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Biomedical subjects

R J MacFadyen

Publications and source records attributed to R J MacFadyen.

At least 37 records · Page 2Linked to original sources
PubMed2000

Is there a role for renin profiling in selecting chronic heart failure patients for ACE inhibitor treatment?

BACKGROUND: It remains uncertain whether angiotensin converting enzyme (ACE) inhibitors benefit all heart failure patients or just those with renin-angiotensin-aldosterone system (RAAS) activation. OBJECTIVE: To determine whether the response to an ACE inhibitor, assessed by urine sodium excretion, was different in patients with low renin versus those with high renin. DESIGN: Plasma renin activity (PRA) was measured in 38 patients with stable chronic heart failure (21 male, 17 female; mean (SD) age 71 (6) years, range 59-82 years) on chronic diuretic treatment alone. They were divided into three groups: low (PRA </= 1.5 ng/ml/h, n = 11); normal (1.5 < PRA < 5, n = 14); and high (PRA > 5, n = 13). The effect of ACE inhibition was then assessed on diuretic induced natriuresis with respect to renin status. RESULTS: There were no significant differences in age and sex distribution between the groups. Plasma angiotensin II and aldosterone increased serially from low to high renin groups, while 24 h urinary sodium concentrations fell from low to high renin groups (low PRA, 96.7 (39.5); normal PRA, 90.4 (26.7); high PRA, 66. 3 (18.9) mmol/l; p = 0.033), despite a higher diuretic dose in the high renin group. This blunted natriuretic effect of loop diuretics was caused by RAAS activation, which could partly be reversed by ACE inhibition. ACE inhibitors increased natriuresis by 22% in the high renin group (p = 0.029), but had no effect in the normal and low renin groups. Within the low renin group, five of the 11 patients had persistently low renin levels despite ACE inhibition. There was a non-significant reduction in natriuresis (-9.6%, p = 0.335) following ACE inhibition in this subgroup of patients. CONCLUSIONS: About one third of heart failure patients in our study had low renin status and a non-activated RAAS, despite diuretic treatment. ACE inhibitors did not alter natriuresis significantly in this subgroup of patients, and enhanced natriuresis only in patients with high renin. There is thus tentative support for renin profiling in targeting ACE inhibitors to the most deserving, by showing that short term sodium retention does not occur in low renin patients if ACE inhibitors are withdrawn.

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PubMed1999

Neurohormonal reactivation in heart failure patients on chronic ACE inhibitor therapy: a longitudinal study.

BACKGROUND: Angiotensin Converting Enzyme inhibitors reduce mortality in heart failure. One therapeutic mechanism is believed to be the reduction of circulating angiotensin II and aldosterone. However, the Renin-Angiotensin-Aldosterone axis (RAAS) is not uniformly suppressed during therapy for heart failure. This effect has been referred to as 'angiotensin II reactivation' and 'aldosterone escape' and their reactivation may herald clinical deterioration. In the CONSENSUS I trial, correlations were seen between mortality, and angiotensin II and aldosterone. Furthermore, mortality was lower in those with good angiotensin II suppression. Therefore, neurohormonal elevation despite adequate treatment may associate with a poorer prognosis. AIMS: To follow chronic heart failure patients on ACE inhibitors for 18 months to assess whether or not angiotensin II and aldosterone reactivation are progressive with time, whether reactivation of both occurs simultaneously, and whether different ACE inhibitors have different neurohormonal profiles. METHODS AND RESULTS: We studied 22 patients (M/F 19:3, 72.5+/-7 years) on stable ACE inhibitors. Five times, in 18 months, samples were taken for neurohormones and ACE activity. Mean levels of neurohormones were remarkably stable over time, although captopril takers had generally higher angiotensin II, but lower aldosterone and renin. Aldosterone 'escape' (> 80 pg/ml) occurred in 13/97 samples (13.5%), in 5/22 (23%) individuals. Angiotensin II was elevated > or =10 pg/ml in 8/102 samples (8%), in 6/22 (27%) individuals. Four subjects had isolated angiotensin II reactivation, and three had aldosterone escape alone. On regression analyses between neurohormones in captopril takers there were significant correlations between; renin and angiotensin II (r = 0.62; P<0.02); angiotensin II and aldosterone (r = 0.6; P<0.02); and renin and aldosterone (r = 0.92; P<0.00001). CONCLUSION: In stable heart failure patients un-suppressed levels of angiotensin II and aldosterone occur despite therapy, but they are not necessarily progressive, nor simultaneous. Furthermore, contemporaneous serum ACE activity makes it unlikely the data presented reflects poor compliance. The results suggest that captopril takers may have different neurohormonal profiles, i.e. higher angiotensin II, and also better correlations between RAAS components, compared to longer acting preparations, although the numbers are small. Our data supports that of Swedberg et al. who showed reductions in both aldosterone and angiotensin II due to ACE inhibitor therapy, but no correlation between ACE activity and angiotensin II and only a limited correlation (r = 0.37) between angiotensin II and aldosterone. This suggests that the interaction between the components of the renin-angiotensin system is not simple and linear. The fact that each phenomenon appears to occur in isolation means that neurohormonal monitoring of individual could provide useful information to direct additional therapy. The RALES study has demonstrated reduced mortality from the addition of spironolactone to an ACE inhibitor emphasising the benefit of enhanced suppression of aldosterone in heart failure. Captopril may be less effective at suppressing the RAAS due to its short duration of action which would logically be associated with a more fluctuating pattern of ACE inhibition. In the presence of high levels of renin and angiotensin I even small differences in ACE activity will produce large variations in angiotensin II levels. Further studies should be directed at understanding the different mechanisms behind angiotensin II and aldosterone generation during ACE inhibition.

