Bruno Trimarco | ScienceDirect (2023)

Article • Open Access

Background: We and others have previously demonstrated that the endothelium is a primary target of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and L-arginine has been shown to improve endothelial dysfunction. However, the effects of L-arginine have never been evaluated in coronavirus disease 2019 (COVID-19). Methods: This is a parallel-group, double-blind, randomized, placebo-controlled trial conducted on patients hospitalized for severe COVID-19. Patients received 1.66 g L-arginine twice a day or placebo, administered orally. The primary efficacy endpoint was a reduction in respiratory support assessed 10 and 20 days after randomization. Secondary outcomes were the length of in-hospital stay, the time to normalization of lymphocyte number, and the time to obtain a negative real-time reverse transcription polymerase chain reaction (RT-PCR) for SARS-CoV-2 on nasopharyngeal swab. This clinical trial had been registered at ClinicalTrials.gov, identifier: NCT04637906. Findings: We present here the results of the initial interim analysis on the first 101 patients. No treatment-emergent serious adverse events were attributable to L-arginine. At 10-day evaluation, 71.1% of patients in the L-arginine arm and 44.4% in the placebo arm (p < 0.01) had the respiratory support reduced; however, a significant difference was not detected 20 days after randomization. Strikingly, patients treated with L-arginine exhibited a significantly reduced in-hospital stay vs placebo, with a median (interquartile range 25^th,75^th percentile) of 46 days (45,46) in the placebo group vs 25 days (21,26) in the L-arginine group (p < 0.0001); these findings were also confirmed after adjusting for potential confounders including age, duration of symptoms, comorbidities, D-dimer, as well as antiviral and anticoagulant treatments. The other secondary outcomes were not significantly different between groups. Interpretation: In this interim analysis, adding oral L-arginine to standard therapy in patients with severe COVID-19 significantly decreases the length of hospitalization and reduces the respiratory support at 10 but not at 20 days after starting the treatment. Funding: Both placebo and L-arginine were kindly provided by Farmaceutici Damor S.p.A., Naples

Article

Background: In 2016, an update of the 2009 recommendations for the evaluation of left ventricular (LV) diastolic function (DF) was released by the American Society of Echocardiography and the European Association of Cardiovascular Imaging. The aims of this study were to assess the concordance between the 2016 and 2009 recommendations and to test the impact of the consideration of “myocardial disease” recommended in the 2016 update on the evaluation of diastolic dysfunction (DD) and LV filling pressures in patients with normal and reduced LV ejection fractions referred to a general echocardiography laboratory. Methods: A total of 1,508 outpatients referred to an echocardiography laboratory during a predefined 5-month period were prospectively enrolled. All patients underwent targeted clinical history and Doppler echocardiographic examination. DD and LV filling pressures were assessed according to 2009 and 2016 recommendations. Concordance was calculated using the κ coefficient and overall proportion of agreement. Results: Overall proportion of agreement between the two recommendations was 64.7% (κ = 0.43). Comparing the 2009 and 2016 recommendations, 47.5% and 36.1% patients, respectively, had DD (P <. 0001), and 22.7% and 12.6% had elevated LV filling pressures (P <. 0001). This difference remained significant in the setting of patients with normal LV ejection fractions (21.6% vs 10.7%, P <. 0001). In the application of the 2016 recommendations, whether or not the presence of “myocardial disease” was considered, the prevalence of indeterminate diastolic function was, respectively, 7.3% versus 13.7%, while patients in whom the DD grade could not be determined were 8.1% versus 14.4% (P <. 0001 for all). Conclusions: Considering the presence of myocardial disease when applying the 2016 recommendations resulted in a lower prevalence of inconclusive diagnosis.

Review

Complex coronary artery bifurcation lesions occurred in hard clinical scenarios, such as acute coronary syndromes, may represent a challenge for interventional cardiologists, with not-defined general consensus on treatment. Even if provisional stenting is the most common option used to restore rapidly the coronary branches flow, improvements in industrial technologies and design of new dedicated bifurcation devices might open new modalities of treatment in these complex cases. The Axxess stent (Biosensors Europe SA, Morges, Switzerland) is a self-expanding biolimus-eluting conical V-shape stent, specifically designed to treat “easily” coronary artery bifurcation lesions, with reported favorable long-term clinical results in stable patients compared to a provisional technique. We report for the first time the feasibility to use this device in a case of “true double coronary bifurcation lesion” occurred in the context of acute coronary syndrome. Moreover, we reviewed studies with bifurcation dedicated devices and available cases of “true double bifurcation lesions” underlying advantages/disadvantages of using one device over the others during acute coronary syndrome.

