Incidence of new-onset hypertension before, during, and after the COVID-19 pandemic: a 7-year longitudinal cohort study in a large population.

BACKGROUND: While the augmented incidence of diabetes after COVID-19 has been widely confirmed, controversial results are available on the risk of developing hypertension during the COVID-19 pandemic. METHODS: We designed a longitudinal cohort study to analyze a closed cohort followed up over a 7-year period, i.e., 3 years before and 3 years during the COVID-19 pandemic, and during 2023, when the pandemic was declared to be over. We analyzed medical records of more than 200,000 adults obtained from a cooperative of primary physicians from January 1, 2017, to December 31, 2023. The main outcome was the new diagnosis of hypertension. RESULTS: We evaluated 202,163 individuals in the pre-pandemic years and 190,743 in the pandemic years, totaling 206,857 when including 2023 data. The incidence rate of new hypertension was 2.11 (95% C.I. 2.08-2.15) per 100 person-years in the years 2017-2019, increasing to 5.20 (95% C.I. 5.14-5.26) in the period 2020-2022 (RR = 2.46), and to 6.76 (95% C.I. 6.64-6.88) in 2023. The marked difference in trends between the first and the two successive observation periods was substantiated by the fitted regression lines of two Poisson models conducted on the monthly log-incidence of hypertension. CONCLUSIONS: We detected a significant increase in new-onset hypertension during the COVID-19 pandemic, which at the end of the observation period affected ~ 20% of the studied cohort, a percentage higher than the diagnosis of COVID-19 infection within the same time frame. This observation suggests that increased attention to hypertension screening should not be limited to individuals who are aware of having contracted the infection but should be extended to the entire population.

Long-Lasting Control of LDL Cholesterol Induces a 40% Reduction in the Incidence of Cardiovascular Events: New Insights from a 7-Year Study.

Recent studies have yielded controversial results on the long-term effects of statins on the risk of cardiovascular (CV) events. To fill this knowledge gap, we assessed the relationship between low-density lipoprotein cholesterol (LDL-C) levels and CV events in hypertensive patients without previous CV events and naïve to antidyslipidemic treatment within the "Campania Salute Network" in Southern Italy. We studied 725 hypertensive patients with a mean follow-up of 85.4 ± 25.7 months. We stratified our cohort into three groups based on LDL cholesterol (LDL-C) levels in mg/dl: group 1) patients showing during the follow-up a mean LDL-C value ≤100 mg/dl in absence of statin therapy; group 2) statin-treated patients with LDL ≤100 mg/dl; and group 3) patients with LDL-C >100 mg/dl. No significant difference among the groups was observed in terms of demographic and clinical characteristics and medications. The incidence of first CV events was 5.7% in group 1, 6.0% in group 2, and 11.9% in group 3 (P < 0.05 vs. group 1 and group 2). A stable long-term satisfactory control of LDL-C plasma concentration (≤100 mg/dl) reduced the incidence of major CV events from one event every 58.6 patients per year to one event every 115.9 patients per year. These findings were confirmed in a Cox regression analysis, adjusting for potential confounding factors. Collectively, our data demonstrate that a 7-year stable control of LDL-C reduces the incidence of CV events by 40%. SIGNIFICANCE STATEMENT: There are several discrepancies between Mendelian studies and other investigations concerning the actual effects of reduction of plasma concentration of low-density lipoprotein (LDL) cholesterol on the incidence of major cardiovascular events. Taken together, our data in nondiabetic subjects show that a 7-year stable control of LDL cholesterol induces a ∼40% reduction of the incidence of cardiovascular events.

Achieving a Systolic Blood Pressure Below 130 mmHg Reduces the Incidence of Cardiovascular Events in Hypertensive Patients with Echocardiographic Left Ventricular Hypertrophy.

