Philip Roberts-Thomson

Comparative hemodynamic effects of amiodarone, sotalol, and d-sotalol

The effects of intravenous boluses of amiodarone (5 mg/kg), racemic sotalol (enantiomeric ratio d/l-sotalol 1:1;1.5 mg/kg), and d-sotalol (0.75 mg/kg) on mean arterial pressure (MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), left ventricular end-diastolic pressure (LVEDP), and peak rate of change of left ventricular pressure (LV dp/dt) were assessed in conscious rabbits. Amiodarone and sotalol had a modest negative inotropic effect: amiodarone reduced peak LV dp/dt by 8 +/ 2% (mean +/- SEM) (p < 0.05) and sotalol by 6 +/- 2% (p < 0.05). These two drugs had quite different effects on CO as a result of differences in their actions on peripheral blood vessels: amiodarone caused a 13 +/- 3% (p < 0.05) increase in CO associated with a substantial vasodilatory effect (TPR reduced 25 +/- 3%; p < 0.01); sotalol did not produce any substantial change in either CO or TPR. Bolus intravenous injection of amiodarone was associated with a significant increase in HR (12 +/- 3%; p < 0.01), whereas sotalol reduced HR by 7 +/- 1% (p < 0.05). In contrast, administration of the dextro-rotatory optical isomer, d-sotalol, produced no significant change in peak LV dp/dt, LVEDP, CO, TPR, or HR. These results confirm that amiodarone and racemic sotalol have a comparatively weak cardiodepressant action. The experiments also show that the reduction in cardiac performance associated with racemic sotalol is mediated predominantly through the beta-adrenoreceptor blocking action of the levo-rotatory isomer (l-sotalol) rather than any substantial cardiodepressant effect of the dextro-rotatory isomer.

Accuracy of Cuff-Measured Blood Pressure: Systematic Reviews and Meta-Analyses

BACKGROUNDnHypertension (HTN) is the single greatest cardiovascular risk factor worldwide. HTN management is usually guided by brachial cuff blood pressure (BP), but questions have been raised regarding accuracy.nnnOBJECTIVESnThis comprehensive analysis determined the accuracy of cuff BP and the consequent effect on BP classification compared with intra-arterial BP reference standards.nnnMETHODSnThree individual participant data meta-analyses were conducted among studies (from the 1950s to 2016) that measured intra-arterial aortic BP, intra-arterial brachial BP, and cuff BP.nnnRESULTSnA total of 74 studies with 3,073 participants were included. Intra-arterial brachial systolic blood pressure (SBP) was higher than aortic values (8.0xa0mmxa0Hg; 95% confidence interval [CI]: 5.9 to 10.1xa0mmxa0Hg; pxa0< 0.0001) and intra-arterial brachial diastolic BP was lower than aortic values (-1.0xa0mmxa0Hg; 95% CI:xa0-2.0 toxa0-0.1xa0mmxa0Hg; pxa0=xa00.038). Cuff BP underestimated intra-arterial brachial SBP (-5.7xa0mmxa0Hg; 95% CI:xa0-8.0 toxa0-3.5xa0mmxa0Hg; pxa0< 0.0001) but overestimated intra-arterial diastolic BP (5.5xa0mmxa0Hg; 95% CI: 3.5 to 7.5xa0mmxa0Hg; pxa0< 0.0001). Cuff and intra-arterial aortic SBP showed a small mean difference (0.3xa0mmxa0Hg; 95% CI:xa0-1.5 to 2.1xa0mmxa0Hg; pxa0=xa00.77) but poor agreement (mean absolute difference 8.0xa0mmxa0Hg; 95% CI: 7.1 to 8.9xa0mmxa0Hg). Concordance between BP classification using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure cuff BP (normal, pre-HTN, and HTN stages 1 and 2) compared with intra-arterial brachial BP was 60%, 50%, 53%, and 80%, and using intra-arterial aortic BP was 79%, 57%, 52%, and 76%, respectively. Using revised intra-arterial thresholds based on cuff BP percentile rank, concordance between BP classification using cuff BP compared with intra-arterial brachial BP was 71%, 66%, 52%, and 76%, and using intra-arterial aortic BP was 74%, 61%, 56%, and 65%, respectively.nnnCONCLUSIONSnCuff BP has variable accuracy for measuring either brachial or aortic intra-arterial BP, and this adverselyxa0influences correct BP classification. These findings indicate that stronger accuracy standards for BP devices mayxa0improve cardiovascular risk management.