Article

Background and aims: Reduction of left ventricular mass index (LVMi) during antihypertensive treatment is less likely to occur in obese subjects. The aim of the study was to assess whether weight loss influences reduction of LVMi in treated, obese, hypertensive patients. Methods and results: From the Campania Salute Network registry, we identified 1546 obese hypertensive patients (50 ± 9 years, 43% women) with more than 12 months follow-up. Echocardiographic reduction of LVMi was considered as achievement of normal values (<47 g/m ^2.7 in women or <50 g/m ^2.7 in men) or a reduction of ≥10% during follow-up. Weight loss was considered as ≥5% reduction in body weight, and occurred in 403 patients (26%) during a median follow-up of 50 months (IQrange:31–93). Median weight loss was 8.6% (IQrange:6.5–12). Patients with weight loss had higher baseline body mass index (p < 0.05), while there was no difference in age, sex, duration of hypertension, prevalence of diabetes, metabolic syndrome and average blood pressure during follow-up. During follow-up, 152 patients (9.8%) exhibited reduction of LVMi. Reduction of LVMi was more frequent (12.9% vs 9.1%, p < 0.030) in patients losing weight than in those who did not. In logistic regression analysis, weight loss was associated with reduction of left ventricular mass index (OR 1.51 [95%CI 1.02–2.23], p = 0.039), independent of significant associations with younger age, lower average systolic blood pressure during follow-up, longer follow-up time and higher LVMi at baseline. Conclusion: In treated obese hypertensive patients, weight loss during follow-up promotes significant reduction of LVMi, independent of baseline characteristics and blood pressure control.

Article

Background and aim: In autosomal dominant polycystic kidney disease (ADPKD) cardiac abnormalities have been observed before the onset of hypertension or renal dysfunction. We sought to characterize, in ADPKD patients, left ventricular (LV) function and its changes after somatostatin-analogue octreotide-LAR treatment. Methods: In a 1:1:1 cross-sectional study, we evaluated LV function by speckle-tracking echocardiography in 34 ADPKD patients from one ALADIN-trial center and in 34 age- and gender-matched healthy controls and 34 equally-matched renal controls with non-cystic chronic kidney disease. Changes in LV function were compared in the 16 and 18 ADPKD patients originally randomized to 3 year-treatment with octreotide-LAR or placebo, respectively. Results: LV twist and untwisting rates were lower in ADPKD patients that in healthy or renal controls (6.1 ± 2.6° vs. 11.1 ± 2.1° and 10.2 ± 3.7°; −49.5 ± 18.1°/s vs. −79.8 ± 12.2°/s and −84.3 ± 25.9°/s, respectively, all p < 0.001). The correlation between LV mass or diastolic BP and untwisting rate was positive in ADPKD patients (r = 0.38, p = 0.025 and r = 0.44, p = 0.011, respectively), not significant in healthy controls and negative in renal controls (r = −0.38; p = 0.023 and r = −0.40, p = 0.012, respectively. LV untwisting rate improved from −49.9 ± 18.6°/s to −70.3 ± 27.5°/s with octreotide-LAR, but did not change with placebo (p = 0.027 for treatment effect). At adjusted linear regression analysis, octreotide-LAR therapy emerged as the only independent predictor of untwisting rate improvement at final visit [beta coefficient −0.504 (95% CI −46.905–−6.367), p = 0.014]. Conclusions: In ADPKD patients LV function is early impaired. Somatostatin-analogue therapy might help in preventing or ameliorating LV dysfunction in this population. Clinical Trial Registration http://www.clinicaltrials.gov, NCT0030928.

Data paper • Open Access

In this article, we report anthropometric, clinical and laboratory data from Autosomal Dominant Polycystic Kidney Disease (ADPKD) patients with mild to moderate renal dysfunction and normal LV ejection fraction and from age- and sex-matched healthy controls and renal controls. Factors influencing LV untwisting rate in the group of ADPKD patients are also reported. For further interpretation and discussion please refer to the research article “Left ventricular dysfunction in ADPKD and effects of Octreotide-LAR: a cross-sectional and longitudinal sub study of the ALADIN trial” (Spinelli et al., 2018) [1].