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PubMed1999

How often are angiotensin II and aldosterone concentrations raised during chronic ACE inhibitor treatment in cardiac failure?

OBJECTIVE: Angiotensin II (AII) and aldosterone are not always fully suppressed during chronic angiotensin converting enzyme (ACE) inhibitor treatment. In congestive heart failure (CHF) such failure of hormonal suppression is associated with increased mortality. This study examined how common AII and aldosterone increases are observed during routine clinical practice. PATIENTS AND METHODS: 91 patients with symptomatic (mean New York Heart Association class 2.7) CHF (mean (SD) left ventricular ejection fraction 29.9 (8)%, range 9-46%) were studied 4-6 hours after ACE inhibitor dosing. A representative range of ACE inhibitors (enalapril, lisinopril, captopril, perindopril, and fosinopril) was examined. RESULTS: Supine measurements showed a wide range of AII (10.5 (25.5) pg/ml), aldosterone (130.8 (136) pg/ml), and serum ACE (12.1 (13.3) EU/l; excludes captopril data) concentrations on diuretics. AII concentrations > 10 pg/ml were seen in 15% of patients, and aldosterone concentrations > 144 pg/ml were seen in 38% of patients. AII concentrations were significantly correlated (p < 0.001) with ACE but not with aldosterone concentrations. Aldosterone concentrations were not significantly correlated with ACE concentrations. CONCLUSIONS: AII "reactivation" occurred in 15% and failure of aldosterone suppression in 38% of routine CHF patients taking ACE inhibitor treatment. AII "reactivation" was associated with both low and high levels of ACE activity, which suggests that multiple different mechanisms are at play. In patients with high plasma ACE concentrations, non-compliance should be considered along with inadequate dose titration. In patients with low plasma ACE and high AII concentrations, non-ACE mediated production of AII may be operative. Raised aldosterone concentrations appear to be more common than AII "reactivation". It is important to establish the cause of detectable or increased AII concentrations in a heart failure patient treated with an ACE inhibitor. The measurement of serum ACE may help to identify the likely cause as poor compliance or inadequate dose.

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PubMed1999

Non-adherence with ACE inhibitor treatment is common in heart failure and can be detected by routine serum ACE activity assays.

