Brian Clapp

Inflammation and Endothelial Function Direct Vascular Effects of Human C-Reactive Protein on Nitric Oxide Bioavailability

Background—Circulating concentrations of the sensitive inflammatory marker C-reactive protein (CRP) predict future cardiovascular events, and CRP is elevated during sepsis and inflammation, when vascular reactivity may be modulated. We therefore investigated the direct effect of CRP on vascular reactivity. Methods and Results—The effects of isolated, pure human CRP on vasoreactivity and protein expression were studied in vascular rings and cells in vitro, and effects on blood pressure were studied in rats in vivo. The temporal relationship between changes in CRP concentration and brachial flow-mediated dilation was also studied in humans after vaccination with Salmonella typhi capsular polysaccharide, a model of inflammatory endothelial dysfunction. In contrast to some previous reports, highly purified and well-characterized human CRP specifically induced hyporeactivity to phenylephrine in rings of human internal mammary artery and rat aorta that was mediated through physiological antagonism by nitric oxide (NO). CRP did not alter endothelial NO synthase protein expression but increased protein expression of GTP cyclohydrolase-1, the rate-limiting enzyme in the synthesis of tetrahydrobiopterin, the NO synthase cofactor. In the vaccine model of inflammatory endothelial dysfunction in humans, increased CRP concentration coincided with the resolution rather than the development of endothelial dysfunction, consistent with the vitro findings; however, administration of human CRP to rats had no effect on blood pressure. Conclusions—Pure human CRP has specific, direct effects on vascular function in vitro via increased NO production; however, further clarification of the effect, if any, of CRP on vascular reactivity in humans in vivo will require clinical studies using specific inhibitors of CRP.

Peripheral Augmentation Index Defines the Relationship Between Central and Peripheral Pulse Pressure

Peripheral systolic blood pressure is amplified above central aortic systolic pressure, but the late systolic shoulder of the peripheral pulse may approximate central systolic pressure. Because late systolic pressure also determines the peripheral augmentation index, a measure of pressure wave reflection within the systemic circulation, this implies a direct relationship between amplification and augmentation. We compared the late systolic shoulder of the peripheral pressure waveform with estimates of central systolic pressure obtained using a transfer function in 391 subjects undergoing diagnostic coronary angiography and/or elective angioplasty (30% with insignificant coronary artery disease). In a subset (n=12) we compared the late systolic shoulder of the peripheral pulse with central pressure obtained with a catheter placed in the aortic root. Measurements were made at baseline, during atrial pacing, and during administration of nitroglycerin. Late systolic shoulder pressure closely approximated transfer function estimates of central pressure (R=0.96; P<0.0001; mean difference±SD: 0.5±5.2 mm Hg). Despite changes in waveform morphology induced by pacing and nitroglycerin (reducing mean values±SE of the augmentation index from 76±3.8% to 66±4.6% and 60±3.3%, respectively), there was close agreement between the late systolic shoulder of the peripheral pulse and measured values of central pressure (R=0.96; P<0.001; mean difference: 1.7±4.8 mm Hg). In conclusion, the late systolic shoulder of the peripheral pulse closely approximates central systolic pressure and peripheral augmentation index, the ratio of central:peripheral pulse pressure. Interventions to lower augmentation index and peripheral vascular resistance will have multiplicative effects in lowering central blood pressure.

Progenitors in motion: mechanisms of mobilization of endothelial progenitor cells

Endothelial progenitor cells are a population of bone marrow-derived mononuclear cells thought to engage in endothelial repair and hence are considered potential therapeutic agents in many pathological conditions. The mechanism of their exit from the bone marrow to the circulation and damaged tissues, termed mobilization, has not been fully elucidated. Despite this, several pharmacological interventions have been shown to influence mobilization of these specialized cells. Here we review the current understanding of their mobilization.

Augmentation pressure is influenced by ventricular contractility/relaxation dynamics: novel mechanism of reduction of pulse pressure by nitrates.

