Robert J. MacFadyen

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.

Impaired Exercise Tolerance in Hypertensive Patients

Sustained arterial hypertension is an asymptomatic condition associated with a major increase in illness and death caused by cardiovascular disease. The development of sustained hypertension in adolescence and adulthood has been defined through studies of blood pressure in children [1]. The prevalence of hypertension increases exponentially from 1% to 2.5% of teenagers [2] to approximately a third of all persons older than the age of 65 years [3]. Blood pressure readings at rest are normally used to define hypertension. During the late 1950s and the 1960s [4, 5], many studies were done to assess the hemodynamic responses to exercise in known hypertensive persons and, separately, in persons who at that time were thought to be at risk for developing hypertension. The results initiated interest in the pathophysiology and natural history of hypertension. It became apparent that functional testing unmasked subtle abnormalities that were not apparent at rest. The recent development of ambulatory blood pressure monitoring has been useful in evaluating blood pressure in an environment that is separate from the stress-filled environment of the physicians office [6]. However, ambulatory blood pressure recordings are not easily correlated with the various physical activities that the patient engages in throughout the day. Standardized exercise testing protocols are now generally available and are an established element of the management of coronary heart disease. These protocols are not routinely used for assessing hypertensive patients unless evidence suggests concurrent myocardial ischemia. In controlled circumstances, formal exercise testing shows that work capacity in asymptomatic hypertensive patients is impaired compared with age- and fitness-matched controls [7]. In this review, we examine the origins and nature of this finding. Despite progress in the understanding of hypertension in terms of diagnosis and assessment of its complications, it is prudent to reexamine the value of exercise testing. Functional testing with modern techniques can give further insights into the pathophysiology of the disorder and may allow a better evaluation of the prognosis of high-risk normotensive persons or those with borderline hypertension. The blood pressure elevation during exercise is better correlated with end-organ damage [8-11] than are casual measurements. Thus, the response to exercise in hypertensive patients may be a more useful end point to assess the efficacy of antihypertensive therapy than is resting blood pressure. In this review we also evaluate the role of exercise testing as an adjunctive investigative tool in hypertension management and drug assessment. Methods We searched the MEDLINE database to identify all articles about exercise testing in persons with hypertension published between 1985 and February 1995. We also searched the bibliographies of relevant textbooks and articles. We analyzed data on hemodynamic responses of hypertensive patients and persons thought to be at risk for developing hypertension in terms of correlations with end-organ damage, death, and exercise tolerance. Where appropriate, we highlight the methodologic flaws of the selected studies to obtain a better understanding of experimental exercise testing. Methodologic Considerations Unlike exercise stress testing in coronary heart disease, no universally accepted guidelines on exercise testing are directed specifically toward assessing hypertensive patients. Few studies have been published on the comparative merits of different exercise-testing protocols. It has even been assumed that otherwise healthy patients with hypertension have normal exercise oxygen kinetics [12]. Most methodologic comparisons have therefore been done on normal persons and on patients with ischemic heart disease or heart failure. Until this vacuum is filled, we must be guided by these research findings. Types of Stress Testing The cardiovascular system can be tested using isometric techniques, isotonic techniques, or both. In clinical practice, hand grip has been used as a beside isometric stress test but is of little use for stressing the whole cardiovascular system. Dynamic or isotonic exercise, which is more often used in research and clinical practice, represents muscle contraction with constant tone and therefore muscle shortening. The cycle ergometer and treadmill are the two commonly used tools. These can be calibrated, and delivered workloads may be accurately defined during staged exercise protocols. The two techniques differ in several respects. Hemodynamic Effects of Body Position Supine cycle ergometry is associated with a higher heart rate for a given level of work than is upright cycle ergometry. Accordingly, with supine ergometry, patients with coronary heart disease develop angina at a lower double product, and the ST segment is more depressed at any given work level [13]. Upright