Sympathetic activation in heart failure.

Sympathetic activation has been long appreciated exclusively as a fundamental compensatory mechanism of the failing heart and, thus, welcome and to be supported. In the initial clinical phases of heart failure (HF), the sympathetic nervous system overdrive plays a compensatory function aimed at maintaining an adequate cardiac output despite the inotropic dysfunction affecting the myocardium. However, when the sympathetic reflex response is exaggerated it triggers a sequence of unfavourable remodelling processes causing a further contractile deterioration that unleashes major adverse cardiovascular consequences, favouring the HF progression and the occurrence of fatal events. Eventually, the sympathetic nervous system in HF was demonstrated to be a 'lethality factor' and thus became a prominent therapeutic target. The existence of an effective highly specialized intracardiac neuronal network immediately rules out the old concept that sympathetic activation in HF is merely the consequence of a drop in cardiac output. When a cardiac damage occurs, such as myocardial ischaemia or a primary myocardial disorder, the adaptive capability of the system may be overcame, leading to excessive sympatho-excitation coupled with attenuation till to abolishment of central parasympathetic drive. Myocardial infarction causes, within a very short time, both a functional and anatomical remodelling with a diffuse up-regulation of nerve growth factor (NGF). The subsequent nerve sprouting signal, facilitated by a rise in the levels of NGF in the left stellate ganglion and in the serum, triggers an increase in cardiac nerve density in both peri-infarct and non-infarcted areas. Finally, NFG production decreases over time, supposedly as an adaptative response to the prolonged exposure to sympathetic overactivity, leading in the end to a reduction in sympathetic nerve density. Accordingly, NGF levels were markedly reduced in patients with severe congestive heart failure. The kidney is the other key player of the sympathetic response to HF as it indeed reacts to under-perfusion and to loop diuretics to preserve filtration at the cost of many pathological consequences on its physiology. This vicious loop ultimately participates to the chronic and disruptive sympathetic overdrive. In conclusion, sympathetic activation is the natural physiological consequence to life stressors but also to any condition that may harm our body. It is the first system of reaction to any potential life-threatening event. However, in any aspect of life over reaction is never effective but, in many instances, is, actually, life threatening. One for all is the case of ischaemia-related ventricular fibrillation which is, strongly facilitated by sympathetic hyperactivity. The take home message? When, in a condition of harm, everybody is yelling failure is just around the corner.

Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: rationale, design, and demographic characteristics of the T.O.S.CA. Registry.

Recent evidence supports the concept that progression of chronic heart failure (CHF) depends upon an imbalance of catabolic forces over the anabolic drive. In this regard, multiple hormonal deficiency syndrome (MHDS) significantly has impacts upon CHF progression, and is associated with a worse clinical status and increased mortality. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Therapy in Heart Failure) Registry (clinicaltrial.gov = NCT02335801) tests the hypothesis that anabolic deficiencies reduce survival in a large population of mild-to-moderate CHF patients. The T.O.S.CA. Registry is a prospective multicenter observational study coordinated by "Federico II" University of Naples, and involves 19 centers situated throughout Italy. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydroepiandrosterone , and insulin are measured at baseline and every year for a patient-average follow-up of 3 years. Subjects with CHF are divided into two groups: patients with one or no anabolic deficiency, and patients with two or more anabolic deficiencies at baseline. The primary endpoint is the composite of all-cause mortality and cardiovascular hospitalization. Secondary endpoints include the composite of all-cause mortality and hospitalization, the composite of cardiovascular mortality and cardiovascular hospitalization, and change of VO2 peak. Patient enrollment started in April 2013, and was completed in July 2017. Demographics and main clinical characteristics of enrolled patients are provided in this article. Detailed cross-sectional results will be available in late 2018. The T.O.S.CA. Registry represents the most robust prospective observational trial on MHDS in the field of CHF. The study findings will advance our knowledge with regard to the intimate mechanisms of CHF progression and hopefully pave the way for future randomized clinical trials of single or multiple hormonal replacement therapies in CHF.

