Malatino, Lorenzo

Abstract Objectives SSc is characterized by widespread microangiopathy and fibrosis of skin and visceral organs. Left ventricle involvement is usually subclinical, characterized by systolic and/or diastolic dysfunction. The global longitudinal strain (GLS), a validated and reliable technique for the measurement of ventricular longitudinal deformation by means of echocardiography, may detect subclinical systolic dysfunction of SSc myocardium. The improvement of myocardial perfusion by means of intravenous Iloprost administration could ameliorate the contractility of SSc heart. Therefore, we aimed to evaluate GLS in a series of SSc patients prior and after Iloprost infusion. Methods Fifteen consecutive SSc patients (age: 54 ± 11 years; 12 females) treated with Iloprost because of the presence/history of digital ulcers underwent echocardiography, including GLS technique. This evaluation was conducted immediately before Iloprost administration and at the end of the 6-h infusion session. Results Significant improvement in the mean GLS was observed after Iloprost administration (from −13.5 ± 2.5 to −15 ± 3.3; P = 0.011). The echocardiographic data obtained from the four-chamber view showed the best quality for GLS analysis and showed a highly significant improvement of the strain after Iloprost administration (from −13.4 ± 2.2 to −15.6 ± 3; P = 0.001). The degree of GLS improvement did not correlate with any SSc parameters. Conclusion Iloprost administration improved GLS, suggesting that the increase of myocardial perfusion allowed, at least in part, a correction of left ventricular systolic dysfunction. Further studies are needed to confirm these findings, further exploring the mid/long-term effects of Iloprost on myocardial contraction.

Introduction: Blood pressure (BP) control remains low despite combination therapy in resistant hypertension (RH). Thus, there is an unmet need for novel strategies targeting RH. Recently we have reported that M-ANP, a novel Mayo engineered ANP-based peptide, possesses greater and more sustained biological actions compared to ANP and is more resistant to neprilysin degradation. The current study was designed to investigate for the first time the efficacy of a single daily subcutaneous (SQ) injection of M-ANP using a chronic canine model of hypertension induced by angiotensin II (Ang-II). Hypothesis: We hypothesize that a daily SQ M-ANP injection would have potent BP lowering and renal enhancing properties in our chronic hypertensive canine model. Methods: We induced hypertension in canines (n=5) by continuous Ang II (80 ng/kg/min) osmotic mini-pump administration for 24 days. Continuous 24 hour mean BP (MBP) was measured by telemetry and a 24 hour urine collection was used to assess urinary volume, sodium (Na) and cGMP, the second messenger for the ANP system. M-ANP was administered SQ for 5 days (10μg/kg/day). Data are mean±SE. ΨP<0.05 Ang II Day 16 vs. baseline; *P<0.05 Ang II Day 16 vs. M-ANP (Table 1). Results: Chronic Ang II administration resulted in model of severe hypertension, with an increase in MBP from 112±2 to 157±2 mmHg (day 16). As seen in Table 1, M-ANP significantly reduced MBP, significantly increased plasma cGMP as well as urinary cGMP excretion, urinary volume rate (UV) and urinary Na excretion (UNa), without significant changes in heart rate (HR). Furthermore, there was a trend for plasma ANP to increase and plasma aldosterone to decrease with SQ M-ANP injection. Conclusions: This study demonstrates for the first time that chronic SQ administration of M-ANP reduces BP, activates plasma cGMP, and increases UV and UNa, without significant changes in HR in an experimental model of chronic hypertension.

C-type natriuretic peptide (CNP) possesses well-established cardiovascular properties. Although present in the mammalian kidney, CNP production in human kidney and its modulation in human renal disease remain less defined. We investigated the presence of CNP in normal human kidney and in patients with nephrotic syndrome (NS). We also addressed whether or not a low-protein diet (LPD) alters plasma CNP and urinary CNP excretion in NS. In situ hybridization studies demonstrated CNP mRNA expression in tubular cells and glomeruli of normal human kidneys. CNP immunoreactivity was positive in proximal, distal, and medullary collecting duct tubular cells in both controls and patients with NS. The ratios of plasma CNP and urinary CNP to creatinine were significantly higher in patients with NS compared with controls. Urinary CNP, but not plasma CNP, was significantly lowered in patients with NS after an LPD. Similarly, the ratios of urinary protein to creatinine and urinary albumin to creatinine, but not urinary guanosine 3′,5′-cyclic monophosphate to creatinine, decreased significantly with an LPD. These data confirm and extend previous reports and demonstrate for the first time the presence of CNP in human kidney with NS. We also report increased plasma CNP concentration and urinary CNP excretion in NS patients and a significant reduction of CNP excretion with an LPD. Our findings demonstrate that CNP metabolism is altered in patients with NS and support the hypothesis that activation of renal CNP can be partially offset by an LPD. These results underscore that the beneficial effect of an LPD on protein excretion is paralleled by a substantial reduction in intrarenal CNP release.