Augmentation pressure (AP), the increment in aortic pressure above its first systolic shoulder, is thought to be determined mainly by pressure wave reflection but could be influenced by ventricular ejection characteristics. We sought to determine the mechanism by which AP is selectively reduced by nitroglycerin (NTG). Simultaneous measurements of aortic pressure and flow were made at the time of cardiac catheterization in 30 subjects (11 women; age, 61±13 years [mean±SD]) to perform wave intensity analysis and calculate forward and backward components of AP generated by the ventricle and arterial tree, respectively. Measurements were made at baseline and after NTG given systemically (800 &mgr;g sublingually, n=20) and locally by intracoronary infusion (1 &mgr;g/min; n=10). Systemic NTG had no significant effect on first shoulder pressure but reduced augmentation (and central pulse pressure) by 12.8±3.1 mm Hg (P<0.0001). This resulted from a reduction in forward and backward wave components of AP by 7.0±2.4 and 5.8±1.3 mm Hg, respectively (each P<0.02). NTG had no significant effect on the ratio of amplitudes of either backward/forward waves or backward/forward compression wave energies, suggesting that effects on the backward wave were largely secondary to those on the forward wave. Time to the forward expansion wave was reduced (P<0.05). Intracoronary NTG decreased AP by 8.3±3.6 mm Hg (P<0.05) with no significant effect on the backward wave. NTG reduces AP and central pulse pressure by a mechanism that is, at least in part, independent of arterial reflections and relates to ventricular contraction/relaxation dynamics with enhanced myocardial relaxation.Augmentation pressure (AP), the increment in aortic pressure above its first systolic shoulder, is thought to be determined mainly by pressure wave reflection but could be influenced by ventricular ejection characteristics. We sought to determine the mechanism by which AP is selectively reduced by nitroglycerin (NTG). Simultaneous measurements of aortic pressure and flow were made at the time of cardiac catheterization in 30 subjects (11 women; age, 61±13 years [mean±SD]) to perform wave intensity analysis and calculate forward and backward components of AP generated by the ventricle and arterial tree, respectively. Measurements were made at baseline and after NTG given systemically (800 μg sublingually, n=20) and locally by intracoronary infusion (1 μg/min; n=10). Systemic NTG had no significant effect on first shoulder pressure but reduced augmentation (and central pulse pressure) by 12.8±3.1 mm Hg ( P <0.0001). This resulted from a reduction in forward and backward wave components of AP by 7.0±2.4 and 5.8±1.3 mm Hg, respectively (each P <0.02). NTG had no significant effect on the ratio of amplitudes of either backward/forward waves or backward/forward compression wave energies, suggesting that effects on the backward wave were largely secondary to those on the forward wave. Time to the forward expansion wave was reduced ( P <0.05). Intracoronary NTG decreased AP by 8.3±3.6 mm Hg ( P <0.05) with no significant effect on the backward wave. NTG reduces AP and central pulse pressure by a mechanism that is, at least in part, independent of arterial reflections and relates to ventricular contraction/relaxation dynamics with enhanced myocardial relaxation. # Novelty and Significance {#article-title-30}

Augmentation Pressure Is Influenced by Ventricular Contractility/Relaxation DynamicsNovelty and Significance: Novel Mechanism of Reduction of Pulse Pressure by Nitrates

Augmentation pressure (AP), the increment in aortic pressure above its first systolic shoulder, is thought to be determined mainly by pressure wave reflection but could be influenced by ventricular ejection characteristics. We sought to determine the mechanism by which AP is selectively reduced by nitroglycerin (NTG). Simultaneous measurements of aortic pressure and flow were made at the time of cardiac catheterization in 30 subjects (11 women; age, 61±13 years [mean±SD]) to perform wave intensity analysis and calculate forward and backward components of AP generated by the ventricle and arterial tree, respectively. Measurements were made at baseline and after NTG given systemically (800 &mgr;g sublingually, n=20) and locally by intracoronary infusion (1 &mgr;g/min; n=10). Systemic NTG had no significant effect on first shoulder pressure but reduced augmentation (and central pulse pressure) by 12.8±3.1 mm Hg (P<0.0001). This resulted from a reduction in forward and backward wave components of AP by 7.0±2.4 and 5.8±1.3 mm Hg, respectively (each P<0.02). NTG had no significant effect on the ratio of amplitudes of either backward/forward waves or backward/forward compression wave energies, suggesting that effects on the backward wave were largely secondary to those on the forward wave. Time to the forward expansion wave was reduced (P<0.05). Intracoronary NTG decreased AP by 8.3±3.6 mm Hg (P<0.05) with no significant effect on the backward wave. NTG reduces AP and central pulse pressure by a mechanism that is, at least in part, independent of arterial reflections and relates to ventricular contraction/relaxation dynamics with enhanced myocardial relaxation.Augmentation pressure (AP), the increment in aortic pressure above its first systolic shoulder, is thought to be determined mainly by pressure wave reflection but could be influenced by ventricular ejection characteristics. We sought to determine the mechanism by which AP is selectively reduced by nitroglycerin (NTG). Simultaneous measurements of aortic pressure and flow were made at the time of cardiac catheterization in 30 subjects (11 women; age, 61±13 years [mean±SD]) to perform wave intensity analysis and calculate forward and backward components of AP generated by the ventricle and arterial tree, respectively. Measurements were made at baseline and after NTG given systemically (800 μg sublingually, n=20) and locally by intracoronary infusion (1 μg/min; n=10). Systemic NTG had no significant effect on first shoulder pressure but reduced augmentation (and central pulse pressure) by 12.8±3.1 mm Hg ( P <0.0001). This resulted from a reduction in forward and backward wave components of AP by 7.0±2.4 and 5.8±1.3 mm Hg, respectively (each P <0.02). NTG had no significant effect on the ratio of amplitudes of either backward/forward waves or backward/forward compression wave energies, suggesting that effects on the backward wave were largely secondary to those on the forward wave. Time to the forward expansion wave was reduced ( P <0.05). Intracoronary NTG decreased AP by 8.3±3.6 mm Hg ( P <0.05) with no significant effect on the backward wave. NTG reduces AP and central pulse pressure by a mechanism that is, at least in part, independent of arterial reflections and relates to ventricular contraction/relaxation dynamics with enhanced myocardial relaxation. # Novelty and Significance {#article-title-30}