Managing erectile dysfunction in heart failure.

Nowadays, erectile dysfunction (ED) is considered an increasingly important clinical condition in men with heart failure (HF) which may influence the therapeutic approach to these patients. Since there is cogent evidence that ED is a "sentinel marker" of acute cardiovascular events especially in men younger than 65 years or in those affected by type 2 diabetes mellitus, it deserves an early diagnosis and an appropriate treatment. In NYHA III-IV class HF patients, sexual activity could lead to acute cardiovascular events and this should be taken into account when approaching ED patients. Moreover, it is well known that some classes of drugs, normally employed in the treatment of HF patients (e.g.thiazide diuretics, spironolactone and ß-blockers), might worsen or even contribute to ED development. On the other hand, growing evidence suggests that PDE 5 inhibitors (vardenafil, tadalafil and sildenafil) seem to better satisfy the needs of NYHA HF I- II class men suffering from ED. In fact, they show few side effects, while improving both cardiopulmonary parameters and quality of life. Therefore, the aim of this review is to sum up the most recent evidence regarding the management of ED in men suffering from HF.

Prognostic role of sub-clinical hypothyroidism in chronic heart failure outpatients.

BACKGROUND: It has been suggested that low thyroid hormones levels may be associated with increased mortality in patients with cardiovascular disease. AIM: To evaluate the prognostic role of thyroid function deficiency in patients with chronic heart failure (CHF). METHODS: We evaluated 338 consecutive outpatients with stable CHF receiving conventional therapy, all of whom underwent a physical examination, electrocardiography and echocardiography. Blood samples were drawn to assess renal function, and Na+, hemoglobin, NT-proBNPs, fT3, fT4 and TSH levels. Patients with hyperthyroidism were excluded. RESULTS: During the follow-up (15+/-8 months), heart failure progression was observed in 79 patients (including 18 who died of heart failure after hospitalisation and six who underwent transplantation). Univariate regression analysis showed that TSH (p<0.0001), fT3 (p<0.0001), fT4 (p=0.016) and fT3/fT4 (p<0.0001) were associated with heart failure progression but multivariate analysis showed that only TSH considered as a continuous variable (p = 0.001) as well as subclinical hypothyroidism (TSH > 5.5 mUI/l; p=0.014) remained significantly associated with the events. CONCLUSIONS: In CHF patients TSH levels even slightly above normal range are independently associated with a greater likelihood of heart failure progression. This supports the need for prospective studies aimed at clarifying the most appropriate therapeutic approach to sub-clinical hypothyroidism in such patients.

[Cardiopulmonary sensitivity and chemosensitivity]. / Sensibilità cardiopolmonare e chemosensibilità.

The autonomic control of the cardiovascular system plays an important role in maintaining the arterial pressure at the levels necessary for adequate tissue perfusion. In cardiovascular diseases, the impairment of the basic reflex mechanisms that are responsible for the moment-to-moment regulation could increase sympathetic activity and is correlated with an adverse outcome. The objective of the present review was to provide information about the methodological aspects exploring cardiopulmonary and chemoreceptor reflexes. Different techniques are available and all of them include assessment of reflexes through the activation or deactivation of either the cardiopulmonary baroreceptors or chemoreceptors. Intravenous saline load, head-down tilt, passive legs raising, head-out water immersion and the application of a lower body positive pressure are the principal methods utilized for activating cardiopulmonary baroreceptors; on the contrary deactivation could be achieved by acutely induced hypovolemia by furosemide or blood donation, inflation of a congestion cuff on the thighs or application of a negative pressure on the lower body. The transient exposure to a hypoxic or a hypercapnic gas mixture is frequently used to determine the peripheral and central chemoreflexes, respectively. The reflexes are quantified by the gain between output (i.e. heart rate, sympathetic activity, vascular resistance, ventilation) and input (oxygen saturation, end-tidal CO2 or changes in central venous pressure). One important limitation in assessing the cardiopulmonary baroreflex by using currently available techniques is that the involvement of the arterial baroreflex cannot be avoided. In addition, chemoreflexes cannot be interpreted unless the breathing rate is controlled. To date, several techniques are available for the quantification of cardiopulmonary baroreceptor and chemoreceptor reflexes and could provide new information on the abnormal autonomic mechanisms contributing to the pathophysiology of several cardiovascular diseases.

