(Hypertension. 2001;37:856.)
© 2001 American Heart Association, Inc.
Scientific Contributions |
Adverse Cardiac Effects of Salt With Fludrocortisone in Hypertension
From the Hypertension Research Center, Cardiovascular Research Group, Department of Clinical Pharmacology and Therapeutics (C.A.J.F., A.D.S.), and Department of Endocrinology and Diabetes (R.T.J.), Ninewells Hospital and Medical School, University of Dundee (UK).
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Abstract |
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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.
Key Words: sodium • fludrocortisone • hypertension • QT dispersion • diastole
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Introduction |
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The etiologic importance of sodium chloride (salt) in the genesis or maintenance of hypertension remains controversial. Salt is, however, an independent predictor of left ventricular hypertrophy (LVH),1 which raises the intriguing possibility that salt can damage target organs independently of its effects on blood pressure (BP). In general, confusion about the role of salt may well have arisen for 2 reasons. First, only certain subpopulations of hypertensive patients may be harmed by excess salt. Second, to this point most studies have examined whether salt alters BP per se rather than whether salt adversely affects the target organs independently of any effect on BP. In the present study we examined the effect of salt on QT dispersion and on left ventricular (LV) diastolic function in patients with relative aldosterone excess. QT dispersion is thought to be an index that represents the degree of inhomogeneity of cardiac electric repolarization. QT dispersion >80 ms has been reported to be a potent prognostic marker of sudden cardiac death in hypertension.2 The diagnostic test of salt loading with the addition of low-dose fludrocortisone is used in hypertensive subjects who have a raised aldosterone/renin ratio (ARR) to look for evidence of autonomous aldosterone production, as occurs in primary aldosteronism. Patients undergoing this routine procedure provided us with a susceptible group in whom to test our hypothesis that salt could worsen QT dispersion and LV diastolic relaxation. Patients with raised ARR have inappropriate aldosterone activity,3 and animal studies4 suggest an important interaction between excess salt and excess aldosterone in producing target-organ damage in the heart.
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Methods |
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Subject Selection
All hypertensive patients referred to our center had blood samples taken for plasma renin activity (PRA, ng/mL per hour) and aldosterone (pmol/L) after the patients had been sitting for 10 minutes. The ARR was used to identify potential patients with primary aldosteronism.5 Those patients with an elevated ratio (
750) were hospitalized as part of a
routine clinical workup over a 4-day period for the salt loading and
fludrocortisone suppression test, the protocol of which has previously
been described.5 Briefly,
this involved 28.8 g (480 mmol) of sodium chloride and 1.5 mg
of fludrocortisone in divided doses over the period of hospitalization.
All subjects were also given 2 tablets of Slow-K (600 mg/8.06 mmol
of potassium chloride each) daily to maintain normokalemia. Plasma and
not urinary sodium, together with other electrolytes, was measured at
baseline and at the end of the study period. Patients were on ad
libitum dietary sodium intake, averaging 3.5 g/d throughout the study
while in the hospital. Body weight, supine BP measured with an
automatic sphygmomanometer (NPB 4000, Nellcor Puritan Bennett),
and ECG with simultaneous 12-lead acquisition at a paper
speed of 25 mm/s (Hewlett Packard 4700A electrograph) were
recorded before and after treatment, as was an
echocardiographic examination performed to assess LV
structure and systolic and diastolic function.
Nonsuppression of plasma aldosterone (ie, 140 pmol/L at
1200 hours, upright and ambulant and/or at 0800 hours, supine) at the
end of the test period was deemed diagnostic for primary
aldosteronism.6 The salt
loading and fludrocortisone suppression test, ECG recording,
and echocardiographic examination formed part of our
routine hypertension assessment in our center. Therefore, formal
ethical approval for this observational study was not required from the
Tayside Medical Ethics Committee other than informed consent, which was
obtained from each study subject.