Article

Introduction: Platelets activation/aggregation with subsequent thrombus formation is the main event in the pathophysiology of acute coronary syndrome. Once activated, platelets show an extensive cytoskeleton rearrangement that leads to recruitment of additional platelets to finally cause haemostatic plug formation. Thus, the cytoskeleton plays a pivotal role in this phenomenon. Colchicine (COLC) is an anti-inflammatory drug proven to reduce major cardiovascular events in patients with coronary artery disease. The molecular mechanisms by which COLC exerts these protective effects remain partially still unknown. Since COLC causes disruption of tubulin, a component of cell cytoskeleton, we investigated whether this drug might interfere with platelet aggregation by acting on cytoskeleton rearrangement. Methods and results: Platelets isolated from healthy volunteers were activated with Adenosine Diphosphate (ADP, 20 μM) Collagen (COLL, 60 μg/ml) and Thrombin Activating Receptor Peptide (TRAP 25 μM) with/without COLC 10 μM pretreatment. After stimulus, aggregation was measured by light aggregometry overtime. Microtubules structure was assessed by immunohistochemistry and key proteins involved in regulation of actin-filament assembly and contractility such as Myosin Phosphatase Targeting subunit (MYPT), LIM domain kinase 1(LIMK1) and cofilin were evaluated by Western Blot analysis. Colchicine pretreatment significantly blunted ADP/COLL/TRAP-induced platelet aggregation (up to 40%). COLC effects appeared mediated by microtubules depolymerization and cytoskeleton disarrangement associated to inactivation of MYPT and LIMK1 that finally interfered with cofilin activity. Conclusions: Our data indicate that colchicine exerts anti-platelet effects in vitro via inhibition of key proteins involved in cytoskeleton rearrangement, suggesting that its beneficial cardiovascular properties may be due, at least in part, to an inhibitory effect of platelet activity.

Article

Background: Left atrial (LA) volume is a predictor of outcome in hypertension. It is unclear whether or not this effect depends on coexisting target organ damage (TOD). Purpose: To investigate whether LA volume predicts outcome independently of TOD [left ventricular (LV) hypertrophy (LVH) and/or carotid plaque] in a registry of hypertensive treated patients. Methods: From the Campania Salute Network registry, we selected 5844 young adult hypertensive patients <65 years old (mean age 50 ± 9 years, 41% women, 8% diabetic) without prevalent CV or valvular heart disease more than mild, with normal LV ejection fraction, stage III or less CKD and available follow-up. LA volume was estimated from LA diameter applying a validated nonlinear equation, and indexed to body height in meters to the second power (eLAVI). Composite fatal and non-fatal stroke, myocardial infarction, sudden cardiac death, heart failure, TIA, myocardial revascularization, de novo angina, carotid stenting or atrial fibrillation (AF) were adjudicated as incident CV events. Results: 565 (10%) patients exhibited dilated initial eLAVI. During a median follow-up of 49 months, 233 patients developed CV events. Multivariable Cox regression analysis, demonstrated that dilated eLAVI increased risk of incident composite CV events (HR 1.90, 95%CI 1.26–2.88, p = 0.002), independently of significant effect of older age, male sex, presence LVH and carotid plaque. Conclusions In middle aged, treated hypertensive patients, dilated eLAVI is associated with adverse CV risk profile and is a predictor of CV events independently of other markers of TOD. LA dilatation should be considered as a TOD.

Article

Background and aims: Circulating uric acid (UA) is positively associated with body mass index (BMI), blood glucose, blood pressure (BP), markers of inflammation, and altered lipid profile. UA has also anti-oxidative properties which might be beneficial for cardiovascular (CV) system. It is still debated whether or not UA is independently associated with increased CV morbidity and/or mortality. Methods and results: We studied prognostic impact of UA in 8833 hypertensive adults (mean age 53 ± 12 yrs, 3857 women) from the Campania Salute Network, without prevalent CV disease and more than stage 3 CKD. We calculated standardized UA Z-score, adjusted for age, sex, glomerular filtration rate, and BMI. Low and high UA and UA Z-score quartiles were compared to the 2 middle quartiles assumed to be “normal”. Prevalence of obesity and diabetes was higher in low and high than in normal UA Z-score group (all p < 0.001). Systolic BP, left ventricular mass, carotid intima thickness were significantly higher and ejection fraction was reduced in the presence of high UA Z-score (all p < 0.001). Over 33-months average follow-up, incident major CV end-points (MACE) were not significantly different among low, normal and high UA or UA Z-score. In the latter analysis, however, incident MACE tended to be more frequent in the low than the high UA Z-score. Despite the results of multivariable analyses, the effect of less aggressive therapy in low UA Z-score cannot be excluded with certainty. Conclusion: In treated hypertensive patients, high levels of UA normalized for major biological determinants do not independently predict CV outcome. ClinicalTrials.gov Identifier: NCT02211365.

