duration to the ICT. MAIN RESULTS The ICT derived from carotid pulse wave analysis was closely related to that measured by echocardiography (r  =  0.90, p  <  0.0001), with homogeneous distribution in Bland-Altman analysis (mean difference and 95% confidence interval  =  0.2 from  -14.2 to 14.5 ms). ICT and PEP were higher in cardiac patients than in healthy volunteers (p  <  0.0001). The ratio between PEP and left ventricular ejection time was related to the ejection fraction measured with echocardiography (r  =  0.555, p  <  0.0001). SIGNIFICANCE The timing of electro-mechanical cardiac events can be reliably obtained from the carotid pulse waveform and carotid-femoral PWV, evaluated using arterial tonometry. Systolic time intervals assessed with this approach showed good agreement with measurements performed with conventional echocardiography and may represent a promising additional application of arterial tonometry.

Characterisation of cardiac autonomic function in multiple sclerosis based on spontaneous changes of heart rate and blood pressure

BACKGROUND Prevalence of cardiovascular autonomic dysfunction (CAD) in multiple sclerosis (MS) varies between studies. Cardiac autonomic function is usually assessed by cardiovascular reflex tests. We hypothesized that MS is associated with CAD, quantifiable by non-invasive means including quantification of baroreceptor sensitivity (BRS) and heart rate variability. METHODS In this study a comprehensive suite of cardiovascular autonomic tests based only on the spontaneous changes of heart rate and blood pressure was applied to 23 MS patients and age and gender-matched controls. From 5-min continuous non-invasive recording of the electrocardiogram and blood pressure, heart-rate, blood pressure, and autonomic function variables were calculated. Analysis included heart rate variability in the time domain, heart rate and blood pressure variability in the frequency domain, and baroreceptor sensitivity in both the time and frequency domain. RESULTS BRS measured by the frequency technique in high frequency band was found to be significantly lower in MS (16 ± 9 ms/mmHg) compared to controls (29 ± 17 ms/mmHg) (p < 0.05). Also mean of BRS modulus in MS averaged 15 ± 8 ms/mmHg which is significantly lower compared to controls (25 ± 15 ms/mmHg) (p < 0.05). Systolic blood pressure variability in the high frequency band (0.15-0.5 Hz) was found to be significantly higher in the MS compared to controls (5.8 ± 16.7 mmHg2 vs. 1.3 ± 0.8 mmHg2) (p < 0.05). CONCLUSIONS The results, using techniques novel to MS investigation, showed diminished baroreceptor reflex and impaired sympathetic function using frequency domain systolic blood pressure variability analysis.