QT Dispersion Measurement
A single observer (C.A.J.F.), blinded to the order of
ECG recording and other measurements, analyzed all the
ECGs. The methodology used in measuring the QT intervals (QT dispersion
[QT and QTc dispersion] and QTcmax), which has
an intraobserver coefficient of variation of <10%, has been described
elsewhere.7
Echocardiographic
Examination
All echocardiographic examinations
were conducted by a single operator (P.S.) using a Hewlett Packard
Sonos 2500. All echocardiographic
parameters were measured in triplicate and averaged over 3
cardiac cycles. The following indexes of LV dimensions were
recorded/derived from M-mode measurements obtained at the level of
the papillary muscles in the short-axis view: LV internal diameter in
diastole (LVIDD), LV internal diameter in systole (LVIDS),
fractional shortening (FS), and LV mass index
(LVMI).8 LVH was considered
present if LVMI was 134 g/m2 in men
and 110 g/m2 in women. Left atrial (LA)
size was measured by planimetry from the apical 4-chamber view. To
assess diastolic function, transmitral Doppler indexes
(peak velocities of the early [E] and late [A] waves and E/A ratio)
and isovolumic relaxation time (IVRT) were obtained as previously
described.9 The color M-mode
flow propagation velocity (CMMFPV) was measured according to the method
described by Brun and
colleagues.10
Laboratory Testing
The radioimmunoassay techniques used to measure PRA
and plasma aldosterone have been described
elsewhere.3 11
Statistical Analysis
Descriptive statistics were expressed as mean (SD).
Pretreatment and posttreatment changes in the QT indexes (QT
dispersion, QTc dispersion, and QTcmax) were
analyzed with paired t
tests. Linear regressional analyzes were used to assess
relationships between baseline QT indexes with correlated factors such
as BP and plasma electrolytes and neurohormones. The effects of age and
gender on QT indexes were also assessed, although these factors have
not been shown in previous studies to affect QT indexes. Model and
distributional assumptions inherent in the regressional
analyzes were assessed. The Pearson correlation coefficients
between baseline and changes in QT indexes, baseline and changes in
plasma aldosterone (supine and ambulant), electrolytes, and
echocardiographic indexes were calculated. All
statistical tests were 2-tailed, and probability values 
0.05 were
considered significant. The statistical software package MINITAB 13.1
was used for these
analyses.
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Results |
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For a period of 21 months from May 1995, a total of 465 hypertensive subjects had ARR measured. Seventy-seven subjects (16.6%) had an elevated ratio of
750, as previously
reported.5 Of these, 29
subjects (14 men) aged 56 (SD 11) years consented to participate in
this study when they were hospitalized for the salt loading and
fludrocortisone suppression test. The ECG recordings were of
good quality, and therefore the mean number of leads measurable was
11.6 (SD 0.6). There were no significant changes in body weight, supine
pulse rate, or BP with salt and fludrocortisone
(Table 1). Twenty-four of 29 study subjects (82.8%) failed
to suppress their plasma aldosterone <140 pmol/L with salt
and fludrocortisone. None of these subjects had an adrenal adenoma or
glucocorticoid suppressible hyperaldosteronism.
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QT Dispersion
At baseline only 1 subject had a QT dispersion >80 ms,
but after administration of salt and fludrocortisone 12 subjects
(41.4%) crossed this threshold for high risk of sudden cardiac death
(Figure).
However, when the 5 subjects with suppressible aldosterone
were excluded, this value rose to 50%. The QT indexes in the 5
subjects with suppressible aldosterone were also increased,
achieving statistical significance for QTc dispersion
(Table 2).
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There were no significant relationships between baseline QT and QTc dispersion and age or gender. The QTcmax was, however, significantly higher in female subjects (448.7 [SD 27.0] versus 425.8 [SD 25.0] ms; P=0.025) at baseline, but the changes in QTcmax with salt and fludrocortisone were not different between genders. There were significant correlations between QT indexes with both systolic BP (QT dispersion, r=0.36, P=0.062; QTc dispersion, r=0.384, P=0.044) and ambulant plasma aldosterone (QT dispersion, r=0.602, P=0.001; QTc dispersion, r=0.515, P=0.007). Ambulant plasma aldosterone accounted for 36.3% of the variance of baseline QT dispersion (37.6+0.0334 aldosterone; P=0.001, r2=36.3%). As for QTc dispersion, the effect of systolic BP remained significant when added into a linear multiple regressional model with ambulant aldosterone (-14.2+0.0392 aldosterone, +0.358 systolic BP; P=0.003, r2=39.4%).
