Cinzia Forleo

High circulating levels of endogenous ouabain in the offspring of hypertensive and normotensive individuals.

Objective Impaired diastolic function and left ventricular hypertrophy can occur early in the natural history of essential hypertension. High circulating levels of endogenous ouabain (EO) have been described in essential hypertension and have also been associated with left ventricular hypertrophy. The aim of this study was to investigate whether these cardiac modifications are related to plasma EO levels in the offspring of hypertensive families. Methods The study involved 41 subjects with (FAM+) and 45 subjects without (FAM−) a family history of hypertension. Arterial blood pressure, left ventricular geometry and function, and plasma EO levels were measured in each subject. Results Plasma EO levels were higher in the FAM+ subjects (221.5 ± 10.95 versus 179.6 ± 9.58 pmol/l, P = 0.004), and directly correlated with both systolic (r = 0.417, P < 0.0001) and diastolic blood pressure (r = 0.333, P = 0.002). Plasma EO was inversely related to an index of cardiac diastolic function determined as the ratio between the early and late peak flow velocity (r = −0.286, P = 0.012) and isovolumetric relaxation time (IVRT) (r = 0.32, P = 0.003). The IVRT was also significantly higher in FAM+, correlated with the IVRT (r = 0.32, P = 0.003). The IVRT was also significantly higher in FAM+, whereas the other echocardiographic parameters were similar to FAM−. Conclusions Among the offspring of families with a positive history of hypertension, circulating EO levels and blood pressure are increased. Plasma EO levels are related to alterations of some indexes of diastolic heart function in these individuals.

Head-up tilt testing for diagnosing vasovagal syncope: a meta-analysis.

BACKGROUND A systematic evaluation focused on sensitivity and specificity of head-up tilt testing (HUT) for diagnosing vasovagal syncope has not been previously performed. We conducted a meta-analysis of studies comparing HUT outcome between patients with syncope of unknown origin and control subjects without previous syncope. METHODS We searched Pubmed and Embase databases for all English-only articles concerning case-control studies estimating the diagnostic yield of HUT, and selected 55 articles, published before March 2012, including 4361 patients and 1791 controls. The influence of age, test duration, tilt angle, and nitroglycerine or isoproterenol stimulation on tilt testing outcome was analyzed. RESULTS Head-up tilt testing demonstrated to have a good overall ability to discriminate between symptomatic patients and asymptomatic controls with an area under the summary receiver-operating characteristics curve of 0.84 and an adjusted diagnostic odds ratio of 12.15 (p<0.001). A significant inverse relationship between sensitivity and specificity of tilt testing for each study was observed (p<0.001). At multivariate analysis, advancing age and a 60° tilt angle showed a significant effect in reducing sensitivity and increasing specificity of the test. Nitroglycerine significantly raised tilt testing sensitivity by maintaining a similar specificity in comparison to isoproterenol. CONCLUSIONS The results from this meta-analysis show the high overall performance of HUT for diagnosing vasovagal syncope. Our findings provide useful information for evaluating clinical and instrumental parameters together with pharmacological stressors influencing HUT accuracy. This could allow the drawing of tilt testing protocols tailored on the diagnostic needs of each patient with unexplained syncope.

Beta1- and beta2-adrenergic receptor polymorphisms affect susceptibility to idiopathic dilated cardiomyopathy.