treadmill exercise produces lower peak systolic blood pressure than does supine cycle ergometry at the same workload. When the treadmill and upright cycle ergometry are compared at similar workloads, the increase in both heart rate and arterial blood pressure are lower with treadmill testing [14], but the maximal oxygen uptake is 6% to 25% higher [15-17]. Upright cycle ergometry therefore places a greater stress on the cardiovascular system but is less sensitive in eliciting a positive diagnostic response when the patient is being tested for ischemic heart disease [13]. Exercise Testing Protocols The testing protocol defines the incremental or continuous nature of the test, the duration, and the workload associated with each stage. Measured maximal oxygen uptake differs depending on the protocol used. Maximal oxygen uptake is significantly higher when the test lasts between 8 and 17 minutes [15]. When assessed in patients with heart failure, protocols with slow incremental workloads give reproducible stage indices of metabolic work but result in a longer test and underestimation of maximal oxygen uptake [18]. Protocols that last less than 10 minutes [19] and those with a large incremental increase in workloads [18] are associated with greater variability on repeat testing. The ramp concept was created to minimize this variability. A constant workload rate (ramp rate) is set such that maximal exercise for each person can be achieved in approximately 10 minutes. This protocol provides excellent correlations between observed and predicted oxygen uptake calculated from workloads increased at a constant rate [16]. This is a useful protocol in cases in which ventilatory gas analysis is not available, but it is inconvenient: A preliminary maximal exercise test (using a slow protocol) is necessary to estimate maximal exercise capacity and set the ramp rate. This protocol is therefore not widely used in clinical practice. Whichever protocol is used for research purposes, many studies have shown that patients must be familiarized with the protocol and the demands of the test. The motivation of the supervising staff and patient remain key features in the outcome and duration of a test [20]. Blood Pressure Measurement during Exercise Many studies have shown that at-rest blood pressure measurements obtained using sphygmomanometry may differ from those obtained using intraarterial recordings. In a study of 35 patients with early hypertension, Lund-Johansen [5] found that when an indirect method of cuff sphygmomanometry was used compared with intra-arterial measurements, at-rest systolic blood pressure was underestimated by a mean of 4.5 mm Hg and at-rest diastolic blood pressure was overestimated by a mean of 5.1 mm Hg. His findings are not unique [21, 22]. Gould and colleagues [23] compared indirect and direct blood pressure in 25 patients with hypertension during exercise with cycle ergometry and found that systolic blood pressure during exercise was underestimated by 15 to 18 mm Hg. The mean difference in diastolic blood pressure during exercise ranged from 2 to 4 mm Hg. Diastolic blood pressure is more difficult to determine during exercise. In a separate study of patients with coronary disease [24], diastolic blood pressure could not be measured with a sphygmomanometer during exercise in as many as 12.5% of patients. During exercise, sphygmomanometry is compromised by movement, respiratory effort, and the noise of the equipment. When cuff methods are compared with intra-arterial methods, intrapatient and interpatient variability may increase as exercise progresses [23]. The use of an automated blood pressure measuring system would be more convenient for clinicians supervising an exercise test. Manual and automated methods of exercise blood pressure measurement have also been compared; unfortunately, automated systems tend to be both inaccurate and unreliable [25-28]. Garcia-Gregory and colleagues [25] compared these methods and found that an automated method (the Blood Pressure Measuring System developed by NASA [National Aeronautic and Space Administration]) overestimated systolic blood pressure and underestimated diastolic blood pressure during exercise. At peak exercise, systolic blood pressure was overestimated by 20 mm Hg; in addition, the blood pressure measurements during exercise were inconsistent, with standard errors 2 to 3 times that of the manual method. The utility of Finapres blood pressure estimations (a finger blood-pressure estimation device), which correlate well with intra-arterial monitoring in pressor dose-response studies [29], has not been fully evaluated during exercise. A calculated mean arterial blood pressure (by convention, one third of the pulse pressure plus diastolic blood pressure) is only valid while the patient is at rest. During exercise, measured mean intra-arterial pressure shifts to the middle of the pulse pressure with an increase in heart rate and changing vascular resistance [30]. Because blood pressure during exercise decreases rapidly as

