Pitt O. Lim

Potentially high prevalence of primary aldosteronism in a primary-care population

or more has a sensitivity of 93% in the prediction of primary aldosteronism, about one in ten hypertensive patients in this population had primary aldosteronism, similar to the proportion found in specialist referral clinics. Early diagnosis and treatment of primary aldosteronism may prevent target-organ damage. The high prevalence of this potentially treatable disorder justifies routine screening at least in patients with poor blood-pressure control or in those taking multiple antihypertensive drugs. In our experience, the specific aldosterone antagonist spironolactone is highly effective in normalising otherwise resistant hypertension in this group of patients. Plasma renin activity and aldosterone measurements may present logistic difficulties in the community, but the benefit to patients and potential savings on drugs makes this goal worthwhile.

A review of the medical treatment of primary aldosteronism.

Purpose Use of the aldosterone-to-renin ratio (ARR) has suggested that at least one in 10 hypertensive subjects have primary aldosteronism (PA). There is thus a timely need to review the literature for effective drug therapies and to speculate on other therapeutic options by taking into account recent advances in understanding of the PA disease pathophysiological process. Data source A MEDLINE and EMBASE search of all articles published from the start of the databases until July 1999 and reviews of the bibliographies of textbooks. Study selection Primary research articles on the medical treatment of PA with emphasis on diagnosis, treatment option, drug dosage, therapeutic response and adverse drug effect. Data extraction Study design and quality were assessed. Relevant data on diagnostic methodology, drug usage and response were analysed and compared. Data synthesis A select number of subjects with aldosterone-producing adenoma (APA) can be expected to respond well to surgical treatment. For the majority of PA cases especially subjects with idiopathic hyperaldosteronism (IHA), long-term medical treatment is now safe and feasible although no randomized controlled trials have been carried out to date. The best therapeutic response is obtained by directly antagonizing aldosterone at the receptor level using medium to low dose spironolactone and this response can be predicted by a raised ARR. The response to other potassium-sparing diuretics and calcium channel blockers are modest. IHA responds better than angiotensin II-unresponsive APA to angiotensin converting enzyme inhibitors and this may also be true with angiotensin II receptor blockers. The discovery of the aldosterone synthase gene opens up the possibility for gene therapy. Conclusion The diagnosis of PA allows appropriate management with resultant blood pressure control in many hypertensive subjects who otherwise have resistant hypertension despite multiple drug therapy.

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

Adverse Cardiovascular Effects of Acute Salt Loading in Young Normotensive Individuals

We sought to explore the effects of salt loading in young normotensives on vascular endothelial function, echocardiographic left ventricular diastolic function, and electrocardiographic QT dispersion. Sixteen healthy normotensive male volunteers were randomized in a double-blind crossover fashion to 5-day treatment periods with either placebo or salt tablets (200 mmol/d of sodium) separated by a 2-week washout period. Throughout the study the volunteers were asked to maintain a low-salt diet. Forearm venous occlusion plethysmography and intraarterial infusions of acetylcholine (ACh), sodium nitroprusside (SNP), and NG-monomethyl-l-arginine (L-NMMA) were used to assess vascular reactivity. Baseline and postsalt loading 12-lead ECGs and echocardiograms were also obtained. Twenty-four-hour ambulatory systolic blood pressure rose (117±11 to 121±8 mm Hg) significantly with salt loading. The endothelium-dependent responses to ACh were significantly blunted with salt compared to placebo (&Dgr;FBF% 403 [50] versus 296 [31]; P<0.05) and L-NMMA (&Dgr;FBF% −47.2 [4] versus −31 [3]; P<0.01). In contrast, the endothelium-independent response to SNP was not different between treatments. Color M-mode flow propagation velocity (CMMFPV), a preload index of left ventricular diastolic function, was significantly reduced with salt (64 [6] versus 59 [16] cm/s; P<0.05) suggesting increased ventricular stiffness. QT dispersion was also significantly increased with salt (58 [16] versus 48 [17] ms; P=0.02). Salt loading impaired vascular endothelial function, left ventricular mechanical relaxation, and electric repolarization in young healthy normotensives.