Background: Recent reports have evidenced an increased mortality rate in hypertensive patients with electrocardiographic left ventricular hypertrophy (ECG-LVH) achieving systolic blood pressure (SBP) <130 mmHg. However, to the best of our knowledge, the actual effects of blood pressure reduction to the ≤130/80 mmHg target on the incidence of cardiovascular (CV) events have never been determined in hypertensive patients with a diagnosis of left ventricular hypertrophy based on echocardiographic criteria (Echo-LVH). Methods: To fill this long-standing knowledge gap, we harnessed a population of 9511 hypertensive patients, followed-up for 33.6 [interquartile range 7.9-72.7] months. The population was divided into six groups according to the average SBP achieved during the follow-up (≤130, 130-139, and ≥140 mmHg) and absence/presence of Echo-LVH. The primary endpoint was a composite of fatal or nonfatal myocardial infarction and stroke, sudden cardiac death, heart failure requiring hospitalization, revascularization, and carotid stenting. Secondary endpoints included atrial fibrillation and transient ischemic attack. Results: During the follow-up, achieved SBP and diastolic blood pressure (DBP) were comparable between patients with and without Echo-LVH. Strikingly, the rates of primary and secondary endpoints were significantly higher in patients with Echo-LVH and SBP >130 mmHg, reaching the highest values in the Echo-LVH group with SBP ≥140 mmHg. By separate Cox multivariable regressions, after adjusting for potential confounders, both primary and secondary endpoints were significantly associated with SBP ≥140 mmHg and Echo-LVH. Instead, DBP reduction ≤80 mmHg was associated with a significant increased rate of secondary events. Conclusions: In hypertensive patients with Echo-LVH, achieving an average in-treatment SBP target ≤130 mmHg has a beneficial prognostic impact on incidence of CV events. SIGNIFICANCE STATEMENT: Contrary to recent findings, achieving in-treatment SBP ≤130 mmHg lowers the incidence of CV events in hypertensive patients with Echo-LVH. However, reducing DBP ≤80 mmHg is linked to increased CV complications. Cox multivariable regression models, considering potential confounders, reveal that the rate of hard and soft CV events is significantly associated with Echo-LVH and SBP ≥140 mmHg. Our data indicate that therapeutic strategies for Echo-LVH patients should target SBP ≤130 mmHg while avoiding lowering DBP ≤80 mmHg.

Pro-inflammatory cells sustain leukemic clonal expansion in T-cell large granular lymphocyte leukemia.

T-cell large granular lymphocyte leukemia (T-LGLL) is a chronic lymphoproliferative disorder characterized by the clonal expansion of T-cell large granular lymphocytes (T-LGL). Immunophenotypic and genotypic features contribute to discriminate symptomatic (CD8+ STAT3-mutated T-LGLL) from clinically indolent patients, this latter group including CD8+ wildtype (wt), CD4+ STAT5B-mutated and wt cases. T-LGL lymphoproliferation is sustained both by somatic gain-offunction mutations (i.e., STAT3 and STAT5B) and by pro-inflammatory cytokines, but little information is available on the activity of T-LGLL non-leukemic cells. In this study, we characterized pro-inflammatory cells in the peripheral blood of T-LGLL patients and analyzed their role in supporting the leukemic growth. In symptomatic patients we found that cell populations not belonging to the leukemic component showed a discrete pro-inflammatory pattern. In particular, CD8+ STAT3-mutated cases showed a skewed Th17/Treg ratio and an abnormal distribution of monocyte populations characterized by increased intermediate and non-classical monocytes. We also demonstrated that monocytes released high levels of interleukin-6 after CCL5 stimulation, a chemokine specifically expressed only by leukemic LGL. Conversely, in asymptomatic cases an altered distribution of monocyte populations was not detected. Moreover, T-LGLL patients' monocytes showed abnormal activation of signaling pathways, further supporting the different pathogenic role of monocytes in patients in discrete clinical settings. Altogether, our data contribute to deepening the knowledge on the different cell subtypes in T-LGLL, focusing particularly on non-leukemic cell populations and thus offering the rationale for new therapeutic strategies.

