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Aims The combined prophylactic strategy of sodium bicarbonate plus N-acetylsyteine (NAC) seems to be effective in preventing contrast induced acute kidney injury (CI-AKI) in patients at low-to-medium risk. However, in patients at high and very high risk the rate of CI-AKI is still high. In this subset of patients the anticipated advantages of the RenalGuard(tm) System should be investigated. The RenalGuard(tm) System (PLC Medical Systems, Inc., Franklin, MA, USA) is a real-time measurement and real time matched fluid replacement device designed to accommodate the RenalGuard therapy, which is based on the theory that creating and maintaining a high urine output is beneficial by allowing a quick elimination of contrast media, and, therefore, reducing its toxic effects. Methods and results The REMEDIAL II trial is a randomised, multicentre, investigator-sponsored trial addressing the hypothesis that the RenalGuard System is superior to the prophylaxis with sodium bicarbonate infusion plus NAC in preventing CI-AKI in high and very high risk patients. Consecutive patients with chronic kidney disease (CKD) and at high to very high risk for CI-AKI, referred to our institutions for coronary and/or peripheral procedures, will be randomly assigned to 1) prophylactic administration of sodium bicarbonate plus NAC (control group) and 2) RenalGuard System treatment (RenalGuard group). All enrolled patients must have an estimated glomerular filtration rate ≤ 30 ml/min/1.73 m2 and/or a contrast nephropathy risk score ≥ 11. In all cases iodixanol (an iso-osmolar, non-ionic contrast agent) will be administered. The primary endpoint is an increase of ≥ 0.3 mg/dL in the serum creatinine concentration 48 hours after the procedure. Conclusions The REMEDIAL II trial will give important answers on how to prevent CI-AKI in high and very high risk patients undergoing contrast media exposure.

The role of statins in the prevention of contrast-induced acute kidney injury (CIAKI) is controversial. METHODS AND RESULTS: First, we investigated the in vivo effects of atorvastatin on CIAKI. Patients with chronic kidney disease enrolled in the Novel Approaches for Preventing or Limiting Events (NAPLES) II trial were randomly assigned to (1) the atorvastatin group (80 mg within 24 hours before contrast media [CM] exposure; n=202) or (2) the control group (n=208). All patients received a high dose of N-acetylcysteine and sodium bicarbonate solution. Second, we investigated the in vitro effects of atorvastatin pretreatment on CM-mediated modifications of intracellular pathways leading to apoptosis or survival in renal tubular cells. CIAKI (ie, an increase >10% of serum cystatin C concentration within 24 hours after CM exposure) occurred in 9 of 202 patients in the atorvastatin group (4.5%) and in 37 of 208 patients in the control group (17.8%) (P=0.005; odds ratio=0.22; 95% confidence interval, 0.07-0.69). CIAKI rate was lower in the atorvastatin group in both diabetics and nondiabetics and in patients with moderate chronic kidney disease (estimated glomerular filtration rate, 31-60 mL/min per 1.73 m(2)). In the in vitro model, pretreatment with atorvastatin (1) prevented CM-induced renal cell apoptosis by reducing stress kinases activation and (2) restored the survival signals (mediated by Akt and ERK pathways). CONCLUSIONS: A single high loading dose of atorvastatin administered within 24 hours before CM exposure is effective in reducing the rate of CIAKI. This beneficial effect is observed only in patients at low to medium risk.

The aim of this study was to assess the feasibility, safety and diagnostic accuracy of two-dimensional echocardiography performed during adenosine infusion (140 μg/Kg/min for 6 min) in recognizing segments of viable myocardium as assessed by thallium-201 scintigraphy (exercise-redistribution-reinjection protocol). For this purpose, 27 patients (25 males and 2 females, mean age 54 ± 6 years) with previous myocardial infarction, angiographically proven coronary artery disease and mild left ventricular systolic dysfunction (election fraction 35-45%) performed adenosine two-dimensional echocardiography and thallium-201 scintigraphy within 7 days in the absence of effective treatment. A 22 segment model of the left ventricle was used for both techniques. A score index ranging from 1 (normokinesia) to 4 (dyskinesia) was used for two-dimensional echocardiography. In the 102 segments identified as a-dyskinetic at rest echocardiography, 40 were classified as viable during echo-adenosine (improvement of ≤ 1 grade at peak hyperkinesia) and 62 necrotic. A concordance of 97.5% was found between the two diagnostic techniques in the former segments and of 82% in the latter. Our results indicate that iv adenosine infusion combined with two-dimensional echocardiography imaging can safely be used for the diagnosis of viable myocardium and may represent a useful alternative to thallium-201 scintigraphy in evaluating patients to be addressed to revascularization procedures.