Intravenous sodium nitrite in acute ST-elevation myocardial infarction: a randomized controlled trial (NIAMI)

Aim Despite prompt revascularization of acute myocardial infarction (AMI), substantial myocardial injury may occur, in part a consequence of ischaemia reperfusion injury (IRI). There has been considerable interest in therapies that may reduce IRI. In experimental models of AMI, sodium nitrite substantially reduces IRI. In this doubleblind randomized placebo controlled parallel-group trial, we investigated the effects of sodium nitrite administered immediately prior to reperfusion in patients with acute ST-elevation myocardial infarction (STEMI). Methods and results A total of 229 patients presenting with acute STEMI were randomized to receive either an i.v. infusion of 70 μmol sodium nitrite (n = 118) or matching placebo (n = 111) over 5 min immediately before primary percutaneous intervention (PPCI). Patients underwent cardiac magnetic resonance imaging (CMR) at 6–8 days and at 6 months and serial blood sampling was performed over 72 h for the measurement of plasma creatine kinase (CK) and Troponin I. Myocardial infarct size (extent of late gadolinium enhancement at 6–8 days by CMR-the primary endpoint) did not differ between nitrite and placebo groups after adjustment for area at risk, diabetes status, and centre (effect size −0.7% 95% CI: −2.2%, +0.7%; P = 0.34). There were no significant differences in any of the secondary endpoints, including plasma troponin I and CK area under the curve, left ventricular volumes (LV), and ejection fraction (EF) measured at 6–8 days and at 6 months and final infarct size (FIS) measured at 6 months. Conclusions Sodium nitrite administered intravenously immediately prior to reperfusion in patients with acute STEMI does not reduce infarct size.

Reduced myocardial velocities of left ventricular long-axis contraction identify both systolic and diastolic heart failure—a comparison with brain natriuretic peptide

Echocardiographic diagnosis of radial fractional shortening or global ejection fraction fails to diagnose all patients with heart failure; about 40%, with apparently normal global systolic function, will have elevated brain natriuretic peptide (BNP) concentrations and “pure” diastolic dysfunction. Screening methods do not include assessment of left ventricular (LV) longitudinal function, however, which is a more sensitive marker of subclinical disease.

High Levels of Costimulatory Receptors OX40 and 4-1BB Characterize CD4+CD28null T Cells in Patients With Acute Coronary Syndrome

Rationale: Patients with acute coronary syndrome (ACS) predisposed to recurrent coronary events have an expansion of a distinctive T-cell subset, the CD4+CD28null T cells. These cells are highly inflammatory and cytotoxic in spite of lacking the costimulatory receptor CD28, which is crucial for optimal T cell function. The mechanisms that govern CD4+CD28null T cell function are unknown. Objective: Our aim was to investigate the expression and role of alternative costimulatory receptors in CD4+CD28null T cells in ACS. Methods and Results: Expression of alternative costimulatory receptors (inducible costimulator, OX40, 4–1BB, cytotoxic T lymphocyte associated antigen-4, programmed death-1) was quantified in CD4+CD28null T cells from circulation of ACS and stable angina patients. Strikingly, in ACS, levels of OX40 and 4-1BB were significantly higher in circulating CD4+CD28null T cells compared to classical CD4+CD28+ T lymphocytes. This was not observed in stable angina patients. Furthermore, CD4+CD28null T cells constituted an important proportion of CD4+ T lymphocytes in human atherosclerotic plaques and exhibited high levels of OX40 and 4-1BB. In addition, the ligands for OX40 and 4-1BB were present in plaques and also expressed on monocytes in circulation. Importantly, blockade of OX40 and 4-1BB reduced the ability of CD4+CD28null T cells to produce interferon-&ggr; and tumor necrosis factor-&agr; and release perforin. Conclusions: Costimulatory pathways are altered in CD4+CD28null T cells in ACS. We show that the inflammatory and cytotoxic function of CD4+CD28null T cells can be inhibited by blocking OX40 and 4-1BB costimulatory receptors. Modulation of costimulatory receptors may allow specific targeting of this cell subset and may improve the survival of ACS patients.

