Primary aldosteronism (PA) causes cardiovascular damage in excess to the blood pressure elevation, but there are no prospective studies proving a worse long-term prognosis in adrenalectomized and ...medically treated patients. We have, therefore, assessed the outcome of PA patients according to treatment mode in the PAPY study (Primary Aldosteronism Prevalence in Hypertension) patients, 88.8% of whom were optimally treated patients with primary (essential) hypertension (PH), and the rest had PA and were assigned to medical therapy (6.4%) or adrenalectomy (4.8%). Total mortality was the primary end point; secondary end points were cardiovascular death, major adverse cardiovascular events, including atrial fibrillation, and total cardiovascular events. Kaplan-Meier and Cox analysis were used to compare survival between PA and its subtypes and PH patients. After a median of 11.8 years, complete follow-up data were obtained in 89% of the 1125 patients in the original cohort. Only a trend (
=0.07) toward a worse death-free survival in PA than in PH patients was observed. However, at both univariate (90.0% versus 97.8%;
=0.002) and multivariate analyses (hazard ratio, 1.82; 95% confidence interval, 1.08-3.08;
=0.025), medically treated PA patients showed a lower atrial fibrillation-free survival than PH patients. By showing that during a long-term follow-up adrenalectomized aldosterone-producing adenoma patients have a similar long-term outcome of optimally treated PH patients, whereas, at variance, medically treated PA patients remain at a higher risk of atrial fibrillation, this large prospective study emphasizes the importance of an early identification of PA patients who need adrenalectomy as a key measure to prevent incident atrial fibrillation.
Background
A silent polymorphism (+1166 A/C single-nucleotide polymorphism) localized in the 3′-UTR (untranslated region) of the human angiotensin II type-1 receptor (AT1R) has been associated with ...hypertension and cardiovascular complications. The +1166 A/C is recognized by a specific microRNA-155 (miR-155), which is basepairing complementary with the +1166 A-allele but not with the mutant +1166 C allele. Aim of our study was to investigate the interplay between miR-155 and AT1R protein expression.
Methods
Sixty-four subjects were selected for the +1166 A/C from the cohort of hypertensives (n = 573) of the Hypertension and Ambulatory Recording Venetia Study (HARVEST): 25 were homozygous for the 1166 A allele, 20 heterozygous, and 19 homozygous for the 1166 C allele.
Results
miR-155 expression was significantly decreased in subjects with CC genotype in comparison to AA and AC genotype. AT1R protein expression was significantly increased in the CC group in comparison to AA and AC (P < 0.01) although AT1R mRNA expression was not significantly different in the three groups. AT1R protein expression was positively correlated with systolic and diastolic blood pressure and negatively correlated with miR-155 expression level. Plasma transforming growth factor-β1 (TGF-β1) may have a modulator role in the interplay between miR-155 and AT1R protein expression as it was correlated negatively with miR-155 expression and positively with AT1R protein expression in subjects with CC genotype.
Conclusion
The interplay between miR-155 expression, +1166C polymorphism,and AT1R protein expression may have a role in the regulation of blood pressure.
Despite the fact that sheep are a widely used animal model in cardiovascular research, reference values for transthoracic echocardiography in normal growing animals are not available. Eight healthy ...female lambs underwent two-dimensional, M-mode and pulsed wave Doppler echocardiographic examination at 100 days of age and every three months thereafter over a 12-month period. The study was conducted under sedation with midazolam, butorphanol and constant rate infusion of intravenous propofol. Their growth phase was completed at about one year of age. All the echocardiographic parameters considered were significantly correlated with body weight and age class except for the left ventricular systolic and diastolic diameters. Functional indices were not correlated to body weight or age except for the E-point to septal separation distance (EPSS). Doppler-derived parameters were not influenced by independent variables. Transthoracic echocardiography can be considered an applicable method for cardiovascular research using a growing lamb animal model after appropriate adjustments for age and body size.