Left ventricular hypertrophy secondary to hypertension has been associated with a reduction of maximum coronary flow per unit mass as shown by the increase in the minimal threshold of coronary vascular resistance per gramme. This phenomenon has usually been attributed to an increase in muscle mass with absent or inadequate vascular compensation. However, chronic hypertension may induce a function reduction in coronary flow. In particular, it has been recently shown that coronary vascular resistances are influenced by a cardio-cardiac reflex involving the baroreceptor response. Left ventricular hypertrophy could alter the function of the ventricular receptors and favourise myocardial ischemia by preventing the adaptation of coronary flow to myocardial metabolic demands.

To investigate whether the response of atrial natriuretic factor (ANF) to volume expansion is impaired in the early stages of dilated cardiomyopathy, the effects of saline load (SL; 0.25 ml/kg.min for 120 min) were assessed in 12 patients with dilated cardiomyopathy and asymptomatic to mildly symptomatic heart failure (HF) and in nine normal subjects (N). SL increased plasma ANF levels in N (from 14.3 +/- 2 to 19.5 +/- 3 and 26 +/- 4 pg/ml, at 60 and 120 min, respectively, P less than 0.001), but not in HF (from 42.9 +/- 9 to 45.9 +/- 9 and 43.9 +/- 8 pg/ml). Left ventricular end-diastolic volume (LVEDV) and stroke volume were increased (P less than 0.001) by SL in N but not in HF. Urinary sodium excretion (UNaV) increased in N more than in HF during SL, whereas forearm vascular resistance (FVR) did not change in N and increased in HF (P less than 0.001). In five HF patients SL was performed during ANF infusion (50 ng/kg, 5 ng/kg.min) that increased ANF levels from 37.1 +/- 10 to 146 +/- 22 pg/ml. In this group, SL raised both LVEDV (P less than 0.01) and ANF (P less than 0.05), whereas FVR did not rise. In addition, the UNaV increase and renin and aldosterone suppressions by SL were more marked than those observed in HF under control conditions. Thus, in patients with dilated cardiomyopathy and mild cardiac dysfunction, plasma ANF levels are not increased by volume expansion as observed in N. The lack of ANF response is related to the impaired cardiac adaptations. The absence of an adequate increase of ANF levels may contribute to the abnormal responses of HF patients to saline load.

In 20 patients with mild or moderate essential hypertension who responded favorably to indenolol antihypertensive therapy, echocardiography was performed in the basal condition and 6 and 12 months after the beginning of permanent antihypertensive treatment. Indenolol induced a significant decrease in blood pressure, from a basal value of 170 +/- 3/100 +/- 8 mmHg to 142 +/- 4/87 +/- 2 mmHg after 6 months (p less than 0.01) and to 133 +/- 4/84 +/- 2 mmHg after 1 year (p less than 0.01), and in heart rate, from 72 +/- 5 to 61 +/- 3 bpm after 6 months (p less than 0.01) and to 60 +/- 2 bpm after 1 year (p less than 0.01). Simultaneously, there was a significant reduction in cardiac output (from 6.3 +/- .4 to 5.7 +/- .2 liters/min after 6 months, p less than 0.05, and to 5.6 +/- .2 liters/min after 1 year, p less than 0.01), due to a reduction in heart rate, increased stroke volume, and improved left ventricular performance after indenolol. Total peripheral resistance was also reduced, although statistical significance was not attained. However, a significant inverse correlation was found between the initial value of cardiac output and total peripheral resistance and the changes in these parameters induced by indenolol treatment (cardiac output: r = -0.824 and -0.855, total peripheral resistance: r = -0.876 and -0.899 at 6- and 12-month controls, respectively, all p less than 0.001). Finally, there was a parallel decrease in left ventricular wall and septal thickness and estimated left ventricular mass in patients with left ventricular hypertrophy, whereas no change in left ventricular anatomy could be detected in patients with normal left ventricular mass.