Background— Diastolic dysfunction associated with high blood pressure (BP) leads to cardiac remodeling and fibrosis and progression to congestive heart failure. B-type natriuretic peptide (BNP) has BP-lowering, antifibrotic, and antihypertrophic properties, which makes BNP an attractive agent for attenuating the adverse cardiac remodeling associated with hypertension. In the current study, we tested the effects of sustained cardiac proBNP gene delivery on BP, cardiac function, and remodeling in spontaneously hypertensive rats (SHR). Methods and Results— We used the myocardium-tropic adeno-associated virus serotype 9 (AAV9) vector to achieve continuously enhanced cardiac rat proBNP expression. In SHR, a single systemic administration of AAV9 vector allowed long-term cardiac BNP overexpression, resulting in reductions in systolic and diastolic BP for 9 months after injection. Left ventricular (LV) thickness, LV end-systolic dimensions, and LV mass were reduced, whereas ejection fraction was significantly increased, in BNP-treated compared with untreated SHR. Circumferential systolic strain and strain rate of the early phase of diastole were improved in BNP-treated compared with untreated SHR. Noncardiac overexpression of BNP via AAV2 vector was not associated with changes in BP and plasma BNP in SHR. Furthermore, normal Wistar rats injected with AAV9 proBNP vector showed significantly reduced heart weights 4 weeks after injection without BP reduction. Conclusions— AAV9 vector facilitates sustained cardiac proBNP overexpression and improves LV function in hypertensive heart disease. Long-term proBNP delivery improved both systolic and diastolic function. The effects on cardiac structure and function occurred independently of BP-lowering effects in normal Wistar rats.

Background— The renal actions of brain natriuretic peptide (BNP) in congestive heart failure (CHF) are associated with increased diuresis and natriuresis, preserved glomerular filtration rate (GFR), and lack of activation of the renin-angiotensin-aldosterone system (RAAS). In contrast, diuretic-induced natriuresis may be associated with reduced GFR and RAAS activation. The objective of this study was to test the hypothesis that exogenous BNP enhances the renal diuretic and natriuretic actions of furosemide (Fs) and retards the activation of aldosterone in a model of CHF. Methods and Results— CHF was produced in 2 groups of dogs by ventricular pacing. One group received continuous (90-minute) intravenous Fs (1 mg · kg −1 · h −1 ). A second group (Fs+BNP) received 45-minute intravenous coinfusion of Fs (1 mg · kg −1 · h −1 ) and low-dose (2 pmol · kg −1 · min −1 ) BNP followed by 45-minute coinfusion of Fs (1 mg · kg −1 · h −1 ) and high-dose (10 pmol · kg −1 · min −1 ) BNP. Fs increased urinary flow, but the effect of Fs+BNP was greater. Similarly, urinary sodium excretion was higher in the Fs+BNP group. Although GFR tended to decrease in the Fs group, it increased in the Fs+BNP group (35±3 to 56±4*) (* indicates P <0.05 versus baseline) ( P <0.0001 between groups). Plasma aldosterone increased with Fs (41±10 to 100±11* ng/dL) but was attenuated in the Fs+BNP group (44±11 to 54±9 ng/dL low-dose and to 47±7 ng/dL high-dose) ( P =0.0007 between groups). Conclusions— Fs+BNP has more profound diuretic and natriuretic responses than Fs alone and also increases GFR without activation of aldosterone. Coadministration of BNP and loop diuretic is effective in maximizing natriuresis and diuresis while preserving renal function and inhibiting activation of aldosterone.

Background — Omapatrilat (OMA), a vasopeptidase inhibitor, simultaneously inhibits angiotensin-converting enzyme (ACE) and neutral endopeptidase, which degrades vasodilatory factors (eg, ADM) and natriuretic peptides. Based on the beneficial cardiorenal and humoral properties of the natriuretic peptides, we hypothesized that an acute vasopeptidase inhibitor with or without diuretic would result in more favorable cardiorenal and hormonal actions than ACE inhibition plus diuretic (ACEI+D) in congestive heart failure. Methods and Results — We compared the actions of OMA alone and with diuretic (OMA+D) to ACEI+D in a model of pacing-induced congestive heart failure. OMA+D decreased pulmonary arterial and pulmonary capillary wedge pressures to a greater level than OMA alone or ACEI+D. Glomerular filtration rate was lower with ACEI+D than with either OMA group. Plasma renin activity and aldosterone immediately increased with ACEI+D, whereas OMA+D resulted in higher plasma renin activity and a delayed increase in aldosterone. OMA alone did not increase plasma renin activity and aldosterone, but resulted in a sustained increase in plasma adrenomedullin, with higher urinary atrial natriuretic peptide, adrenomedullin, and cGMP excretions than with ACEI+D. Conclusions — Acute administration of OMA with or without diuretic results in more favorable cardiorenal and humoral responses in experimental congestive heart failure than does ACEI+D. There is no acute activation of renin and aldosterone with OMA alone such as occurs with ACEI+D and OMA+D. Thus, OMA with or without a diuretic possesses beneficial cardiorenal and humoral actions comparable to those observed with ACEI+D that can be explained by potentiation of natriuretic peptides.