Objective β1- and β2-adrenergic receptors (ARs) play a pivotal role in myocardial function. We investigated whether functionally relevant polymorphisms within the genes encoding for these receptors indicate susceptibility to idiopathic dilated cardiomyopathy (DCM). Methods This case–control association study involved 189 patients with DCM and 378 gender- and age-matched control subjects. All of the subjects were characterised by polymerase chain reaction–restriction fragment length polymorphism analysis in terms of Ser49Gly and Arg389Gly polymorphisms in the β1-AR, and the 5′ leader cistron Arg19Cys, Arg16Gly, Gln27Glu, and Thr164Ile polymorphisms in the β2-AR. Genotype, allele and haplotype frequencies were analysed. Results Univariate analysis showed that the distribution of genotype and allele frequencies of the β1-Ser49Gly, β1-Arg389Gly and β2-Arg16Gly polymorphisms was significantly different between the patients and controls, and the β1-Gly49/β1-Arg389 haplotype was significantly more represented in the patients. Multivariate analysis showed that only the β1-Gly49 variant (odds ratio 1.91; 95% confidence interval 1.24–2.95; P = 0.003) and β2-Gly16Gly genotype (odds ratio 1.58; 95% confidence interval 1.10–2.26; P = 0.013) carriers were at significantly higher risk of developing DCM. Conclusions In our population from southern Italy, the Gly49 allele of the β1-AR and the Gly16Gly genotype of the β2-AR were significantly and independently associated with the DCM phenotype, thus suggesting their role in favouring susceptibility to the disease.

Impaired arterial baroreflex function before nitrate-induced vasovagal syncope during head-up tilt test

AIMS The aim of this study was to evaluate arterial baroreflex control of heart rate immediately before head-up tilt test (HUT)-induced vasovagal syncope (VVS). METHODS AND RESULTS We enrolled 97 otherwise healthy subjects with recurrent unexplained syncope. After 10 min of rest in supine position, they underwent a passive HUT potentiated with nitroglycerin administration after 20 min. Beat-to-beat heart rate and systolic blood pressure were continuously recorded. Sequence method was used to measure two complementary parameters reflecting arterial baroreflex control of heart rate: the baroreflex sensitivity (BRS) and the baroreflex effectiveness index (BEI). Twenty-one patients fainted before nitrate administration (HUT+) and 37 after nitrate administration (NTG+). Immediately before syncope, the NTG+ patients showed significantly lower BRS values than those observed at the end of the test in the patients without syncope (5.5 +/- 2.8 vs. 7.7 +/- 3.4 ms/mmHg; P = 0.004) and a significantly lower BEI (30 +/- 20% vs. 53 +/- 24%; P < 0.001). The HUT+ patients did not show any significant differences in BRS and BEI before syncope from the values observed during the corresponding tilt period in the other groups. CONCLUSION A significant depression in BRS and BEI occurs immediately before syncope in patients who faint after nitrate administration, thus suggesting that arterial baroreflex dysfunction plays a role in mediating nitrate-induced VVS.

Clinical and functional characterization of a novel mutation in lamin a/c gene in a multigenerational family with arrhythmogenic cardiac laminopathy.

Mutations in the lamin A/C gene (LMNA) were associated with dilated cardiomyopathy (DCM) and, recently, were related to severe forms of arrhythmogenic right ventricular cardiomyopathy (ARVC). Both genetic and phenotypic overlap between DCM and ARVC was observed; molecular pathomechanisms leading to the cardiac phenotypes caused by LMNA mutations are not yet fully elucidated. This study involved a large Italian family, spanning 4 generations, with arrhythmogenic cardiomyopathy of different phenotypes, including ARVC, DCM, system conduction defects, ventricular arrhythmias, and sudden cardiac death. Mutation screening of LMNA and ARVC-related genes PKP2, DSP, DSG2, DSC2, JUP, and CTNNA3 was performed. We identified a novel heterozygous mutation (c.418_438dup) in LMNA gene exon 2, occurring in a highly conserved protein domain across several species. This newly identified variant was not found in 250 ethnically-matched control subjects. Genotype-phenotype correlation studies suggested a co-segregation of the LMNA mutation with the disease phenotype and an incomplete and age-related penetrance. Based on clinical, pedigree, and molecular genetic data, this mutation was considered likely disease-causing. To clarify its potential pathophysiologic impact, functional characterization of this LMNA mutant was performed in cultured cardiomyocytes expressing EGFP-tagged wild-type and mutated LMNA constructs, and indicated an increased nuclear envelope fragility, leading to stress-induced apoptosis as the main pathogenetic mechanism. This study further expands the role of the LMNA gene in the pathogenesis of cardiac laminopathies, suggesting that LMNA should be included in mutation screening of patients with suspected arrhythmogenic cardiomyopathy, particularly when they have ECG evidence for conduction defects. The combination of clinical, genetic, and functional data contribute insights into the pathogenesis of this form of life-threatening arrhythmogenic cardiac laminopathy.