Renal function in the basal state and after sodium load has been investigated in 21 borderline, hypertensive, first-degree relatives of established hypertensives and in 21 age- and sex-matched, normal subjects with no family history of hypertension. During intravenous infusion of inulin and p-aminohippurate in saline, both groups showed a decrease in plasma aldosterone levels (p less than 0.05) but renal plasma flow (595 +/- 48 vs. 750 +/- 59 ml/min, p less than 0.05), diuresis (1.4 +/- 0.2 vs. 2.2 +/- 0.5 ml/min, p less than 0.05), natriuresis (0.21 +/- 0.02 vs. 0.3 +/- 0.02 mEq/min, p less than 0.05) and sodium clearance (1.05 +/- 0.1 vs. 2.4 +/- 0.4 ml/min, p less than 0.05) in borderline hypertensives were higher than in the control group. After the salt load (NaCl, 1.35% i.v., 5 ml/min for 2 h) there was an increase in blood pressure and a decrease in plasma aldosterone and potassium levels in both groups. However, borderline hypertensives showed higher diuresis, natriuresis, sodium clearance and also kaliuresis compared to normotensives. These results suggest that borderline hypertensives already present the changes in renal function which are characteristics of established hypertensives.

Twenty patients with mild or moderate essential hypertension participated in a double-blind crossover randomized trial aimed at assessing, by echocardiography, the hemodynamic effects of the antihypertensive therapy with atenolol administered once daily (100 mg) alone or combined with chlortalidone (25 mg) in fixed combination. Blood pressure and heart rate were measured at rest and during bicycle exercise before and after four-week periods of treatment. Both atenolol and atenolol plus chlortalidone reduced significantly blood pressure and heart rate. The reduction in blood pressure was mediated by a reduction in cardiac output. However, the combined treatment was also able to prevent the increase in stroke volume observed after atenolol alone. Furthermore, the combined treatment was able to significantly lower blood pressure during exercise, while atenolol alone failed. These results suggest that the association of chlortalidone potentiates the antihypertensive effect of atenolol by acting through a different mechanism.

The hypotensive action of guanfacine and alpha-methyldopa has been compared in 30 patients wth moderate essential hypertension. After 2 weeks of placebo treatment, the patients were randomly allocated to a 12 week treatment with either of the two drugs. The treatment was started with guanfacine, 1 mg twice daily p.o., or alpha-methyldopa, 250 mg three time a day p.o. This dose of guanfacine was able to induce a satisfactory control of blood pressure in all patients while the dose of alpha-methyldopa was gradually increased to a predetermined maximum daily dose (2 g) in those patients with unsatisfactory blood pressure control, i.e., systolic blood pressure above 160 mmHg and diastolic above 95 mmHg. Then the two treatments were dicontinued for one week. Both drugs induced a significant reduction of systolic and diastolic blood pressure. However, guanfacine induced a more marked decrease in systolic blood pressure after the 14th day of treatment while the reduction of diastolic blood pressure was significantly higher only at the end of the final wash-out period, thus indicating a longer lasting effect of guanfacine as compared to alpha-methyldopa. Two patients treated with guanfacine developed dryness of the mouth and three of those in the alphamethyldopa group complained of excessive sedation.

The hemodynamic changes induced by coronary occlusion were investigated in anesthetized dogs. Coronary occlusion elicited an immediate but transient increase in the systemic blood pressure and in the vascular resistance of the hind limb perfused at constant flow. Thereafter, systemic hypotension and vasodilatation in the perfused region were observed. Vagotomy abolished the initial increase of the systemic and perfusion pressure and reduced significantly the late vasodilator response both systemically and in the perfused hind limb. After the subsequent administration of hexamethonium the vasodilatation in the hind limb was no longer manifest but the fall in blood pressure was unmodified. These results seem to suggest that multiple mechanisms are involved in the hemodynamic response to coronary occlusion.