Federico Pieruzzi

BACKGROUND: Chronic activation of the renin-angiotensin system (RAS) plays an important role in the pathogenesis of heart failure. Increasing evidence indicates that other than the circulating RAS, a local RAS exists in several tissues, including the heart. The present study was carried out to quantify cardiac, renal, and pulmonary mRNA levels of renin, angiotensin-converting enzyme (ACE), and types 1 and 2 angiotensin II receptors (AT-1 and AT-2), in rats with different severities of heart failure. METHODS AND RESULTS: Heart failure was induced by the creation of an aortocaval fistula below the renal arteries. Rats with aortocaval fistula either compensate and maintain a normal sodium balance or decompensate and develop severe sodium retention. Six days after placement of the aortocaval fistula, heart weight (normalized to body weight) increased 35% (P < .05) in compensated and 65% in decompensated rats compared with control rats. Plasma renin activity increased 45% (P < .05) in rats in sodium balance and 127% in sodium-retaining rats. Total RNA was extracted from the heart, kidneys, and lungs, followed by reverse transcription-quantitative polymerase chain reaction. Renin mRNA levels in the heart, after 40 cycles, increased 68% (P < .01) and 140% in rats with either compensated or decompensated heart failure, respectively. Renal renin-mRNA levels also increased 130% (P < .05) in decompensated and only 52% (P < .05) in compensated animals. ACE-mRNA increased in a similar pattern in the heart but not in either the kidneys or lungs. Moreover, pulmonary, renal, and cardiac ACE immunoreactivity levels, assessed by Western blot analysis, showed the same trend. AT-1 receptor mRNA levels decreased 54% (P < .05) only in the myocardium of decompensated rats, whereas AT-2 receptor mRNA did not change in any tissue studied. CONCLUSIONS: The development of heart failure is associated with a remarkable increase in the expression of a local RAS in the heart, which may contribute to the pathogenesis of this clinical syndrome.

OBJECTIVES: To study the prevalence of high blood pressure (BP) in an Italian paediatric population, and to verify whether in this population elevated BP values are associated with overweight (OW). STUDY DESIGN: Children (1206 males, 1210 females) from the lower-grade public schools (ages 6-11 years) were studied. Body weight, height and BP were measured in each child. Elevated BP was defined if resting systolic and/or diastolic BP values equalled or exceeded the 95th percentile according to gender, age and height, based on the US normative BP tables. Overweight children were identified using four different methods: (1) the classification based on the relative body weight; (2) the French references by Rolland-Cachera et al. (Am J Clin Nutr 1982; 36:178-184); (3) the International Obesity Task Force charts; and (4) the Italian charts defined by Cacciari et al. (Eur J Clin Nutr 2002; 56:171-180). RESULTS: The prevalence of high BP in our population was 4.2% and was significantly higher in females (65/1210 = 5.4%) than in males (37/1206 = 3.1%), P = 0.005. The different methods used to define OW provide different estimates of OW prevalence (from 17.0 to 38.6%). The percentage of high BP subjects was significantly higher in OW than in normal-weight children regardless of the method used for the definition of the weight class (P < 0.0001), in both genders. In addition, for each age range, absolute systolic and diastolic BP values were higher in OW as compared to normal-weight children both in males and in females (P < 0.0001). CONCLUSIONS: Our study indicates the importance of performing BP screenings in the paediatric population, and to promote interventions that may reduce the prevalence of OW in children.

Fabry disease is an X-linked inherited lysosomal disorder that causes accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and reduced life expectancy. It can affect both males and females and can be classified into classic or later-onset phenotypes. In classic Fabry disease, α-galactosidase A (α-Gal A) activity is absent or severely reduced and disease manifestations have an early onset that can affect multiple organs. In contrast, in later-onset Fabry disease, patients have residual α-Gal A activity and clinical features are primarily confined to the heart. Individualized therapeutic goals in Fabry disease are required due to varying phenotypes and patient characteristics, and the wide spectrum of disease severity. An international group of expert physicians convened to discuss and develop practical clinical recommendations for disease- and organ-specific therapeutic goals in Fabry disease, based on expert consensus and evidence identified through a structured literature review. Biomarkers reflecting involvement of various organs in adult patients with classic Fabry disease are discussed and consensus recommendations for disease- and organ-specific therapeutic goals are provided. These consensus recommendations should support the establishment of individualized approaches to the management of patients with classic Fabry disease by considering identification, diagnosis, and initiation of disease-specific therapies before significant organ involvement, as well as routine monitoring, to reduce morbidity, optimize patient care, and improve patient health-related quality of life.

BACKGROUND: The p.Asn215Ser or p.N215S GLA variant has been associated with late-onset cardiac variant of Fabry disease. METHODS: To expand on the scarce phenotype data, we analyzed natural history data from 125 p.N215S patients (66 females, 59 males) enrolled in the Fabry Registry (NCT00196742) and compared it with data from 401 patients (237 females, 164 males) harboring mutations associated with classic Fabry disease. We evaluated interventricular septum thickness (IVST), left ventricular posterior wall thickness (LVPWT), estimated glomerular filtration rate and severe clinical events. RESULTS: In p.N215S males, mildly abnormal mean IVST and LVPWT values were observed in patients aged 25-34 years, and values gradually increased with advancing age. Mean values were similar to those of classic males. In p.N215S females, these abnormalities occurred primarily in patients aged 55-64 years. Severe clinical events in p.N215S patients were mainly cardiac (males 31%, females 8%) while renal and cerebrovascular events were rare. Renal impairment occurred in 17% of p.N215S males (mostly in patients aged 65-74 years), and rarely in females (3%). CONCLUSION: p.N215S is a disease-causing mutation with severe clinical manifestations found primarily in the heart. Cardiac involvement may become as severe as in classic Fabry patients, especially in males.