Franco Rabbia

Drug Effects on Aldosterone/Plasma Renin Activity Ratio in Primary Aldosteronism

Primary aldosteronism is a specifically treatable and potentially curable form of secondary hypertension. The aldosterone/plasma renin activity ratio (ARR) is routinely used as a screening test. An...

Long-Term Cardio- and Cerebrovascular Events in Patients With Primary Aldosteronism

BACKGROUND Aldosterone plays a detrimental role on the cardiovascular system and PA patients display a higher risk of events compared with EH. OBJECTIVES The objectives of the study were to compare cardio- and cerebrovascular events in patients with primary aldosteronism (PA) and matched essential hypertension (EH). METHODS We retrospectively compared the percentage of patients experiencing events at baseline and during a median follow-up of 12 years in 270 PA patients case-control matched 1:3 with EH patients and in PA subtypes [aldosterone-producing adenoma (n = 57); bilateral adrenal hyperplasia (n = 213)] vs matched EH. RESULTS A significantly higher number of PA patients experienced cardiovascular events over the entire period of the study (22.6% vs 12.7%, P < .001). At the diagnosis of PA, a higher number of patients had experienced total events (14.1% vs 8.4% EH, P = .007); furthermore, during the follow-up period, PA patients had a higher rate of events (8.5% vs 4.3% EH, P = .008). In particular, stroke and arrhythmias were more frequent in PA patients. During the follow-up, a higher percentage of PA patients developed type 2 diabetes. Parameters that were independently associated with the occurrence of all events were age, duration of hypertension, systolic blood pressure, presence of diabetes mellitus, and PA diagnosis. After division into PA subtypes, patients with either aldosterone-producing adenoma or bilateral adrenal hyperplasia displayed a higher rate of events compared with the matched EH patients. CONCLUSIONS This study demonstrates in a large population of patients the pathogenetic role of aldosterone excess in the cardiovascular system and thus the importance of early diagnosis and targeted PA treatment.

Roles of clinical criteria, computed tomography scan, and adrenal vein sampling in differential diagnosis of primary aldosteronism subtypes.

CONTEXT In patients with primary aldosteronism (PA), it is fundamental to distinguish between subtypes that benefit from different therapies. Computed tomography (CT) scans lack sensitivity and specificity and must be followed by adrenal venous sampling (AVS). Because AVS is not widely available, a list of clinical criteria that indicate the presence of an aldosterone-producing adenoma (APA) has been suggested. OBJECTIVE AND DESIGN The objective of the study was to test the sensitivity and specificity of the last generation CT scans, test prospectively the usefulness of clinical criteria in the diagnosis of APA, and develop a flow chart to be used when AVS is not easily available. SETTING Hypertensive patients referred to our hypertension unit were included in our study. PATIENTS Seventy-one patients with confirmed PA participated in our study. INTERVENTION All patients had a CT scan and underwent AVS. MAIN OUTCOME MEASURE Final diagnosis of APA was the main measure. RESULTS A total of 44 and 56% of patients were diagnosed as having an APA and a bilateral adrenal hyperplasia (BAH), respectively. Twenty percent of patients with PA displayed hypokalemia. CT scans displayed a sensitivity of 0.87 and a specificity of 0.71. The posture test displayed a lower sensitivity and specificity (0.64 and 0.70, respectively). The distribution grades of hypertension were not significantly different between APA and BAH. Biochemical criteria of high probability of APA displayed a sensitivity of 0.32 and a specificity of 0.95. CONCLUSIONS This study underlines the central role of AVS in the subtype diagnosis of PA. The use of the clinical criteria to distinguish between APA and BAH did not display a satisfactory diagnostic power.

Heart rate variability in childhood obesity.