OBJECTIVE: To assess whether serum angiotensin converting enzyme (ACE) activity during routine clinical practice accurately reflects patient adherence to ACE inhibitor treatment for chronic heart failure (CHF). DESIGN: Retrospective assessment of ACE inhibitor adherence and serum ACE activity measurements. SETTING: Teaching hospital outpatient department PATIENTS AND INTERVENTIONS: During 1994-95, serum ACE was measured in 73 CHF patients who were routinely attending the heart failure clinic at Ninewells Hospital. At the same time, the medicines monitoring unit collected data on whether and when prescriptions for ACE inhibitors were redeemed at community pharmacies, which enabled each patient's adherence over a prolonged period to be assessed. MAIN OUTCOME MEASURES: Routine collected serum ACE measurements were correlated with measured adherence with ACE inhibitor treatment. RESULTS: In total, 18% of CHF patients appeared to exhibit < 70% adherence with their ACE inhibitor treatment with 34% exhibiting less than 85% adherence and 58% exhibiting < 100% adherence. A serum ACE activity of > 12 u/l gave 91% positive predictive accuracy that the patient was < 100% adherent with their ACE inhibitor treatment. At the other extreme, a serum ACE < 6.5 u/l gave 81% positive predictive accuracy that the patient was > 85% adherent with ACE inhibitor treatment. CONCLUSIONS: Non-adherence with ACE inhibitor treatment was found to be common in patients with CHF. The simple, inexpensive test of serum ACE activity can be used in CHF patients to identify many, although not all, non-adherent patients so that adherence enhancing strategies can be targeted towards them. Further work is clearly required to explore the precise clinical use of this promising test.

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PubMed1997

Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients.

BACKGROUND: Experimental data suggest that aldosterone has harmful effects promoting myocardial fibrosis and disturbing autonomic balance. There has been no evidence of these potential effects in intact man. METHODS AND RESULTS: We report the findings in 31 patients with stable chronic heart failure (CHF) who were treated with spironolactone (50-100 mg/day) or placebo in addition to diuretics and angiotensin converting enzyme (ACE) inhibition. In a controlled randomised double-blind study, we found that spironolactone treatment reduced circulating levels of procollagen type III N-terminal amino peptide, a marker of vascular collagen turnover, and in addition increased time-domain parameters of heart rate variability (n = 24). These latter parameters suggest a parasympathomimetic effect for additional spironolactone. Spironolactone significantly reduced heart rate (prolonged RR interval) particularly during the dawn hours (06.00-09.00 h). In this unbalanced study it was not possible to provide a detailed diurnal assessment of the impact of spironolactone on heart rate variability, but the preliminary data suggest that there may be an interaction with the autonomic nervous system which varies in time. CONCLUSIONS: These are the first human data to show that use of the aldosterone antagonist, spironolactone, can positively improve time-domain heart rate variability and reduce myocardial collagen turnover, as reflected by further reductions in serum procollagen peptide, despite concurrent ACE inhibitor treatment. Residual aldosterone after ACE inhibitor treatment may therefore have a role promoting arrhythmia and cardiac death by two mechanisms. Effects of additional spironolactone on slowing heart rate (and potentially the detrimental effect of aldosterone) were most prominent between 6 a.m. and 10 a.m. when cardiac death is also known to be most prominent.

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PubMed1997

Further evidence that chronic perindopril treatment maintains neurohormonal suppression but does not lower blood pressure in chronic cardiac failure.

AIMS: Previous studies in heart failure (CHF) after temporary diuretic withdrawal have suggested that perindopril is associated with no first dose hypotension in comparison with other ACE inhibitors (ACEI) or placebo. The aim of this study was to explore further the profile of perindopril during chronic dosing. METHODS: We report the effects of acute and chronic (8 weeks) treatment with the ACE inhibitor perindopril (Per, 2-->4 mg daily) or placebo (P) in a double-blind parallel group study of 24 diuretic treated patients (17M; 67 +/- 8 years, 80 +/- 17 kg) with ischaemic cardiomyopathy (fractional shortening, 19 +/- 5%; radionuclide ejection fraction, 31 +/- 3%). Baseline biochemical, hormonal (ACE, Ang I, Ang II), isotopic renal function (GFR, ERPF, ECFV), pretreatment diuretic dose and heart failure scores were similar between groups. Concomitant cardiac treatments remained unchanged and diuretic withdrawal was not used to introduce treatment. RESULTS: There were no significant effects on electrolytes, liver function tests, serum or erythrocyte magnesium. There was no significant first dose fall in SBP over 6 h) (P, baseline 137 +/- 18; min 115 +/- 16 mmHg; Per, baseline 137 +/- 15; min 118 +/- 17 mmHg). Neither supine nor erect BP was significantly affected by chronic treatment (P, erect baseline 134 +/- 23/76 +/- 10 to 124 +/- 41/74 +/- 10 mmHg; Per, baseline 135 +/- 21/76 +/- 14 to 128 +/- 22/70 +/- 12 mmHg, P=NS). Active treatment was associated with significant ACE inhibition (P, baseline 47 +/- 17 to 43 +/- 17; Per baseline 49 +/- 15 to 14 +/- 7); aldosterone (P, baseline 337 +/- 179 to 375 +/- 306; Per, baseline 335 +/- 357 to 293 +/- 155 pg ml(-1)) and Ang II suppression (P, baseline 9 +/- 9 to 20 +/- 39; Per baseline 10 +/- 9 to 3 +/- 3 pM). Isotopic renal function was unaffected by either treatment. CONCLUSIONS: At this dose (2-4 mg orally) chronic perindopril therapy has no significant effect on blood pressure or renal function. Sustained neurohormonal suppression of ACE and AII occurred without evidence of AII reactivation. A lack of effect on BP at these doses may make perindopril suitable for study in unstable patients with acute HF or useful in those patients where there are concerns over ACEI induced hypotension.