Matrix Metalloproteinases in Coronary Artery Disease:Clinical and Therapeutic Implications and Pathological Significance

Matrix metalloproteinases (MMP) and their inhibitors (TIMP) are central factors in the control of extracellular matrix turnover. They are important in normal physiology and also during a range of pathological states. Only recently has their role in cardiovascular disease been explored and their analysis through measurements in blood been studied. We have systematically identified clinical articles relevant to coronary artery disease from the last 10 years using MEDLINE. In this review we outline the structure, function and regulation of metalloproteinases and their key roles in angiogenesis, stable and unstable coronary artery disease. Metalloproteinases and their inhibitors are fundamental mediators of change in aging and atherosclerosis, the cell membrane, and in myocardial and vascular tissue. Defining their overall importance and understanding their complex interrelationships with pressure, thrombosis and local neural and hormonal tone will require detailed clinical study. The modulation of MMP and TIMP activity using drugs that affect the expression and function of these proteins will provide us with new ways to treat these serious and disabling diseases, and we explore potential mechanisms and treatments.

The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation

The current manuscript is the second update of the original Practical Guide, published in 2013 [Heidbuchel et al. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace 2013;15:625-651; Heidbuchel et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace 2015;17:1467-1507]. Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative for vitamin K antagonists (VKAs) to prevent stroke in patients with atrial fibrillation (AF) and have emerged as the preferred choice, particularly in patients newly started on anticoagulation. Both physicians and patients are becoming more accustomed to the use of these drugs in clinical practice. However, many unresolved questions on how to optimally use these agents in specific clinical situations remain. The European Heart Rhythm Association (EHRA) set out to coordinate a unified way of informing physicians on the use of the different NOACs. A writing group identified 20 topics of concrete clinical scenarios for which practical answers were formulated, based on available evidence. The 20 topics are as follows i.e., (1) Eligibility for NOACs; (2) Practical start-up and follow-up scheme for patients on NOACs; (3) Ensuring adherence to prescribed oral anticoagulant intake; (4) Switching between anticoagulant regimens; (5) Pharmacokinetics and drug-drug interactions of NOACs; (6) NOACs in patients with chronic kidney or advanced liver disease; (7) How to measure the anticoagulant effect of NOACs; (8) NOAC plasma level measurement: rare indications, precautions, and potential pitfalls; (9) How to deal with dosing errors; (10) What to do if there is a (suspected) overdose without bleeding, or a clotting test is indicating a potential risk of bleeding; (11) Management of bleeding under NOAC therapy; (12) Patients undergoing a planned invasive procedure, surgery or ablation; (13) Patients requiring an urgent surgical intervention; (14) Patients with AF and coronary artery disease; (15) Avoiding confusion with NOAC dosing across indications; (16) Cardioversion in a NOAC-treated patient; (17) AF patients presenting with acute stroke while on NOACs; (18) NOACs in special situations; (19) Anticoagulation in AF patients with a malignancy; and (20) Optimizing dose adjustments of VKA. Additional information and downloads of the text and anticoagulation cards in different languages can be found on an EHRA website (www.NOACforAF.eu).

Short-Term Adjuvant Atorvastatin Improves Frequency Domain Indices of Heart Rate Variability in Stable Systolic Heart Failure

The autonomic nervous system marks beneficial drug responses in systolic heart failure management. The impact of statin therapy in this broad disease class is unclear and patient studies are extremely limited.Methods: We studied a group of 23 patients with stable systolic ventricular impairment and randomised them single (patient) blind to high dose Atorvastatin 40 mg daily or placebo in addition to standard therapies over a 12-week treatment interval. Impact on the autonomic nervous system was assessed by anonymised short-term (20 min) standardised supine heart rate variability analyses.Results: Two subjects withdrew one due to decompensation and one due to gastric intolerance. The remaining subjects completed both monitoring events without changes in standard medicines. Frequency domain but not time domain HRV indices improved with active statin therapy suggesting beneficial effects in attenuating sympathetic tone.Conclusions: In this small study we saw short-term high potency statin treatment had a beneficial impact on frequency domain HRV measures suggestive of an impact on sympatho-activation. We found no effect on time domain HRV indices. This may suggest a lesser or no effect on parasympathetic tone.

Elevated platelet microparticles in stable coronary artery disease are unrelated to disease severity or to indices of inflammation.