Obesity is characterized by hemodynamic and metabolic alterations. Autonomic control on cardiac function involvement is controversial. The aim of the study was to assess early sign of cardiac autonomic dysfunction in obesity, using time- and frequency-domain heart rate variability (HRV) analysis in a pediatric population. Methods: 32 obese children (OB) (17 M, 15 F; 13.9±1.7 y) were compared with 13 healthy lean subjects (7M, 6F; 12.9±1.6y). For each participant, the authors performed a clinical examination, laboratory testing, blood pressure (BP) measurements, and 24-hour electrocardiograph/ambulatory BP monitoring. The spectral power was quantified in total power, low-frequency (HF) power, index of sympathetic tone, high-frequency (HF) power, index of vagal tone, and LF/HF ratio. Low frequency and HF were averaged to obtain 3 measures: 24-hour, daytime, and nighttime levels. Total, long-term, and short-term time-domain HRV values were calculated. Results: The obese children had higher casual and ambulatory BP, and higher fasting glucose, insulin, and triglyceride levels. Overall HRV values were not significantly lower in OB. The obese children had significantly lower 24-hour and nighttime high-frequency normalized units, and time-domain measures of vagal activity. Low-frequency power showed an inverse but not significant pattern. The OB group had significantly greater 24-hour and nighttime LF/HF ratios. Conclusions: The authors found an increase in heart rate and in BP associated with parasympathetic heart rate control decrease in stabilized obese normotensive children.

OBESITY AND AUTONOMIC FUNCTION IN ADOLESCENCE

Hypertension and obesity are risk factors for coronary heart diseases in adults. In turn, childhood overweight and high blood pressure increase the risk of subsequent obesity and hypertension in adulthood. Human obesity is characterized by profound alterations of hemodynamic and metabolic states. Whether these alterations involve sympathetic nervous system control on cardiac function is controversial. We report the results of our study, conducted in a sample of obese adolescents by using power spectral analysis of heart rate variability. An increase in sympathetic tone coupled with a reduction in vagal tone was found. This allowed us to hypothesize that autonomic nervous system changes depend on the time course of obesity development. It is still unclear if treatment of obesity in adolescence prevents subsequent autonomic imbalance and hypertension.

CYP11B2 Gene Polymorphisms in Idiopathic Hyperaldosteronism

Primary aldosteronism is characterized by autonomous production of aldosterone and arterial hypertension, and it occurs in 2 principal forms: aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA). APA can be cured through removal of the adenoma, whereas IHA leads to hypertension that must be treated with medication. The origin of the autonomous aldosterone production in IHA is poorly understood, but genetic factors may contribute to its cause. To test the hypothesis that variants of the aldosterone synthase gene may contribute to susceptibility to IHA, we compared genotypes at 3 polymorphic sites in the CYP11B2 gene in patients with IHA (n=90) with those found in patients with APA (n=38), in patients with essential hypertension (n=72), and in normotensive individuals (n=102). We observed significant linkage disequilibrium among the 3 polymorphisms with 2 frequent haplotypes in all groups studied. One haplotype (C2R) was found to be increased in frequency in the IHA group (47%) compared with the other groups, which had a similar haplotype frequency (36%). The 3 polymorphisms studied have been implicated in either essential hypertension or excess aldosterone production in previous studies. Because of the strong linkage disequilibrium, the observed results could be due to the action of any 1 of the 3 alleles or to another allele in linkage disequilibrium with them. Our results suggest that variations in the CYP11B2 gene may contribute to dysregulation of aldosterone synthesis and lead to susceptibility to IHA.

Protective effect of anti-hypertensive treatment on cognitive function in essential hypertension: analysis of published clinical data.

Hypertension is a risk factor for stroke and may also contribute to the development of vascular cognitive impairment (VCI) and vascular dementia (VaD). Cognitive complications of hypertension and the influence of anti-hypertensive treatment were underestimated until recently. In this paper, trials investigating the effect of anti-hypertensive treatment on cognitive function were evaluated. Analysis of these studies revealed that until approximately 1990-1995 investigations have assessed primarily if anti-hypertensive treatment impaired cognitive function. Only more recent studies have investigated positive effects on cognition of anti-hypertensive medication. Drugs more extensively evaluated were diuretics, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, sartanes and Ca(2+) channel blockers. Available studies have confirmed that elevated diastolic blood pressure or pulse pressure and isolated systolic hypertension play an important role in the development of cognitive impairment. Randomized placebo-controlled trials have provided evidence that reduction of hypertension safely and effectively decreases morbidity and mortality rates and cognitive complications of hypertension. Ca(2+) channel blockers and ACE inhibitors have been shown to be effective and probably better than diuretics and beta-blockers on cognitive domains of hypertension. More extensive investigations could contribute to establishing optimal choice and drug dosage for the treatment of cognitive complications of hypertension.