EXPERIMENTAL HYPERTENSION PRODUCES DIVERSE CHANGES IN THE REGIONAL VASCULAR RESPONSES TO ENDOTHELIN-1 IN THE RABBIT AND THE RAT

Objective: To examine the effects of hypertension on systemic and regional haemodynamic responses to endothelin-1. Design: Comparison of responses between age-matched control and hypertensive rabbits (two-kidney, two wrapped), and between spontaneously hypertensive rats (SHR) and control Wistar—Kyoto rats. Methods: Arterial pressure, heart rate and blood flow responses to 0.2 nmol/kg intravenous endothelin-1 were measured in conscious animals. Blood flow was measured by pulsed ultrasound Doppler in the ascending aorta, distal abdominal aorta, left renal artery and superior mesenteric artery. Results: Endothelin-1 produced qualitatively similar effects in the hypertensive and control animals. In the systemic circulation, brief initial vasodilation preceded sustained vasoconstriction. In the hindlimb, marked vasodilation preceded relatively minor vasoconstriction, and profound vasoconstriction occurred in the renal and mesenteric vascular beds. In the rats but not the rabbits, fleeting vasodilation preceded the renal and mesenteric vasoconstriction. Significant differences between hypertensive and control animals were: accentuation of the pressor effect and heart rate responses in hypertensive animals of both species, and accentuation of hindlimb vasodilation in hypertensive rabbits but not SHR; and attenuation of the depressor effect in SHR but not hypertensive rabbits, attenuation of the mesenteric vasoconstriction in both hypertensive rabbits and rats, and attenuation of renal vasoconstriction in SHR. Conclusions: The increased responses to endothelin-1 of some variables in the hypertensive animals may involve structural changes in the resistance vessels. However, the reduced responses in the mesenteric vasculature of both species and the renal vasculature of the SHR are due to some mechanism other than structural change.

Impact of medical consultation frequency on risk factors and medications 6 months after acute coronary syndrome.

OBJECTIVEnInitiatives that support primary care to better enable delivery of optimal prevention services are of great importance. The purpose of this study was to examine the frequency of medical consultations by patients with acute coronary syndrome (ACS) in the 6 months after hospital discharge and to determine whether the frequency of visits was associated with differences in lifestyle, clinical measures and medication prescription.nnnMETHODSnWe conducted a retrospective subgroup analysis of data collected in the Cooperative National Registry of Acute Coronary Care, Guideline Adherence and Clinical Events (CONCORDANCE), which is an ongoing (prospective) clinical initiative providing continuous real-time reporting on the clinical characteristics, management and outcomes of patients admitted to Australian hospitals with ACS. We compared clinical measures, medications, smoking status and receipt of cardiac rehabilitation with frequency of medical consultations 6 months after hospital discharge.nnnRESULTSnPatients with ACS visited their general practitioner (GP) a mean of 4.4 (± 3.8) times and their cardiologist 1.2 (± 0.9) times in the 6-month period after their index admission. Patients who saw a GP in the 6-month period had significantly higher rates of participation in cardiac rehabilitation, receipt of dietary advice and prescription of cardioprotective medications. Factors associated with increased frequency of GP visits were older age groups (oldest fourth vs youngest fourth incidence rate ratio (IRR) 1.08; 95% CI 1.01, 1.14), being female (male vs female IRR 0.83; 95% CI 0.80, 0.86), diagnosis of ST-segment elevation myocardial infarction (STEMI) (STEMI vs non-STEMI IRR 1.08; 95% CI 1.04, 1.13; STEMI vs unstable angina IRR 1.01; 95% CI 0.95, 1.06), being a current smoker (IRR 1.09; 95% CI 1.05, 1.15), history of cardiovascular disease (IRR 1.06; 95% CI 1.01, 1.12), history of diabetes (IRR 1.25; 95% CI 1.21, 1.31), inpatient revascularisation (IRR 0.95; 95% CI 0.91, 0.99), receipt of cardiac rehabilitation referral (IRR 0.93; 95% CI 0.89, 0.97), and discharged on four or more out of five indicated medications (IRR 1.04; 95% CI 1.00, 1.08).nnnCONCLUSIONnThe majority of ACS survivors in this study saw their GP frequently and their cardiologist at least once during the 6 months after index admission. Seizing these opportunities to engage, manage and support patients is important for strengthening prevention in primary care.

Expanding Role for Transcatheter Aortic Valve Replacement: Successful Transfemoral Implantation of a Medtronic CoreValve for Severe Aortic Regurgitation

Severe aortic regurgitation (AR), when intervention is required, is best managed by surgical aortic valve replacement (SAVR). Transcatheter aortic valve replacement (TAVR) for aortic stenosis has recently shown non-inferiority to SAVR and superiority to medical management. Here we describe a successful TAVR for a patient with severe AR that was unsuitable for SAVR due to her high surgical risk.