Background The aim of the study was to investigate the effect of polymorphism A1166C for AGTR1 and –1332G/A for AGTR2 on the incidence of sustained hypertension (HT) and metabolic syndrome in a ...cohort of young patients screened for stage 1 HT. Methods We assessed 420 white hypertensive subjects never treated for HT and followed up for 7.3 years in the HT and Ambulatory Recording Venetia Study (HARVEST). Incident physician-diagnosed HT, increase in ambulatory blood pressure (BP), and new onset metabolic syndrome were the outcome measures. Results For AGTR1, 37.2% of the subjects in the group with AA genotype, 47.5% in the group with AC genotype, and 66.7% in the group with CC genotype developed HT during follow-up (P = 0.001). Ambulatory systolic (P = 0.007) and diastolic (P < 0.001) BPs increased largely in the patients with CC genotype than in the rest of the group. New onset metabolic syndrome during follow-up (n = 30, P = 0.008), and the frequency of the metabolic syndrome at the end of follow-up (n = 65, P = 0.002) were also more common among the patients with CC and AC genotype. In a Cox analysis, subjects with CC genotype had an increased risk of developing HT (hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.2–2.0, P = 0.000) and metabolic syndrome (HR 2.8, 1.5–5.2, P = 0.002) than AA subjects. No association was found between the AGTR2 polymorphism and any outcome measure. Conclusions The AGTR1 A1166C polymorphism may be considered a genetic marker predisposing to an increase in BP and the development of the metabolic syndrome in subjects screened for stage 1 HT. American Journal of Hypertension (2009). doi:10.1038/ajh.2008.319
Hypertension causes cognitive impairment, involving mainly executive functions, but the effect of blood pressure (BP) control on the different cognitive domains is still debated. We correlated ...executive function, attention and memory with BP control and cerebrovascular damage in 60 undemented middle-aged hypertensives at baseline and after 6-year follow-up. At first evaluation, the patients with poor BP control had higher score of white matter lesions, reduced cerebrovascular reserve capacity and greater carotid intima-media thickness (IMT) than those with good BP control. Performance on executive tests correlated with IMT and with performance on attention tests, which was impaired by low diastolic BP. At long-term follow-up, performance in attention and executive tests improved in spite of the minor improvement of BP control, increased IMT and worse memory. Low diastolic BP has a negative effect on attention, which affects executive performance at first cross-sectional examination. This confounding effect has to be taken into consideration when planning studies on cognitive function. Longitudinal studies are required to unravel the effect of BP control on cognitive function, as only long-term antihypertensive treatment improves both attention and executive performance.
Background/aims
: While Angiotensin II (Ang II) is a major factor in the development of cardiomyocyte hypertrophy and a pivotal role for Ang II signals via ERK1/2 has been identified, mechanism(s) ...responsible are still unclear. As Bartter’s and Gitelman’s syndrome patients (BS/GS) have increased Ang II, and yet normo/hypotension, hyporesponsiveness to pressors and blunted Ang II signaling via type 1 receptors (AT1R), this study assesses BS/GS’s left ventricular (LV) mass and structure as well as Ang II induced ERK1/2 phosphorylation compared with essential hypertensive patients (EH) and normotensive healthy subjects (C) to gain insight into Ang II mediated processes.
Methods
: Indices of cardiac hypertrophy were determined by M-mode, two-dimensional echo Doppler and ERK phosphorylation by Western blot.
Results
: None of BS/GS exhibited LV remodelling; LV mass, LV end-diastolic volume and mass/volume ratio were unchanged
vs
C (60±14 g/m
2
vs
64±12, 64±12 ml/m
2
vs
60±8 and 0.95±0.2
vs
1.0±0.2, respectively) and reduced
vs
EH (119±15, p<0.001, 78±9, p<0.05 and 1.52±0.15, p<0.01). Despite BS/GS’s higher plasma renin activity and aldosterone and unchanged level of AT1R, Ang II induced ERK1/2 phosphorylation was reduced
vs
both C and EH: 0.64 d.u.±0.08
vs
0.90±0.06 in C, p<0.006, and
vs
1.45±0.07 in EH, p<0.001.
Conclusion
: The data point to a direct cardioremodeling role for Ang II and support a role of Ang II type 2 receptor (AT2R) signaling as involved in the lack of cardiovascular remodeling in BS/GS. However, further studies using more direct approaches to demonstrate the effects of AT2R signaling must be pursued.
Resistant hypertension is common in clinical practice. The aim of our study was to evaluate inappropriate aldosterone activity in causing resistance to antihypertensive therapy.
Among the patients ...consecutively evaluated for the first time between 1995 and 2001, we selected all those (
n = 157) with an aldosterone-to-renin ratio (ARR) ≥25 (ng/dL)/(ng/mL/h), and plasma aldosterone ≥12 ng/dL. Eight patients with Conn adenoma were excluded from the study. Fifty-eight were diagnosed as idiopathic aldosteronism (IHA), the other 91 patients, who did not meet the criteria for primary aldosteronism, were operatively classified as aldosterone-associated hypertension (AAH). As a control group, we randomly chose 160 patients with essential hypertension and plasma aldosterone <12 ng/dL (EH). Antihypertensive treatment was given in accordance to World Health Organization Guidelines (1999). The study end point was blood pressure (BP) <140/90 mm Hg.
During follow-up (22 ± 2 months), 24 (41.4%) patients with IHA, 35 (38.5%) with AAH, and 72 (54.0%) with EH reached the end point. According to survival analysis, AAH and IHA patients reached the end point in a smaller fraction and in a longer time compared with EH patients, with no difference between IHA and AAH. At the end of follow-up, IHA and AAH patients had higher diastolic BP than EH patients with no difference between IHA and AAH.