Focal adhesion kinase activation by calcium-dependent calpain is involved in chronic lymphocytic leukaemia cell aggressiveness.

Signalling events downstream the B-cell receptor (BCR) are central for the survival and progression of chronic lymphocytic leukaemia (CLL) cells. Focal adhesion kinase (FAK), regulated through calpain, interacts with molecules of BCR signalling, cytoskeletal modelling and disease progression, such as Src/Lyn, cortactin and HS1. Hypothesizing that FAK might play a key role in CLL pathogenesis, we observed a down-modulation of FAK whole form, associated with FAK cleavage due to calpain activity upon BCR stimulation. Patients, whose cells were able to release Ca++ after BCR stimulation, had less amount of full-length FAK, which translated into a higher presence of cleaved/activated form of the protein phosphorylated at Y397, these features being mostly shown by immunoglobulin heavy chain (IGHV)-unmutated poor-prognosis patients. Moreover, we found that cortactin and HS1 proteins were overexpressed in those cells, suggesting a possible interplay with FAK. Treatment with the FAK inhibitor Defactinib was able to induce apoptosis in CLL cells. In conclusion, the malignant phenotype in unfavourable-prognosis patients seems to be encouraged by the overexpression of cortactin and HS1, that, together with FAK, may be involved in a druggable pathogenetic pathway in CLL.

L-Arginine in diabetes: clinical and preclinical evidence.

L-Arginine (L-Arg), is a semi-essential amino acid involved in the formation of nitric oxide. The functional relevance of L-Arg in diabetes mellitus has been evaluated both in animal models and in human subjects. In the literature there are several lines of evidence indicating that L-Arg has beneficial effects in diabetes and numerous studies advocate its administration to attenuate glucose intolerance in diabetic patients. Here we present a comprehensive overview of the main studies exploring the effects of L-Arg in diabetes, including preclinical and clinical reports on this topic.

Beneficial effects of L-Arginine in patients hospitalized for COVID-19: New insights from a randomized clinical trial.

We have recently demonstrated in a double-blind randomized trial the beneficial effects of L-Arginine in patients hospitalized for COVID-19. We hypothesize that one of the mechanisms underlying the favorable effects of L-Arginine is its action on inflammatory cytokines. To verify our hypothesis, we measured longitudinal plasma levels of pro-inflammatory and anti-inflammatory cytokines implied in the pathophysiology of COVID-19 in patients randomized to receive oral L-Arginine or placebo. The study was successfully completed by 169 patients. Patients in the L-Arginine arm had a reduced respiratory support evaluated at 10 and 20 days; moreover, the time to hospital discharge was significantly shorter in the L-Arginine group. The assessment of circulating cytokines revealed that L-Arginine significantly reduced the circulating levels of pro-inflammatory IL-2, IL-6, and IFN-γ and increased the levels of the anti-inflammatory IL-10. Taken together, these findings indicate that adding L-Arginine to standard therapy in COVID-19 patients markedly reduces the need of respiratory support and the duration of in-hospital stay; moreover, L-Arginine significantly regulates circulating levels of pro-inflammatory and anti-inflammatory cytokines.

Therapeutic concordance improves blood pressure control in patients with resistant hypertension.