Regulation of Vascular Tone and Pulse Wave Velocity in Human Muscular Conduit Arteries Selective Effects of Nitric Oxide Donors to Dilate Muscular Arteries Relative to Resistance Vessels

Arterial tone in muscular conduit arteries may influence pressure wave reflection through changes in diameter and pulse wave velocity. We examined the relative specificity of vasodilator drugs for radial artery and forearm resistance vessels during intrabrachial arterial infusion. The nitric oxide (NO) donors, nitroglycerine and nitroprusside, and brain natriuretic peptide were compared with the α-adrenergic antagonist phentolamine, calcium-channel antagonist verapamil, and hydralazine. Radial artery diameter was measured by high resolution ultrasound, forearm blood flow by strain gauge plethysmography, and pulse wave velocity by pressure recording cuffs placed over the distal brachial and radial arteries. Norepinephrine was used to constrict the radial artery to generate a greater range of vasodilator tone when examining pulse wave velocity. Despite dilating resistance vasculature, phentolamine and verapamil had little effect on radial artery diameter (mean dilation <9%). By contrast, for comparable actions on resistance vessels, nitroglycerine and nitroprusside but not brain natriuretic peptide had powerful actions to dilate the radial artery (dilations of 31.3±3.6%, 23.6±3.1%, and 9.8±2.0% for nitroglycerine, nitroprusside, and brain natriuretic peptide, respectively). Changes in pulse wave velocity followed those in arterial diameter irrespective of the signaling pathway used to modulate arterial tone ( R =−0.89, P <0.05). Basal tone in human muscular arteries is relatively unaffected by α-adrenergic or calcium-channel blockade, but is functionally or directly antagonized by NO donors. The differential response to NO donors suggests that there is potential to manipulate the downstream pathway to confer greater specificity for large arteries with a resultant decrease in pressure wave reflection and systolic blood pressure. # Novelty and Significance {#article-title-24}Arterial tone in muscular conduit arteries may influence pressure wave reflection through changes in diameter and pulse wave velocity. We examined the relative specificity of vasodilator drugs for radial artery and forearm resistance vessels during intrabrachial arterial infusion. The nitric oxide (NO) donors, nitroglycerine and nitroprusside, and brain natriuretic peptide were compared with the &agr;-adrenergic antagonist phentolamine, calcium-channel antagonist verapamil, and hydralazine. Radial artery diameter was measured by high resolution ultrasound, forearm blood flow by strain gauge plethysmography, and pulse wave velocity by pressure recording cuffs placed over the distal brachial and radial arteries. Norepinephrine was used to constrict the radial artery to generate a greater range of vasodilator tone when examining pulse wave velocity. Despite dilating resistance vasculature, phentolamine and verapamil had little effect on radial artery diameter (mean dilation <9%). By contrast, for comparable actions on resistance vessels, nitroglycerine and nitroprusside but not brain natriuretic peptide had powerful actions to dilate the radial artery (dilations of 31.3±3.6%, 23.6±3.1%, and 9.8±2.0% for nitroglycerine, nitroprusside, and brain natriuretic peptide, respectively). Changes in pulse wave velocity followed those in arterial diameter irrespective of the signaling pathway used to modulate arterial tone (R=−0.89, P<0.05). Basal tone in human muscular arteries is relatively unaffected by &agr;-adrenergic or calcium-channel blockade, but is functionally or directly antagonized by NO donors. The differential response to NO donors suggests that there is potential to manipulate the downstream pathway to confer greater specificity for large arteries with a resultant decrease in pressure wave reflection and systolic blood pressure.