Plasma Electrolytes
After administration of salt and fludrocortisone,
the plasma sodium concentration increased slightly but significantly,
and the plasma potassium concentration dropped slightly despite oral
supplementation
(Table 1). However, the baseline values of these
electrolytes did not correlate with the QT indexes, and there were no
significant relationships between the changes in these electrolytes and
those of the QT indexes. Plasma urea and creatinine were
both reduced with salt and fludrocortisone, but the pretreatment and
posttreatment ratios of urea to creatinine were not
significantly different
(P=0.626)
(Table 1).
Echocardiography
Fifteen (9 men, aged 57 [SD 11] years) of the
29 subjects had complete research-quality echocardiograms both before
and after treatment. The QT indexes in this subgroup were similarly
increased with salt and fludrocortisone (QT dispersion, +22.2 [SD
18.4] ms [95% CI, 12.0 to 32.4;
P<0.001]; QTc dispersion,
+22.8 [SD 24.9] ms [95% CI, 9.0 to 36.5;
P=0.003]). At baseline, the QT
indexes did not relate significantly to LV structures (LVMI, LVIDD,
LVIDS, LA) or measures of LV systolic (FS) or
diastolic function, except that QT dispersion was
correlated with the maximum early diastolic filling
velocity (Emax)
(r=-0.533,
P=0.041). The mean LVMI at
entry was 148.8 (SD 33.4) g/m2, and 73.3%
of subjects had echocardiographic LVH. The FS, LA size,
LVIDS, and LVIDD were all within normal limits at baseline
(Table 3). These indexes were unchanged after administration
of salt and fludrocortisone in contrast to salt loading with
intravenous sodium chloride
infusion.12 Weight, pulse
rate, and BP were not changed in this subgroup of subjects. However,
most of the LV diastolic filling indexes were significantly
impaired by salt and fludrocortisone
(Table 3), indicating worsening LV
diastolic function. Thus, worsening LV
diastolic function occurred at the same time as increasing
QT dispersion.
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Discussion |
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Our cohort of hypertensive subjects with raised ARR had raised QT dispersion at baseline (55 [SD 17.8] ms). This is consistent with other studies of hypertensive patients, which found the following mean QT indexes: QT dispersion, 50 to 64 ms; QTc dispersion, 67 ms; and QTcmax, 435 to 464 ms.13 Population studies of healthy subjects suggest that a "normal" QT dispersion should be <50 ms, independent of age or gender.13 In approximately a third of our participants, QT dispersion was >80 ms after administration of salt and fludrocortisone, an at-risk level for sudden cardiac death. We have previously reported that approximately 15% of the hypertensive population in our clinic5 have a raised ARR. In theory, this subpopulation of hypertensive subjects may be more at risk if exposed to excess salt, although evidence to this effect is lacking at present. We have not studied subjects without a raised ARR, but, interestingly, the small subset of subjects who suppressed their aldosterone also had increased QT dispersion (QT and QTc dispersion) with salt and fludrocortisone, albeit to a lesser degree. It is therefore possible that QT dispersion changes are not confined to this subgroup of hypertensive subjects, but this should be studied separately in the future.
Our data show that both systolic BP and ambulant plasma aldosterone were independent predictors of QTc dispersion, as has been shown before. LVH7 14 and systolic BP7 15 at baseline have also been reported to correlate positively with QT dispersion, but our study did not find these relationships. One possible reason is that our study subjects were highly selected, and there might not have been enough variation within this subgroup to uncover these relationships. For example, only approximately a quarter of our subjects had normal LV mass.
The key findings in our study were that salt with fludrocortisone increased both QT dispersion and LV diastolic dysfunction. Several possible mediators of this effect can be excluded. Since the study was of short duration, the mechanism for the increased QT dispersion and the diastolic dysfunction is unlikely to be due to increased cardiac fibrosis or LVH. Additionally, since both supine and ambulant plasma aldosterone levels dropped significantly in response to salt and fludrocortisone, it is unlikely that aldosterone directly caused these effects on its own. Our echocardiographic data excluded any significant changes in LV systolic function or LV dimensions; therefore, increased chamber sizes do not explain our findings, nor do the changes in LV systolic function.16 The most likely mediator of salt/fludrocortisone-induced changes in QT dispersion is salt-induced changes in LV stiffness and diastolic dysfunction (the role of fludrocortisone will be discussed below).