Review

Current evidence shows that cholesterol management either reduces the likelihood of cardiovascular disease (CVD) or slows down its progression. Hence, it is important that all health professionals make appropriate use of all the available intervention strategies to control risk factors: from dietary improvement and positive lifestyle changes to the use of functional foods, food supplements, and drugs. This review examines the effect of the most frequently occurring cholesterol-lowering substances in functional foods or in supplements across Europe, namely plant sterols and stanols, monacolin K found in red yeast rice, berberine and beta-glucans. We conclude that currently available supplements and functional foods can effectively reduce plasma LDL cholesterol levels by about 5 to 25%, either alone or in combination. Suitable candidates for these products are mainly individuals at low absolute cardiovascular risk at a young age or according to classic algorithms. Of note, despite being freely available for purchase, these products should be used following shared agreement between the physician and the patient (“concordance”).

Article

Background: Collaterals in patients with coronary artery disease (CAD) limit myocardial infarction and improve survival. Macrophage migration inhibitory factor (MIF) might play a role in collateral development. We aimed this study to evaluate the association of Macrophage migration Inhibitory Factor (MIF) with the extent of collateralization in patients with coronary occlusion. Methods and results: We consecutively enrolled: a) 40 patients undergoing PCI of a chronic coronary total occlusion (CTO); b) 26 patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI (pPCI) of the infarct-related artery (IRA); c) 12 control patients undergoing angiography without significant coronary artery disease (CTRL). CTO patients were grouped in high (HCG) or low collateralization group (LCG). STEMI patients were grouped in COLL+ or COLL− group depending on the presence of collaterals to the IRA. Blood sampling was performed from the arterial sheath (SYSTEMIC), and distal to the occlusion (LOCAL). SYSTEMIC and LOCAL levels were significantly different between the 3 groups. A progressive increase in MIF ratio (defined as: % (LOCAL–SYSTEMIC)/SYSTEMIC) was observed (CTRL: −0.5[−23;28] vs. CTO: 4[−19;32] vs. STEMI: 55[37;87], p < 0.01). In CTO, MIF ratio was significantly higher in HCG vs. LCG (68 [45;120] vs. 46 [29;66], p = 0.02). In STEMI, MIF ratio was not different between COLL+ and COLL− patients; however, in COLL+, LOCAL was significantly higher as compared with SYSTEMIC (83 ng/ml [63;100] vs. 67 ng/ml [40;79], p = 0.04). Conclusions: Local MIF is significantly associated with the extent of collateralization in both acute and chronic total coronary occlusions.

Article • Open Access

Background: In general, women have lower risk for cardiovascular disease. We tested whether this sex-specific protection persists also in the presence of hypertensive left ventricular hypertrophy (LVH). Methods: 12,329 women and men with hypertension and free from prevalent cardiovascular disease enrolled in the prospective Campania Salute Network registry were followed over a median of 4.1 years. Subjects were grouped according to the absence or the presence of LVH identified by echocardiography using validated sex-specific cut-off values of LV mass index (> 47 g/m^2.7 in women and > 50 g/m^2.7 in men). Main outcome was major cardiovascular events (MACE; combined acute coronary syndromes, stroke, hospitalization for heart failure and incident atrial fibrillation). Results: The cardiovascular risk profile accompanying LVH did not differ between sexes, but presence of obesity and diabetes carried higher probability for LVH in women, and LVH was more prevalent in women than men (43.4 vs. 32.1%, p < 0.001). Among patients without LVH (n = 7764), women had a 35% lower hazard rate (HR) for MACE (n = 179) than men (95% confidence interval [CI] 0.44–0.96, p = 0.031) in Cox regression analysis adjusting for cardiovascular risk factors and antihypertensive treatment during follow up. In contrast, among patients with LVH (n = 4565), women had a similar HR for MACE as men (HR 0.94 [95% CI 0.69–1.30], p = 0.720). Conclusion: This study demonstrates that presence of LVH in hypertension offsets the female sex-protection in cardiovascular risk. Thus among hypertensive subjects with LVH, women and men have comparable cardiovascular risk.