Dominance of the Forward Compression Wave in Determining Pulsatile Components of Blood Pressure: Similarities Between Inotropic Stimulation and Essential Hypertension

Pulsatile components of blood pressure may arise from forward (ventricular generated) or backward wave travel in the arterial tree. The objective of this study was to determine the relative contributions of forward and backward waves to pulsatility. We used wave intensity and wave separation analysis to determine pulsatile components of blood pressure during inotropic and vasopressor stimulation by dobutamine and norepinephrine in normotensive subjects and compared pulse pressure components in hypertensive (mean±SD, 48.8±11.3 years; 165±26.6/99±14.2 mm Hg) and normotensive subjects (52.2±12.6 years; 120±14.2/71±8.2 mm Hg). Dobutamine (7.5 &mgr;g/kg per minute) increased the forward compression wave generated by the ventricle and increased pulse pressure from 36.8±3.7 to 59.0±3.4 mm Hg (mean±SE) but had no significant effect on mean arterial pressure or the midsystolic backward compression wave. By contrast, norepinephrine (50 ng/kg per minute) had no significant effect on the forward compression wave but increased the midsystolic backward compression wave. Despite this increase in the backward compression wave, and an increase in mean arterial pressure, norepinephrine increased central pulse pressure less than dobutamine (increases of 22.1±3.8 and 7.2±2.8 mm Hg for dobutamine and norepinephrine, respectively; P<0.02). An elevated forward wave component (mean±SE, 50.4±3.4 versus 35.2±1.8 mm Hg, in hypertensive and normotensive subjects, respectively; P<0.001) accounted for approximately two thirds of the total difference in central pulse pressures between hypertensive and normotensive subjects. Increased central pulse pressure during inotropic stimulation and in essential hypertension results primarily from the forward compression wave.Pulsatile components of blood pressure may arise from forward (ventricular generated) or backward wave travel in the arterial tree. The objective of this study was to determine the relative contributions of forward and backward waves to pulsatility. We used wave intensity and wave separation analysis to determine pulsatile components of blood pressure during inotropic and vasopressor stimulation by dobutamine and norepinephrine in normotensive subjects and compared pulse pressure components in hypertensive (mean±SD, 48.8±11.3 years; 165±26.6/99±14.2 mm Hg) and normotensive subjects (52.2±12.6 years; 120±14.2/71±8.2 mm Hg). Dobutamine (7.5 μg/kg per minute) increased the forward compression wave generated by the ventricle and increased pulse pressure from 36.8±3.7 to 59.0±3.4 mm Hg (mean±SE) but had no significant effect on mean arterial pressure or the midsystolic backward compression wave. By contrast, norepinephrine (50 ng/kg per minute) had no significant effect on the forward compression wave but increased the midsystolic backward compression wave. Despite this increase in the backward compression wave, and an increase in mean arterial pressure, norepinephrine increased central pulse pressure less than dobutamine (increases of 22.1±3.8 and 7.2±2.8 mm Hg for dobutamine and norepinephrine, respectively; P <0.02). An elevated forward wave component (mean±SE, 50.4±3.4 versus 35.2±1.8 mm Hg, in hypertensive and normotensive subjects, respectively; P <0.001) accounted for approximately two thirds of the total difference in central pulse pressures between hypertensive and normotensive subjects. Increased central pulse pressure during inotropic stimulation and in essential hypertension results primarily from the forward compression wave. # Novelty and Significance {#article-title-19}

Estimating central Sbp from the peripheral pulse: influence of waveform analysis and calibration error