There is a wealth of previous work that would explain why salt should lead to myocardial stiffness, which would lead in turn to increased QT dispersion. The hypothesis of Blaustein et al17 states that high extracellular sodium ionic concentration translates into increased intracellular ionic calcium concentration. The plasma sodium concentration rose by a small but significant amount in our study subjects after administration of salt with fludrocortisone, in keeping with this hypothesis. These cytosolic calcium ions increase muscular contractility but impair relaxation.17 This chain of events could lead to a state of increased systemic vascular resistance when the vascular smooth muscle cells are involved and to impaired LV diastolic function when the cardiac myocytes are affected. This might explain our echocardiographic findings. Since salt with fludrocortisone impaired diastolic LV function without altering diastolic BP in this study, this suggests that the myocardium may be even more sensitive to salt-induced stiffness than the peripheral vasculature. Furthermore, it is not surprising that QT dispersion as a measure of LV electric repolarization should reflect LV diastolic relaxation, consistent with the well-known electromechanical feedback phenomenon. The probable link between salt and LV diastolic function that we have found may potentially explain why LV diastolic dysfunction occurs in hypertensives without frank LVH and even in subjects with borderline (or white coat) hypertension.18 Indeed, Schlaich and colleagues19 recently reported that high sodium intake in young hypertensives in comparison to normotensives is associated with less plasma aldosterone suppression and with a deterioration of LV diastolic function, which is consistent with one of our major findings.
Our study had no placebo control, but QT interval measurements were measured blindly, and these have been shown to have good long-term reproducibility, even between observers.20 QT dispersion as a derived index has been used successfully in long-term trials to assess drug effects in hypertensive subjects. As in our present study, a single observer analyzed all the ECGs in these trials.14 15 20 21 Additionally, the QT dispersion was increased in our study rather than reduced in response to an intervention, making "regression to the mean" an unlikely explanation for our findings.14 15 The consistency between increasing QT dispersion and worsening echocardiographic-derived LV diastolic indexes was further evidence for the validity of our data, especially since both measurements were made by different "blinded" individuals. The CMMFPV in particular has been invasively validated,10 and it is one of the most reliable noninvasive diastolic indexes and thought to be unaffected by preload,22 which might be increased with salt and fludrocortisone. In addition, the echocardiographic E/A ratio was significantly reduced and IVRT was prolonged, suggesting worsening LV diastolic function. These changes were the opposite of those that would be expected by increasing preload. However, interpretation of these latter echocardiographic indexes could be confounded by "pseudonormalization," although the CMMFPV data made this unlikely to be an issue in the present study.
The fludrocortisone used in this study had an impact on our findings. The dose used (0.5 mg/d) has a mineralocorticoid effect equipotent with aldosterone.23 However, fludrocortisone has sympatholytic activity,24 and this would tend to reduce QT dispersion15 and improve LV diastolic function.25 Thus, if fludrocortisone had any direct influence on our results, these would be expected to be the opposite of those observed. Instead, the use of fludrocortisone allowed us to demonstrate the adverse effects of salt in a shorter time frame (and with a lesser amount) than otherwise would be needed because fludrocortisone amplified salt retention via its mineralocorticoid activity. In any case, the majority of study subjects had nonsuppressible aldosterone, and the effect of this native mineralocorticoid was likely to have persisted throughout the study.