Patients with elevated aldosterone plasma levels develop resistant hypertension, even in the absence of clinically diagnosed primary aldosteronism. Their identification will allow a targeted therapy and a more effective BP reduction.
When deciding whether to give antihypertensive drugs to reduce the blood pressure after stroke, we should distinguish the early phase (the first 24-48 hours) from the late phase because of the rapid ...changes of cerebral blood flow autoregulation that occur after stroke. In the healthy brain, cerebral blood flow is kept at 50 mL/100 g per minute through a mechanism known as the autoregulation of cerebral perfusion (Fig. 1). This occurs despite wide fluctuations in the perfusion pressure in the range of 70-120 mm Hg. Any increase in pressure automatically results in vasoconstriction and any decrease in vasodilation. These responses lower the risk of cerebral hyper- and hypoperfusion respectively. After an acute ischemic stroke, the autoregulation of cerebral perfusion is lost in the tissues surrounding the ischemic core, the so-called penumbra. This periinfarct zone is a moderately ischemic area affected by varying degrees of injury. The area may be salvaged if blood flow is rapidly restored within hours after the initial injury because, although electrical function has been lost, the ionic pumps have not yet failed. Flow in the range of 10-20 mL/100 g per minute is the border between irreversible and reversible damage. Because of the loss of autoregulation in the penumbra, the extent of cerebral perfusion depends on the perfusion pressure, and a fall in blood pressure during this critical time may reduce cerebral perfusion, extend the ischemic area, induce irreversible damage and worsen the disabling consequences of the initial stroke. Therefore, during the first 24-48 hours a high blood pressure may be desirable to reduce the cerebral damage, until the autoregulation is restored and any further neurologic improvement unlikely. In contrast, in the later phase a smooth rate of blood pressure reduction is recommended, in order to reduce the risk of cerebral edema, hemorrhagic transformation, stroke recurrence and cardiovascular complications. In patients who were not receiving antihypertensive treatment before the ischemic stroke and who have a baseline systolic pressure of 180-220 mm Hg and a diastolic pressure below 120 mm Hg, antihypertensive therapy should be deferred for the first 48 hours after the stroke, unless thrombolytic therapy is indicated. In patients who were already receiving oral antihypertensive therapy before the stroke and who have a baseline blood pressure within the above-mentioned range, antihypertensive therapy should be given to avoid rebound hypertension, with the aim of maintaining a systolic pressure of 180-220 mm Hg and a diastolic pressure below 120 mm Hg. If the systolic pressure is higher than 220 mm Hg and the diastolic pressure higher than 120 mm Hg, intravenous antihypertensive drugs are recommended to keep the blood pressure at about 180/100-105 mm Hg. It is important to select rapidly reversible agents in case neurologic signs and symptoms worsen with the blood pressure reduction.
Diabetes confers an increased risk of adverse cardiovascular and renal events. In the EMPA-REG OUTCOME trial, empagliflozin, a sodium-glucose cotransporter 2 inhibitor, reduced the risk of major ...adverse cardiovascular events in patients with type 2 diabetes at high risk for cardiovascular events. We wanted to determine the long-term renal effects of empagliflozin, an analysis that was a prespecified component of the secondary microvascular outcome of that trial.
We randomly assigned patients with type 2 diabetes and an estimated glomerular filtration rate of at least 30 ml per minute per 1.73 m(2) of body-surface area to receive either empagliflozin (at a dose of 10 mg or 25 mg) or placebo once daily. Prespecified renal outcomes included incident or worsening nephropathy (progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal-replacement therapy, or death from renal disease) and incident albuminuria.
Incident or worsening nephropathy occurred in 525 of 4124 patients (12.7%) in the empagliflozin group and in 388 of 2061 (18.8%) in the placebo group (hazard ratio in the empagliflozin group, 0.61; 95% confidence interval, 0.53 to 0.70; P<0.001). Doubling of the serum creatinine level occurred in 70 of 4645 patients (1.5%) in the empagliflozin group and in 60 of 2323 (2.6%) in the placebo group, a significant relative risk reduction of 44%. Renal-replacement therapy was initiated in 13 of 4687 patients (0.3%) in the empagliflozin group and in 14 of 2333 patients (0.6%) in the placebo group, representing a 55% lower relative risk in the empagliflozin group. There was no significant between-group difference in the rate of incident albuminuria. The adverse-event profile of empagliflozin in patients with impaired kidney function at baseline was similar to that reported in the overall trial population.
In patients with type 2 diabetes at high cardiovascular risk, empagliflozin was associated with slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care. (Funded by the Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance; EMPA-REG OUTCOME ClinicalTrials.gov number, NCT01131676.).
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