Irbesartan reduces QT dispersion in hypertensive individuals.

Angiotensin type 1 receptor antagonists have direct effects on the autonomic nervous system and myocardium. Because of this, we hypothesized that irbesartan would reduce QT dispersion to a greater degree than amlodipine, a highly selective vasodilator. To test this, we gathered electrocardiographic (ECG) data from a multinational, multicenter, randomized, double-blind parallel group study that compared the antihypertensive efficacy of irbesartan and amlodipine in elderly subjects with mild to moderate hypertension. Subjects were treated for 6 months with either drug. Hydrochlorothiazide and atenolol were added after 12 weeks if blood pressure (BP) remained uncontrolled. ECGs were obtained before randomization and at 6 months. A total of 188 subjects (118 with baseline ECGs) were randomized. We analyzed 104 subjects who had complete ECGs at baseline and after 6 months of treatment. Baseline characteristics between treatments were similar, apart from a slight imbalance in diastolic BP (irbesartan [n=53] versus amlodipine [n=51], 99.2 [SD 3. 6] versus 100.8 [3.8] mm Hg; P=0.03). There were no significant differences in BP normalization (diastolic BP <90 mm Hg) between treatments at 6 months (irbesartan versus amlodipine, 80% versus 88%; P=0.378). We found a significant reduction in QT indexes in the irbesartan group (QTc dispersion mean, -11.4 [34.5] milliseconds, P=0.02; QTc max, -12.8 [35.5] milliseconds, P=0.01), and QTc dispersion did not correlate with the change in BP. The reduction in QT indexes with amlodipine (QTc dispersion, -9.7 [35.4] milliseconds, P=0.06; QTc max, -8.6 [33.2] milliseconds, P=0.07) did not quite reach statistical significance, but there was a correlation between the change in QT indexes and changes in systolic BP. In conclusion, irbesartan improved QT dispersion, and this effect may be important in preventing sudden cardiac death in at-risk hypertensive subjects.

Adverse Cardiac Effects of Salt With Fludrocortisone in Hypertension

The effect of salt on blood pressure (BP) is controversial. A more important question is whether salt can produce cardiac target-organ damage, irrespective of its effect on BP. We assessed the effect of salt with fludrocortisone on QT dispersion and echocardiographic left ventricular diastolic function in a prospective interventional study involving 29 hypertensive subjects with a raised aldosterone/renin ratio who were hospitalized for investigation of possible primary aldosteronism. Each subject over 4 days was given a total of 28.8 g (480 mmol) of sodium chloride and 1.5 mg of fludrocortisone with potassium supplementation. Baseline and posttreatment 12-lead ECGs and echocardiograms were obtained. There were no significant changes in body weight, pulse rate, or BP after treatment with salt and fludrocortisone. Plasma sodium was significantly increased from 141.4 (SD 2.1) to 142.6 (SD 2.4) mmol/L (P =0.001). QT and QTc dispersion both significantly increased: +19.6 (SD 16.5) ms (95% CI, 13.4 to 25.9) (P <0.001) and +19.8 (SD 20.9) ms (95% CI, 11.8 to 27.7) (P <0.001), respectively. There were no significant changes in (n=15) left ventricular dimensions or systolic function, but all diastolic filling indexes, including the preload-independent index, flow propagation velocity (55.49 [SD 10.91] to 48.96 [SD 11.40] cm/s, P =0.018) worsened, suggesting significant deterioration of left ventricular diastolic function with salt and fludrocortisone. In conclusion, a combination of salt with fludrocortisone increased QT dispersion and impaired left ventricular diastolic relaxation in hypertensive patients with high aldosterone/renin ratios. This raises the possibility that salt may have BP-independent adverse cardiac effects in susceptible hypertensive subjects.

Exercise blood pressure and endothelial dysfunction in hypertension

Background:  Hypertensive patients with persistent endothelial dysfunction have adverse cardiovascular prognosis. However, current methods aimed to assess endothelial dysfunction in those patients who possess clinical applicability. We hypothesised that such individuals could potentially be identified by an exaggerated systolic blood pressure (BP) response to a submaximal exercise.