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PubMed1997

The practical assessment of compliance with ACE-inhibitor therapy--a novel approach.

Poor compliance may be responsible for symptomatic decompensation or neurohormonal "escape" in patients with heart failure treated over the long term with angiotensin-converting enzyme-1 (ACEI) drugs. Serum ACE activity is a poor index of neurohormonal suppression or haemodynamic effect after ACE-inhibitor treatment. Serum ACE activity may, however, be a useful index of compliance with treatment, as serum ACE is sensitive to the presence of an ACE inhibitor in the blood. Sixteen normotensive male volunteers of known ACE genotype received 7 days of randomised, double-blind therapy on four occasions 2 weeks apart with lisinopril 20 mg (L) or matched placebo (P) to simulate (A) noncompliance (all P), (B) full compliance (all L), (C) partial compliance (L days, 1, 3, 6; P days, 2, 4, 5, 7), or (D) single dose (L day 7; P, 1-6). Supine (30 min) blood pressure (BP)/heart rate (HR), ACE, and angiotensins were measured on d7 before dose and 4-6 h after dose. Results are mean +/- 1 SD. BP showed the expected small decrease with active treatment on d7 (B or D) but not with placebo (A) or partial compliance (C). Prestudy serum ACE, despite a wide range (16-124 U/L), was reproducible within subjects [coefficient of variation (CV), 1.7%]. Serum ACE activity, before (41.9 +/- 30) and after (41 +/- 30) angiotensin (A) I or II, were unaffected by treatment (placebo A). Active treatment (B) resulted in very low serum ACE activity and d7 and a small further suppression after dosing (before, 3.9 +/- 4; after, 1.8 +/- 4). AI was elevated in this group with further elevation after dosing (before, 234 +/- 116; after, 551 +/- 250). AII was only modestly reduced from baseline and showed little further suppression after dosing (before, 7.8 +/- 4; after, 6.3 +/- 5). Partial compliance (C) showed low ACE but no reduction after treatment (before, 7 +/- 3; after, 7 +/- 4), an elevated AI but no dosing effect (before, 187 +/- 198; after, 200 +/- 151) and reduced AII but with no further dose suppression (before, 6.4 +/- 3.4; after, 7 +/- 4) induced increase in peptide (compared with B). Single-dose treatment (D) showed ACE inhibition as expected (before, 47 +/- 30; after, 2.2 +/- 3). There was a dosing-related increase of AI but to a lesser extent than seen with chronic active dosing (B) (before, 39 +/- 10; after, 240 +/- 200). In contrast to long-term dosing, there was marked ANG II suppression (before, 8.8 +/- 4; after, 2.9 +/- 3). With this long-acting ACEI in a dose relevant to congestive heart failure management, we suggest that 4-6 h after-dosing serum ACE (< 5 EU/L) and elevated ANG I (> 300 pg/ml) can be used to confirm compliance with treatment. These absolute values may be altered in patients treated concomitant with loop diuretics. In principle, however, this may be a useful tool in clinical trials or in clinical practice after further work has been done to assess the limits in patients across the doses and across the range of available drugs used.

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PubMed1996

Effects of brain natriuretic peptide on exercise hemodynamics and neurohormones in isolated diastolic heart failure.