Depression but not anxiety influences the autonomic control of heart rate after myocardial infarction.

AIMS: It has been previously hypothesized that the adverse outcome observed in depressed patients after myocardial infarction might be due to an imbalance in autonomic nervous system activity. The aim of this study was to define the role of depressive and anxious symptoms in influencing autonomic control of heart rate after myocardial infarction. METHODS AND RESULTS: The SD of RR intervals, baroreflex sensitivity, and depression and anxiety (Zung's scales) were assessed before discharge in 103 patients with acute myocardial infarction; 32 were found to be depressed. Among the patients who were not taking beta-blockers, those with depression had significantly lower SDs of RR intervals and baroreflex sensitivity than did those without depression (96.3 +/- 22.2 ms vs 119.5 +/- 37.7 ms, P =.016; 8.6 +/- 6.2 ms vs 11.8 +/- 6.5 ms/mm Hg, P =.01, respectively). No differences were found when anxiety was considered or when beta-blockers were given. Among the patients not taking beta-blockers, there was a significant correlation between depression levels and both the SD of RR intervals (r = -0.47) and baroreflex sensitivity (r = -0.40). CONCLUSIONS: In patients with myocardial infarction, depression but not anxiety negatively influences autonomic control of heart rate. Beta-blockers modify these influences.

Usefulness of handgrip to improve ibutilide efficacy in organizing atrial electrical activity during atrial fibrillation.

We analyzed the effect of handgrip on atrial electrical activity during atrial fibrillation (AF) by recording right and left atrial activity in 15 patients with persistent AF under baseline conditions and after saline and ibutilide infusions. The handgrip test for 15 seconds, which was always associated with a significant increase in mean atrial cycle length, was recorded in both atria (right atrium: saline vs saline + handgrip 141 +/- 29 vs 171 +/- 24 ms, p <0.001; ibutilide vs ibutilide + handgrip: 197 +/- 43 vs 221 +/- 39 ms, p <0.005). Handgrip favorably modifies atrial electrophysiologic properties during AF.

Influence of gender and family history of hypertension on autonomic control of heart rate, diastolic function and brain natriuretic peptide.

OBJECTIVE: To verify in a unitary view whether autonomic control of heart rate and cardiac structure and function are modified early in offspring of hypertensive families. METHODS AND RESULTS: We selected 87 age- and sex-matched young normotensive subjects with (n = 45) and without (n = 42) a family history of hypertension who underwent evaluations of arterial pressure, time-domain parameters of autonomic heart rate control (24-h ECG monitoring), spectral baroreflex sensitivity, left ventricular geometry and function (echo-Doppler) and plasma brain natriuretic peptide levels (BNP). The group with a family history of hypertension significantly differed from their counterparts for systolic pressure (119 +/- 11 versus 114 +/- 9 mmHg, P< 0.05), heart rate (RR interval, 766 +/- 64 versus 810 +/- 93 ms, P< 0.05), heart rate variability [the standard deviation of normal RR intervals (SDNN), 147 +/- 29 versus 171 +/- 33 ms, P < 0.051, diastolic function (isovolumetric relaxation time, 65 +/- 9 versus 60 +/- 8 ms, P< 0.05) and BNP (23 +/- 13 versus 37 +/- 10 pg/ml, P< 0.05). Baroreflex sensitivity values did not differ between the two groups. When gender was considered, all the above-mentioned measures, as well as baroreflex sensitivity, were significantly different between males with and without a family history of hypertension but not between females, except for BNP, which was lower in males and females with a history of hypertension (males, 24 +/- 11 versus 38 +/- 8 pg/ml, P< 0.01; females 21 +/- 14 versus 36 +/- 13 pg/ml, P < 0.05). CONCLUSIONS: Male, but not female, hypertensive offspring have modified diastolic function and autonomic control of heart rate; BNP is the only parameter able to characterize hypertensive offspring independently from the influence of gender. This provides the hypothesis that the impaired production of this hormone could play a primary role in the pre-hypertensive state.