Endothelin-1 causes a biphasic response in systemic vasculature and increases myocardial contractility in conscious rabbits.

We studied the effects of an intravenous (i.v.) bolus of endothelin-1 (ET-1, 0.2 nmol/kg) in conscious rabbits, measuring arterial blood pressure (BP), heart rate (HR), myocardial contractility, and cardiac output and evaluating direct and indirect effects of ET-1 with pacing and pharmacologic antagonists. ET-1 caused a brief initial decrease in BP of 18 +/- 1 mm Hg, followed by a sustained increase of 26 +/- 3 mm Hg (n = 16, p < 0.001). HR increased initially by 60 +/- 11 beats/min and then decreased by 68 +/- 6 beats/min (n = 16, p < 0.001). Left ventricular (LV) dP/dt increased by 2,120 +/- 380 mm Hg/s (n = 5, p < 0.01). LV end-diastolic pressure (LVEDP) increased by 4 +/- 1 mm Hg (n = 5, p < 0.05). Cardiac output (CO) increased initially by 34 +/- 4% and then decreased by 28 +/- 3% (n = 16, p < 0.001). Total peripheral resistance (TPR) decreased initially by 34 +/- 3% and then increased by 72 +/- 13% (n = 16, p < 0.001). Pacing did not alter the effect of ET-1 on arterial BP, LVdP/dt, or LVEDP. The combination of propranolol and scopolamine significantly reduced the increase and decrease in HR and the increase in LVdP/dt. None of the antagonists significantly altered the effect of ET-1 on TPR. ET-1 causes brief initial vasodilation and increased myocardial contractility, followed by sustained vasoconstriction. The vascular effects appear to be of greater significance than the cardiac effects at the dose used.(ABSTRACT TRUNCATED AT 250 WORDS)

Targeted LOWering of Central Blood Pressure in patients with hypertension: Baseline recruitment, rationale and design of a randomized controlled trial (The LOW CBP study)

BACKGROUNDnHigh blood pressure (BP) is the most common modifiable cause of death from cardiovascular disease. Lowering BP with medication improves patient outcomes, but even in populations with normal upper arm (brachial) BP there remains considerable residual risk for cardiovascular disease and this may be due to persistently elevated central BP. There has never been a trial to determine the value of targeted central BP lowering among patients with hypertension, and this was the aim of this study.nnnMETHODSnThis is a multi-centre, randomized, open-label, blinded endpoint trial among 308 patients treated for uncomplicated hypertension with controlled brachial BP (<140/90mmHg) but elevated central BP (≥0.5SD above age- and sex-specific normal values). Baseline recruitment has been completed. Participants were randomized to intervention with spironolactone (25mg/d) or usual care and are being followed over 24months, with the primary outcome being left ventricular mass index (using cardiac magnetic resonance imaging). Brachial and central BP will be measured in the clinic, at home over 7-days and by 24-h ambulatory monitoring. Aortic stiffness will be assessed by carotid-to-femoral pulse wave velocity. Primary (intention to treat) analysis will determine the role of central versus brachial BP for predicting changes in left ventricular mass index.nnnCONCLUSIONSnCompared with control, intervention is expected to significantly lower left ventricular mass index, and this effect is expected to be independently correlated with central BP lowering. These findings would support the concept of central BP as an important therapeutic target in hypertension management. Results are expected in 2018.

Arterial reservoir characteristics and central-to-peripheral blood pressure amplification in the human upper limb