BACKGROUND: Experimental models suggest that brain natriuretic peptide (BNP) can modify left ventricular diastolic performance. The aim of this study was to evaluate the effects of BNP on resting and exercise hemodynamics and neurohormones in patients with isolated diastolic heart failure. METHODS AND RESULTS: Six patients with isolated diastolic heart failure were studied. After baseline hemodynamic measurements were obtained with use of thermistor-tipped pulmonary artery catheters, patients were randomized to receive infusion of BNP or placebo in a single-blind, crossover study. Hemodynamic and neurohormonal parameters were measured at rest after 30 minutes of infusion and during incremental supine bicycle exercise. BNP did not significantly affect resting hemodynamics but attenuated the rise in both pulmonary capillary wedge pressure (placebo, 23 +/- 2 mm Hg; BNP, 16 +/- 2 mm Hg; P < .01) and mean pulmonary artery pressure (placebo, 34 +/- 3 mm Hg; BNP, 29 +/- 3 mm Hg; P < .05) during exercise without affecting changes in heart rate, systemic blood pressure, or stroke volume. In response to BNP, there was significant suppression of plasma aldosterone concentration (placebo, 551 +/- 107 pmol/L; BNP, 381 +/- 56 pmol/L; P < .05). CONCLUSIONS: BNP infusion causes beneficial hemodynamic and neurohormonal effects during exercise in patients with isolated diastolic heart failure.

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PubMed1996

Impaired exercise tolerance in hypertensive patients.

PURPOSE: To review information on exercise testing in hypertensive patients and persons at risk for developing hypertension and to determine whether this type of investigation is valuable for diagnosis, prognosis, or assessment of the effect of therapy. DATA SOURCES: A MEDLINE search of English-language articles published between 1985 and 1995 and reviews of the bibliographies of textbooks. STUDY SELECTION: Primary research articles on exercise testing in patients with hypertension, with an emphasis on methods, diagnosis, prognosis, and assessment of drug therapy. DATA EXTRACTION: Study design and quality were assessed, with particular attention paid to methods and aims. Relevant data on hemodynamic responses in hypertensive patients and persons at risk for developing hypertension and correlations to end-organ damage, mortality, and exercise tolerance were analyzed. DATA SYNTHESIS: The exercise capacity of hypertensive patients was found to be reduced by as much as 30% compared with age-matched controls. This exercise impairment increases with age and end-organ damage, and its origin can be traced back to adolescence. Total peripheral resistance also progressively increases. These changes are caused by functional and structural involvement of the cardiovascular system. Diastolic dysfunction of the heart is a prominent factor in this exercise limitation. The blood pressure responses to exercise have prognostic value for the future development of hypertension, end-organ damage, and death. The adequacy of antihypertensive treatment should therefore be evaluated in terms of normalizing these stress-related blood pressure responses. CONCLUSION: Exercise testing is a simple procedure that has great potential for assessing hypertensive patients. More research is necessary, however, to determine whether controlling blood pressure during exercise is beneficial.

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PubMed1996

Dose-ranging study of the angiotensin II receptor antagonist irbesartan (SR 47436/BMS-186295) on blood pressure and neurohormonal effects in salt-deplete men.

We characterised the blood pressure (BP) and hormonal responses to the oral angiotensin II (Ang II) receptor antagonist irbesartan (SR47436/BMS-186295) or placebo in normal men with an activated renin-angiotensin system (RAS) during salt depletion. We also evaluated safety and tolerability. Twelve healthy, normotensive male volunteers followed a standardised salt-depletion regimen for 3 days before each study day. Six different single oral doses of irbesartan (1, 5, 10, 25, 50, and 100 mg) were administered double-blind in a three-panel, dose escalation with placebo randomised in each panel. Supine and erect BP and heart rate (HR), serum and urinary electrolytes: plasma renin activity (PRA), and Ang II were measured at intervals. Urinary electrolytes were measured for the 24-h period before dosing (to confirm salt depletion) and for 24 h afterward. No drug-related side effects were noted. There was a dose-related decrease in supine and erect systolic and diastolic BP (SBP, DBP) with irbesartan from 10 mg and beyond, with no change in HR. Supine mean arterial pressure (MAP) decreased by 18.8 mm Hg. There was a dose-related reactive increase in PRA (to 35 ng/ml/h) and Ang II (to 450 pg/ml) with irbesartan. Irbesartan is an orally active AT1 receptor antagonist. In salt-deplete normal men, it has a dose-related haemodynamic, hormonal, and electrolyte profile characteristic of AT1 antagonists. The dose range studied did not show a plateau or maximum effect.

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