Influence of hydrophilic and lipophilic beta-blockers on heart rate, ventricular repolarization and their interrelationship in normal subjects.

BACKGROUND: It has been hypothesized that hydrophilic and lipophilic beta-blockers have different antiarrhythmic properties because only the latter seem to reduce the rate of sudden death in post-myocardial infarction patients as well as animal models which seem to be independent of their effect on autonomic nervous system modulation. The aim of this study was to evaluate the different effects of a hydrophilic (nadolol) and lipophilic (metoprolol) beta-blocker on ventricular repolarization in normal subjects. METHODS: Seventeen normal subjects entered this randomized, single-blind cross-over study designed to compare the effects of nadolol (80 mg/day) and slow-release metoprolol (200 mg/day) on dynamic ventricular repolarization. The RR intervals, the QT evaluated at the apex (QT apex) and at the end (QT end) of the T wave before and after correction for heart rate, the standard deviation of QT apex and QT end, and the slope of the QT/RR linear relationship (QTa-slope and QTe-slope) were studied using the ELATEC system (ELA Medical, Mountrouge, France), and an evaluation was made of their reproducibility and the effects of each beta-blocker. RESULTS: The most reproducible parameters were QT apex, corrected QT apex and the QTe-slope. Nadolol was associated with a greater adrenergic blockade than metoprolol (lengthening of RR interval +25 +/- 7 and +17 +/- 8% respectively, p = 0.0003) and a lower effect on ventricular repolarization (reduction of corrected QT apex -0.6 +/- 3 and -2.5 +/- 2.1% respectively, p < 0.01; reduction of QTe-slope -5 +/- 16 and -15 +/- 15% respectively, p = 0.03). CONCLUSIONS: At the dosages used in the study, metoprolol showed lower adrenergic blockade but greater effect on ventricular repolarization than nadolol.

New site of temporary storage of rRNA in O. mykiss previtellogenic oocytes.

This article describes a new organelle found in the cytoplasm of the growth stage fish oocytes. In particular, we describe its organization at the morphological level and investigate its composition by different cytochemical and immunocytochemical approaches with both light and electron microscope. The conclusion is that the body is a peculiar protein scaffold functioning as a temporary trap for the storage of rRNA in the mid to late growth stage oocytes. Its presence would be related to the reorganization of the mass of amplified rDNA in micronucleoli and to the consequent temporary stop in the rRNA synthesis.

[Liposarcoma of the spermatic cord: a clinical case]. / Liposarcoma del funicolo spermatico: un caso clinico.

A case of spermatic cord liposarcoma is reviewed. Radical orchiectomy is an adequate form of treatment while retroperitoneal lymphadenectomy and adjunctive radiotherapy or chemotherapy appear to be controversial. A close follow-up is mandatory to detect early relapses or distant metastasis.

[Intrinsic endometriosis of the ureter. Clinical case]. / Endometriosi intrinseca dell'uretere. Caso clinico.

Endometriosis is defined as the presence of endometrial tissue outside the cavity of the uterus. The urinary tract is rarely affected, only 1 to 11%. Bladder is the most frequent urinary localization while the ureteral involvement is rare. We report a case of intrinsic ureteral endometriosis in a woman with left hydronephrosis, lumbar pain and septic fever. Instrumental and laboratory investigations can hardly lead to a reliable diagnosis of ureteral endometriosis. A final diagnosis is feasible only by histologic examination, which obviously implies surgery.