Objective To compare estimation of central cSBP by application of a generalized transfer function (GTF) to a peripheral arterial waveform and from the late systolic shoulder (SBP2) of such a waveform and assess errors introduced by noninvasive calibration of the waveform. Methods The digital arterial pulse was acquired noninvasively with a servo-controlled finger cuff. A high fidelity pressure tipped catheter was placed in the proximal aortic root. Measurements were made at baseline (n = 40), after nitrovasodilation, handgrip exercise (n = 18) and during pacing (n = 10). Estimates of cSBP obtained using a GTF and from SBP2 (using an algorithm applied to individual cardiac cycles) of the digital arterial waveform were compared with values measured at the aortic root. Results When arterial waveforms were calibrated from aortic intra-arterial mean and DBP there was close agreement between estimated and measured cSBP: mean difference between estimated and measured cSBP (SD): 1.0 (5.7) and −0.7 (5.5) mmHg for GTF and SBP2, respectively. Noninvasive oscillometric calibration increased variability in estimation of cSBP [mean difference, 1.3 (11) mmHg for SBP2] but estimates of the cSBP to peripheral systolic pressure increment from oscillometric calibration of SBP2 agreed well with those obtained using invasive calibration [mean difference −2.4 (6.1) mmHg]. Conclusion SBP2 potentially provides a simple measure of cSBP and is of comparable accuracy to a GTF. Noninvasive calibration increases variability for both methods but has less effect on the cSBP to peripheral SBP increment.

Estimating central systolic blood pressure during oscillometric determination of blood pressure: proof of concept and validation by comparison with intra-aortic pressure recording and arterial tonometry.

ObjectivesCentral systolic blood pressure is usually estimated by transformation of a peripheral arterial waveform obtained by tonometry and calibrated from conventional measurements of brachial artery blood pressure from a brachial cuff using the oscillometric principle. We investigated whether central blood pressure could be obtained directly from a brachial cuff waveform, allowing the measurement of central blood pressure to be incorporated into the standard oscillometric determination of blood pressure. MethodsValues of central systolic blood pressure obtained from a brachial cuff waveform were compared with those obtained using a pressure-tipped intra-aortic catheter in 29 individuals undergoing cardiac catheterization. To remove errors introduced by the measurement of peripheral blood pressure, transformed brachial waveforms were calibrated using values of mean and diastolic pressure from the intra-aortic catheter. In a second study, the values obtained from the brachial cuff were compared with those obtained using a noninvasive tonometric method using calibration from mean and diastolic and from systolic and diastolic blood pressure derived from a standard oscillometric algorithm in 100 individuals (46 women, 19–81 years) with blood pressure ranging from 89/52 to 230/117 mmHg. ResultsIn study 1, the mean difference±SD of brachial cuff-derived values and intra-aortic values was 0.0±5.9 mmHg. In study 2, the mean difference for brachial cuff-derived values and tonometer values was −0.6±3.9 and 1.6±4.5 mmHg when calibrated using brachial mean and diastolic and brachial systolic and diastolic pressures, respectively. ConclusionCentral systolic blood pressure can be obtained from a brachial cuff waveform with an accuracy comparable to that of a tonometer.

Patent foramen ovale: the current state of play

### Learning objectives Patent foramen ovale (PFO) is a common finding, occurring in up to 25% of people.1 ,2 An association between PFO and stroke has consistently been seen in up to 50% of patients without an identifiable cause, that is, the so-called cryptogenic stroke (CS) and only in 20% with an identified cause.3 ,4 Many studies have been published testing the hypothesis that paradoxical emboli through a PFO may be implicated, however the available evidence is mixed and conflicting,5 ,6 perhaps in part due to the low recurrence rate and long-term nature of these events. PFOs are associated with numerous other conditions including migraine with aura, decompression sickness, other venoarterial embolic phenomena and platypnoea orthodeoxia. In this review we will describe the embryological development of the interatrial septum, discuss the diagnosis and clinical associations of PFO, as well as evaluate the available data for and against closure. The embryological development of the interatrial septum and foramen ovale is complex, starting at 4–5 weeks post conception with fusion of ventral and dorsal endocardial cushions. Closure of the atrioventricular canal creates two cavities that develop into atria and ventricles and divide into left and right sides. Initially the septum primum grows from the roof of the atria towards the fused endocardial cushion (figure 1A), while the gap, the ostium primum, allows interatrial flow. Before complete atrial separation, a new communication, the ostium secundum, develops by fenestration of the superior region (figure 1B ), allowing continuous right-to-left shunting of oxygenated blood from the umbilical arteries bypassing the fetal pulmonary circulation (figure 1 …