Prevalence and Characteristics of Familial Hyperaldosteronism: The PATOGEN Study (Primary Aldosteronism in TOrino-GENetic forms)

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension, and patients display an increased prevalence of cardiovascular events compared with essential hypertensives. To date, 3 familial forms of PA have been described and termed familial hyperaldosteronism types I, II, and III (FH-I to -III). The aim of this study was to investigate the prevalence and clinical characteristics of the 3 forms of FH in a large population of PA patients. Three-hundred consecutive PA patients diagnosed in our unit were tested by long-PCR of the CYP11B1/CYP11B2 hybrid gene that causes FH-I, and all of the available relatives of PA patients were screened to confirm or exclude PA and, thus, FH-II. Urinary 18-hydroxycortisol and 18-oxocortisol were measured in all of the familial PA patients. Two patients were diagnosed with FH-I (prevalence: 0.66%), as well as 21 of their relatives, and clinical phenotypes of the 2 affected families varied markedly. After exclusion of families who refused testing and those who were not informative, 199 families were investigated, of which 12 were diagnosed with FH-II (6%) and an additional 15 individuals had confirmed PA; clinical and biochemical phenotypes of FH-II families were not significantly different from sporadic PA patients. None of the families displayed a phenotype compatible with FH-III diagnosis. Our study demonstrates that familial forms of hyperaldosteronism are more frequent than previously expected and reinforces the recommendation of the Endocrine Society Guidelines to screen all first-degree hypertensive relatives of PA patients.

Antihypertensive drugs and the sympathetic nervous system.

Hypertension has been associated with several modifications in the function and regulation of the sympathetic nervous system (SNS). Although it is unclear whether this dysfunction is primary or secondary to the development of hypertension, these alterations are considered to play an important role in the evolution, maintenance, and development of hypertension and its target organ damage. Several pharmacological antihypertensive classes are currently available. The main drugs that have been clearly shown to affect SNS function are β-blockers, α-blockers, and centrally acting drugs. On the contrary, the effects of ACE inhibitors (ACE-Is), AT1 receptor blockers (ARBs), calcium channel blockers (CCBs), and diuretics on SNS function remain controversial. These properties are pharmacologically and pathophysiologically relevant and should be considered in the choice of antihypertensive treatments and combination therapies in order to achieve, beyond optimal blood pressure control, a normalization of SNS physiology and the most effective prevention of target organ damage.

18-Hydroxycorticosterone, 18-Hydroxycortisol, and 18-Oxocortisol in the Diagnosis of Primary Aldosteronism and Its Subtypes

CONTEXT Diagnosis of primary aldosteronism (PA) is made by screening, confirmation testing, and subtype diagnosis (computed tomography scan and adrenal vein sampling). However, some tests are costly and unavailable in most hospitals. OBJECTIVE The aim of the study was to evaluate the role of serum 18-hydroxycorticosterone (s18OHB), urinary and serum 18-hydroxycortisol (u- and s18OHF), and urinary and serum 18-oxocortisol (u- and s18oxoF) in the diagnosis of PA and its subtypes, aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia (BAH). PATIENTS The study included 62 patients with low-renin essential hypertension (EH), 81 patients with PA (20 APA, 61 BAH), 24 patients with glucocorticoid-remediable aldosteronism, 16 patients with adrenal incidentaloma, and 30 normotensives. INTERVENTION AND MAIN OUTCOME MEASURES We measured s18OHB, s18OHF, and s18oxoF before and after saline load test (SLT) and 24-h u18OHF and u18oxoF. RESULTS PA patients displayed significantly higher levels of s18OHB, u18OHF, and u18oxoF compared to EH and normal subjects; APA patients displayed s18OHB, u18OHF, and u18oxoF levels significantly higher than BAH patients. Similar results were obtained for s18OHF and s18oxoF. SLT significantly reduced s18OHB, s18OHF, and s18oxoF in all groups, but steroid reduction was much less for APA patients compared to BAH and EH. The s18OHB/aldosterone ratio after SLT more than doubled in EH but remained unchanged in APA patients. CONCLUSIONS u18OHF, u18oxoF, and s18OHB measurements in patients with a positive aldosterone/plasma renin activity ratio correlate with confirmatory tests and adrenal vein sampling in PA patients. If verified, these steroid assays would refine the diagnostic workup for PA.