One possible confounder was the reduction in plasma potassium observed after administration of salt and fludrocortisone. In heart failure, QTc dispersion is nonsignificantly reduced with potassium infusion (P=0.08),26 but a reverse relationship has not been demonstrated. However, if we assume that such a relationship existed and that it was applicable to hypertensive subjects, each mean 0.1-mmol/L fall in plasma potassium might be associated with a 6.7-ms mean increase in QTc dispersion. The change in plasma potassium observed in our study might therefore account for an increase in QTc dispersion of 13.3 ms (a mean plasma potassium reduction of 0.2 mmol/L after salt/fludrocortisone). The observed rise in QTc dispersion was much greater, being nearly 20 ms after treatment. Thus, even if there was a causal relationship between plasma potassium and QTc dispersion, it would not appear to fully explain our results. There are 3 additional reasons for this contention. First, we failed to find any correlation between plasma potassium and QT dispersion. Second, QTcmax26 would be expected to be more sensitive to changes in plasma potassium, but in our study this was not significantly altered with salt and fludrocortisone. Third, changes in plasma potassium should not cause the LV stiffness/diastolic dysfunction that we saw on echocardiographic examination. Nonetheless, the role of potassium on QT dispersion during salt loading in hypertensive subjects deserves to be explored further, since some degree of potassium loss occurs whenever salt intake is increased.
Conclusions
Salt with fludrocortisone increased QT dispersion and
impaired LV diastolic relaxation in hypertensive patients
with high ARR. Therefore, in this subpopulation of hypertensive
patients, salt could cause important cardiac target-organ damage. These
findings provide a potentially novel mechanism whereby an increase in
salt intake might amplify the risk of sudden cardiac death in high-risk
hypertensive subjects. Our data should, however, be treated as pilot
and cannot be extrapolated to the wider hypertensive population.
Nevertheless, the role of salt in QT dispersion and LV
diastolic function merits further
study.
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Acknowledgments |
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We thank Margaret Coull for secretarial assistance and Dr Peter T. Donnan for providing statistical advice.
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Footnotes |
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Reprint requests to Dr Pitt O. Lim, Hypertension Research Center, Department of Clinical Pharmacology and Therapeutics, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK.
Received July 18, 2000; first decision August 1, 2000; accepted September 8, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Messerli FH, Schmieder RE, Weir MR. Salt: a perpetrator of hypertensive target organ disease? Arch Intern Med. 1997;157:2449–2452.
2. Galinier M, Balanescu S, Fourcade J, Dorobantu M, Boveda S, Massabuau P, Cabrol P, Dongay B, Fauvel JM, Bounhoure JP. Prognostic value of ventricular arrhythmias in systemic hypertension. J Hypertens. 1997;15:1779–1783.[Medline] [Order article via Infotrieve]
3. Lim PO, Jung RT, MacDonald TM. Raised aldosterone to renin ratio predicts anti-hypertensive efficacy of spironolactone: a prospective cohort follow-up study. Br J Clin Pharmacol. 1999;48:756–760.[Medline] [Order article via Infotrieve]
4. Ramirez-Gil JF, Delcayre C, Robert V, Wassef M, Trouve P, Mougenot N, Charlemagne D, Lechat P. In vivo left ventricular function and collagen expression in aldosterone/salt-induced hypertension. J Cardiovasc Pharmacol. 1998;32:927–934.[Medline] [Order article via Infotrieve]
5. Lim PO, Dow E, Brennan G, Jung RT, MacDonald TM. High prevalence of primary aldosteronism in the Tayside hypertensive clinic population. J Hum Hypertens. 2000;14:311–315.[Medline] [Order article via Infotrieve]
6. Gordon RD. Mineralocorticoid hypertension. Lancet. 1994;344:240–243.[Medline] [Order article via Infotrieve]
7. Clarkson PBM, Naas AAO, McMahon A, MacLeod C, Struthers AD, MacDonald TM. QT dispersion in essential hypertension. Q J Med. 1995;88:327–332.
8. Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol. 1986;57:450–458.[Medline] [Order article via Infotrieve]
9.
Clarkson PB,
Wheeldon NM, Macleod C, Coutie W, MacDonald TM. Acute effects of atrial
natriuretic peptide on left ventricular
diastolic function: a pulsed wave Doppler study in man.
Eur Heart J. 1995;16:1710–1715.
10. Brun P, Tribouilloy C, Duval AM, Iserin L, Meguira A, Pelle G, Dubois-Rande JL. Left ventricular flow propagation during early filling is related to wall relaxation: a color M-mode Doppler analysis. J Am Coll Cardiol. 1992;20:420–432.[Abstract]
11. Lim PO, Brennan GM, Jung RT, MacDonald TM. Diagnosing primary aldosteronism with frusemide stimulation test in hypertensive patients with raised aldosterone to renin ratio. Med Biochem. 1999;1:225–231.