Background: Arterial reservoir characteristics are related to blood pressure (BP) and independently predict cardiovascular events. It is unknown if arterial reservoir characteristics are modified from the central-to-peripheral large arteries and whether there is a contributory role to BP amplification. The aim of this study was to assess central-to-peripheral changes in arterial reservoir characteristics and determine associations with BP. Methods: Reservoir pressure (RP) and excess pressure (XSP) were derived from intra-arterial BP waveforms among 51 participants (aged 63u200a±u200a13 years, 63% men) undergoing clinically indicated cardiac angiography. BP waveforms were recorded in the ascending aorta, brachial (mid-humerus) and radial (wrist) arteries via catheter pull-back. Results: There was no significant difference in RP between arterial sites (54u200a±u200a15, 53u200a±u200a15 and 52u200a±u200a17u200ammHg for the aorta, brachial and radial artery, respectively; Pu200a=u200a0.68). Conversely, XSP increased stepwise from the aorta to the brachial and radial arteries (24u200a±u200a11, 42u200a±u200a14 and 53u200a±u200a16u200ammHg; Pu200a<u200a0.001), as did SBP (134u200a±u200a18, 141u200a±u200a16 and 146u200a±u200a19u200ammHg; Pu200a=u200a0.004). There were highly significant associations between RP and SBP at all arterial sites (ru200a=u200a0.821, 0.649 and 0.708; Pu200a<u200a0.001 for all), but the strength of associations between peak XSP and SBP increased significantly from the aorta to the radial artery (ru200a=u200a0.121 and 0.508; zu200a=u200a3.04; Pu200a=u200a0.004). Conclusion: Arterial reservoir characteristics are modified through the large arteries of the upper limb. Although RP remains relatively constant, XSP increases significantly and is highly related to BP (SBP and pulse pressure) amplification. These data provide a new understanding on arterial reservoir characteristics and large-artery BP physiology.

Discovery of New Blood Pressure Phenotypes and Relation to Accuracy of Cuff Devices Used in Daily Clinical Practice.

Cuff blood pressure (BP) is the reference standard for management of high BP, but the method is inaccurate and can lead to BP misclassification. The aims of this study were to determine whether distinctive BP phenotypes exist based on BP transmission (amplification) variability from central-to-peripheral arteries and whether applying one standard cuff BP measurement approach (eg, oscillometry) to all people could discriminate the BP phenotypes. Intra-arterial BP was measured at the ascending aorta and brachial and radial arteries in 126 participants (61±10 years; 69% male) after coronary angiography. Central-to-peripheral systolic BP (SBP) transmission (SBP amplification) was defined by ≥5 mm Hg SBP increase between the aorta-to-brachial or brachial-to-radial arteries. Standard cuff BP was measured 4 different times using 3 different devices. Three independent investigators also provided data (n=255 from 4 studies) using another 3 separate cuff BP devices. Four distinct BP phenotypes were discovered based on variability in SBP amplification: phenotype 1, both aortic-to-brachial and brachial-to-radial SBP amplification; phenotype 2, only aortic-to-brachial SBP amplification; phenotype 3, only brachial-to-radial SBP amplification; and phenotype 4, neither aortic-to-brachial nor brachial-to-radial SBP amplification. Aortic SBP was significantly higher among phenotypes 3 and 4 compared with phenotypes 1 and 2 (P=0.00074), but this was not discriminated using any standard cuff BP measures (P=0.31). Data from independent investigators confirmed the key findings. This is the first-in-human discovery of BP phenotypes that have significantly different BPs, but which are not discriminated by standard cuff BP devices used in daily clinical practice. Improved BP device accuracy may be achieved by considering individual phenotypic BP differences.

Identification of the optimal protocol for automated office blood pressure measurement among patients with treated hypertension

BACKGROUNDnAutomated office blood pressure (AOBP) involving repeated, unobserved blood pressure (BP) readings during one clinic visit is recommended for in-office diagnosis and assessment of hypertension. However, the optimal AOBP protocol to determine BP control in the least amount of time with the fewest BP readings is yet to be determined and was the aim of this study.nnnMETHODSnOne hundred and eighty-nine patients (mean age 62.8 ± 12.1 years; 50.3% female) with treated hypertension referred to specialist clinics at 2 sites underwent AOBP in a quiet room alone. Eight BP measurements were taken starting immediately after sitting and then at 2-minute intervals (15 minutes total). The optimal AOBP protocol was defined by the smallest mean difference and highest intraclass correlation coefficient (ICC) compared with daytime ambulatory BP (ABP). The same BP device (Mobil-o-graph, IEM) was used for both AOBP and daytime ABP.nnnRESULTSnAverage 15-minute AOBP and daytime ABP were 134 ± 22/82 ± 13 and 137 ± 17/83 ± 11 mm Hg, respectively. The optimal AOBP protocol was derived within a total duration of 6 minutes from the average of 2 measures started after 2 and 4 minutes of seated rest (systolic BP: mean difference (95% confidence interval) 0.004(-2.21, 2.21) mm Hg, P = 1.0; ICC = 0.81; diastolic BP: mean difference 0.37(-0.90, 1.63) mm Hg, P = 0.57; ICC = 0.86). AOBP measures taken after 8 minutes tended to underestimate daytime ABP (whether as a single BP or the average of more than 1 BP reading).nnnCONCLUSIONSnOnly 2 AOBP readings taken over 6 minutes (excluding an initial reading immediately after sitting) may be needed to be comparable with daytime ABP.