Endothelin system polymorphisms in tilt test-induced vasovagal syncope

ObjectivesAs the endothelin system participates in the regulation of cardiovascular homeostasis, the aim of this study was to analyse the role of endothelin system polymorphisms in influencing tilt-induced vasovagal syncope.MethodsWe evaluated 107 otherwise healthy subjects with recurrent unexplained syncope who underwent a head-up tilt test. All subjects were genotyped for the 3A/4A polymorphism of the EDN1 gene and the H323H T/C polymorphism of the EDNRA gene.ResultsFifty-eight patients (54%) fainted. In terms of the EDNRA polymorphism, eight subjects (8%) had the T/T genotype, 41 were heterozygous (38%) and 58 homozygous (54%) for the C allele. Sixty subjects (56%) carried homozygosis for the 3A allele of the EDN1 polymorphism and 47 were heterozygous (44%). The 4A allele was significantly more frequent in the patients who responded positively to the tilt test than in those who did not: the relative odds ratios and confidence intervals at univariate and multivariate analyses were respectively 2.37 (1.07−5.26) and 2.41 (1.05−5.49). Comparisons with a control group further supported these data. Among the tilt-positive patients, the carriers of the 4A allele were more likely to have a vasodepressive pattern than those who were homozygous for the 3A variant.InterpretationThe 3A/4A polymorphism of the EDN1 gene affects susceptibility to syncope, and the 4A variant associated with increased endothelin-1 expression may promote vasodepressive hemodynamic responses during tilt testing.

Incidence and prevalence of hypothyroidism in patients affected by chronic heart failure: role of amiodarone

BACKGROUND It has been demonstrated that hypothyroidism can lead to significant hemodynamic alterations favoring the onset of chronic heart failure (CHF) as well as its progression. Furthermore, amiodarone, an iodine-containing antiarhythmic drug frequently used in CHF patients, is often the cause of primary hypothyroidism. AIM OF THE STUDY To define the prevalence and incidence of hypothyroidism in a group of CHF outpatients in stable clinical conditions, with particular reference to the role of amiodarone therapy. RESULTS Among the 422 enrolled patients (326 males, aged 65±12 years), 51 (12%) had a previous diagnosis of hypothyroidism while 21 (5%) were newly diagnosed at the enrolment. Then, the overall prevalence of hypothyroidism at the first evaluation was 17%and, as expected, it was significantly higher in females than males (33% vs 13%; p < 0.001). During follow-up (median 28 months) hypothyroidism occurred in further 19 patients (incidence rate: 26/1000/year) and it was mainly attributable to amiodarone therapy. Considering all together the hypothyroid patients, either those affected by thyroid failure at the enrolment than those developing hypothyroidism during the follow-up, levothyroxine therapy was continued or started in 69% of them; however, normal serum TSH values were obtained only in 76% of treated cases (mean levothyroxine dose: 69±44 mcg/day). In any case, in the group of patients affected by hypothyroidism a significantly greater occurrence of heart failure progression was observed. CONCLUSIONS Hypothyroidism, especially the subclinical form, frequently occurs in patients affected by CHF receiving amiodarone therapy. Given the unfavorable impact of hypothyroidism on the progression and prognosis of CHF, and the opportunity to adequately manage thyroid failure by means of levothyroxine replacement therapy without the need to withdraw amiodarone, we recommend regular testing of thyroid function in CHF patients, in particular in those submitted to amiodarone therapy, in order to early diagnose a condition of hypothyroidism and titrate substitutive treatment.