12.
Clarkson
PB, Wheeldon NM, Lim PO, Pringle SD, MacDonald TM. Left atrial size and
function: assessment using echocardiographic automatic
boundary detection. Br Heart
J. 1995;74:664–670.
13.
Sahu P, Lim
PO, Rana BS, Struthers AD. QT dispersion in medicine:
electrophysiological Holy Grail or fool’s
gold? Q J Med. 2000;93:425–431.
14.
Mayet J,
Shahi M, McGrath K, Poulter NR, Sever PS, Foale RA, Thom SA. Left
ventricular hypertrophy and QT dispersion in
hypertension. Hypertension. 1996;28:791–796.
15.
Lim PO, Nys
M, Naas AA, Struthers AD, Osbakken M, MacDonald TM. Irbesartan reduces
QT dispersion in hypertensive individuals.
Hypertension. 1999;33:713–718.
16.
Naas AA,
Davidson NC, Thompson C, Cummings F, Ogston SA, Jung RT, Newton RW,
Struthers AD. QT and QTc dispersion are accurate predictors of cardiac
death in newly diagnosed non-insulin dependent diabetes: cohort study.
BMJ. 1998;316:745–746.
17. Blaustein MP, Hamlyn JM. Sodium transport inhibition, cell calcium, and hypertension: the natriuretic hormone/Na+-Ca2+ exchange/hypertension hypothesis. Am J Med. 1984;77:45–59.[Medline] [Order article via Infotrieve]
18. Glen SK, Elliott HL, Curzio JL, Lees KR, Reid JL. White-coat hypertension as a cause of cardiovascular dysfunction. Lancet. 1996;348:654–657.[Medline] [Order article via Infotrieve]
19. Schlaich MP, Klingbeil A, Hilgers K, Schobel HP, Schmieder RE. Relation between the renin-angiotensin-aldosterone system and left ventricular structure and function in young normotensive and mildly hypertensive subjects. Am Heart J. 1999;138:810–817.[Medline] [Order article via Infotrieve]
20. Kautzner J, Yi G, Camm AJ, Malik M, Short- and long-term reproducibility of QT, QTc, and QT dispersion measurement in healthy subjects. Pacing Clin Electrophysiol. 1994;17:928–937.[Medline] [Order article via Infotrieve]
21. Gonzalez-Juanatey JR, Garcia-Acuna JM, Pose A, Varela A, Calvo C, Cabezas-Cerrato J, de la Pena MG. Reduction of QT and QTc dispersion during long-term treatment of systemic hypertension with enalapril. Am J Cardiol. 1998;81:170–174.[Medline] [Order article via Infotrieve]
22. Garcia MJ, Palac RT, Malenka DJ, Terrell P, Plehn JF. Color M-mode Doppler flow propagation velocity is a relatively preload-independent index of left ventricular filling. J Am Soc Echocardiogr. 1999;12:129–137.[Medline] [Order article via Infotrieve]
23. Whitworth JA, Butkus A, Coghlan JP, Denton DA, Mills EH, Spence CD, Scoggins BA. 9-alpha-Fluorocortisol-induced hypertension: a review. J Hypertens. 1986;4:133–139.[Medline] [Order article via Infotrieve]
24.
Mion D Jr,
Rea RF, Anderson EA, Kahn D, Sinkey CA, Mark AL. Effects of
fludrocortisone on sympathetic nerve activity in humans.
Hypertension. 1994;23:123–130.
25. Clarkson PB, Wheeldon NM, Macleod C, MacDonald TM. Systolic and diastolic effects of beta-adrenergic stimulation in normal humans. Am J Cardiol. 1995;75:206–209.[Medline] [Order article via Infotrieve]
26.
Choy AM,
Lang CC, Chomsky DM, Rayos GH, Wilson JR, Roden DM. Normalization of
acquired QT prolongation in humans by intravenous
potassium. Circulation. 1997;96:2149–2154.
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