Platelet microparticles (PMPs), procoagulant membrane vesicles derived from activated platelets, are elevated in acute myocardial infarction and unstable angina but their relationship to inflammation and indices of coronary artery disease are unclear. We therefore hypothesised that PMPs are related to scores of coronary atheroma and/or coronary stenosis. Our study was completed by comparing PMP data with other platelet markers and with hs-CRP, marking inflammation. We recruited 54 patients attending for coronary angiography, comparing them to 35 age- and sex-matched controls. Peripheral blood was analysed for PMPs, percent platelets positive for CD62P and CD63 (all flow cytometry), soluble P selectin and hsCRP (both immunoassay). Patients exhibited higher PMPs, increased platelet %CD62P, %CD63 and soluble P selectin (all P < 0.01) and hs-CRP (P = 0.0167) than healthy controls. However, analysing only patients with an unequivocal classification, there were no significant (P ≤ 0.01) correlations with coronary atheroma or coronary stenosis. These findings provide no support for the hypothesis that PMPs are related to the degree of coronary artery disease and therefore may simply be a marker of widespread inappropriate platelet activity.

Nonadherence with angiotensin-converting enzyme inhibitor therapy: A comparison of different ways of measuring it in patients with chronic heart failure

OBJECTIVES This study was designed to compare different proposed methods of assessing adherence with angiotensin-converting enzyme (ACE) inhibitor (ACEI) therapy in chronic heart failure. BACKGROUND The use of ACEIs in chronic heart failure gives us a unique opportunity to assess a patients adherence by measuring whether the expected biochemical effect of an ACEI is present in the patients bloodstream. In fact, there are several different ways of assessing ACE in vivo: these are serum ACE activity itself, plasma N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP), urine AcSDKP, plasma angiotensin I (AI), plasma angiotensin II (AII), or the AII/AI ratio. METHODS Patients with chronic heart failure (n = 39) were randomized to regimens of ACEI nonadherence for one week, ACEI adherence for one week or two versions of partial adherence for one week, after which the above six tests were performed. RESULTS All six tests significantly distinguished between full nonadherence for one week and full or partial adherence. Only plasma AcSDKP produced a significantly different result between partial adherence and either full adherence or full nonadherence for one week. In terms of their ability to distinguish full nonadherence from full adherence, plasma AcSDKP was 89% sensitive and 100% specific with an area under its ROC of 0.95. Corresponding figures for urine AcSDKP were 92%, 97% and 0.95 and for serum ACE they were 86%, 95% and 0.90. CONCLUSIONS All six tests distinguished full nonadherence from all other forms of adherence. The rank order of performance was plasma AcSDKP, urine AcSDKP, serum ACE, AII/AI ratio and plasma AII followed by plasma AI.

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 patients 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.

Serum adiponectin in coronary heart disease: ethnic differences and relation to coronary artery disease severity

Adiponectin is a collagen-like protein secreted predominantly by adipose tissue. In humans, plasma adiponectin concentrations are inversely related to measures of insulin resistance, with reduced adiponectin concentrations reported in obesity and patients with essential hypertension, dyslipidaemia, diabetes, and coronary artery disease (CAD).1 Low serum adiponectin concentrations appear to be associated with an increased risk of myocardial infarction,2 but it is not clear if this increased risk is related to increased coronary disease burden. People of South Asian descent have increased susceptibility to glucose intolerance, dyslipidaemia, and CAD, the cause(s) of which are complex and multiple.3 One small study suggested lower adiponectin concentrations in South Asians compared to body mass index (BMI) matched white people,4 but ethnic differences in plasma adiponectin among patients with CAD have not been reported. We hypothesised that serum adiponectin is lower in CAD patients of South Asian descent compared to white counterparts, and secondly, that there was a relation between serum adiponectin and coronary disease severity by angiography. To test these hypotheses, we performed a cross sectional study of consecutive white and South Asian patients undergoing cardiac catheterisation. Consecutive patients attending outpatient diagnostic cardiac catheterisation for the investigation of CAD were recruited. The South Asian patients attending our unit are almost exclusively of Punjabi origin, and their ethnic group was confirmed by direct …

Ambulatory blood pressure monitoring in heart failure: a systematic review

Ambulatory blood pressure monitoring has established its use in the definition of white coat hypertension and monitoring of treatment of essential hypertension. Any role for ambulatory blood pressure monitoring in heart failure is not well defined. However, from the limited studies available, ambulatory blood pressure monitoring may be used to optimise heart failure therapy, and as a prognosis marker in this patient group.