INTRODUCTION: An empathetic approach may be particularly useful in patients with therapy-resistant hypertension (TRH), defined as the failure to achieve target blood pressure (BP) despite a maximal doses of 3 antihypertensive drugs including a diuretic. However, the effects of therapeutic concordance have not been determined in hypertensive patients. METHODS: We designed a study to explore the impact of therapeutic concordance in patients with TRH, who were included in an intervention arm based on a protocol in which trained personnel periodically verified the pharmacological regimen of these patients. RESULTS: From a cohort of 5331 hypertensive patients followed-up for 77.64 ± 34.44 months, 886 subjects were found to have TRH; of these, 322 had apparent TRH (aTRH: uncontrolled office BP but optimal home BP) and 285 refused to participate in a second follow-up study, yielding a population of 279 patients with true TRH (tTRH). These tTRH patients were followed according to the therapeutic concordance protocol for 91.91 ± 54.7 months, revealing that 210 patients (75.27%) remained with uncontrolled BP (uncontrolled tTRH, Group I) while 69 patients (24.73%) reached an optimal BP control (average BP <140/90 mmHg in at least 50% of follow-up visits, Group II). Strikingly, at the end of the second follow-up, the percentage of patients displaying a decline in kidney function was significantly smaller in Group II than in Group I (8.5% vs 23.4%, p < 0.012). CONCLUSIONS: Taken together, our findings indicate for the first time that therapeutic concordance significantly improves the outcome of antihypertensive treatment in a population of patients with TRH.

SIRT1 pharmacological activation rescues vascular dysfunction and prevents thrombosis in MTHFR deficiency.

Beyond well-assessed risk factors, cardiovascular events could be also associated with the presence of epigenetic and genetic alterations, such as the methylenetetrahydrofolate-reductase (MTHFR) C677T polymorphism. This gene variant is related to increased circulating levels of homocysteine (Hcy) and cardiovascular risk. However, heterozygous carriers have an augmented risk of cardiovascular accidents independently from normal Hcy levels, suggesting the presence of additional deregulated processes in MTHFR C677T carriers. Here, we hypothesize that targeting Sirtuin 1 (SIRT1) could be an alternative mechanism to control the cardiovascular risk associated to MTHFR deficiency condition. Flow Mediated Dilatation (FMD) and light transmission aggregometry assay were performed in subjects carrying MTHFR C677T allele after administration of resveratrol, the most powerful natural clinical usable compound that owns SIRT1 activating properties. MTHFR C677T carriers with normal Hcy levels revealed endothelial dysfunction and enhanced platelet aggregation associated with SIRT1 downregulation. SIRT1 activity stimulation by resveratrol intake was able to override these abnormalities without affecting Hcy levels. Impaired endothelial function, bleeding time, and wire-induced thrombus formation were rescued in a heterozygous Mthfr-deficient (Mthfr+/-) mouse model after resveratrol treatment. Using a cell-based high-throughput multiplexed screening (HTS) assay, a novel selective synthetic SIRT1 activator, namely ISIDE11, was identified. Ex vivo and in vivo treatment of Mthfr+/- mice with ISIDE11 rescues endothelial vasorelaxation and reduces wire-induced thrombus formation, effects that were abolished by SIRT1 inhibitor. Moreover, platelets from MTHFR C677T allele carriers treated with ISIDE11 showed normalization of their typical hyper-reactivity. These results candidate SIRT1 activation as a new therapeutic strategy to contain cardio and cerebrovascular events in MTHFR carriers.

L-Arginine Enhances the Effects of Cardiac Rehabilitation on Physical Performance: New Insights for Managing Cardiovascular Patients During the COVID-19 Pandemic.

Cardiac rehabilitation (CR) following acute myocardial infarction (AMI) improves physical capacities and decreases hospitalizations and cardiovascular mortality. L-arginine is the substrate used by nitric oxide (NO) synthase to generate NO and it has been shown to exert its beneficial effects on endothelium driving vasodilatation, reducing inflammation, and ameliorating physical function. We hypothesized that L-arginine could enhance physical capacities in patients who underwent CR after AMI. We designed a study aimed to assess the effects of L-arginine administration on the physical capacity of patients who underwent coronary revascularization after AMI. The trial was carried out amid the COVID-19 pandemic. Patients were assigned, with a 2:1 ratio, to add to their standard therapy one bottle containing 1.66 g of L-arginine or one bottle of identical aspect apart from not containing L-arginine, twice a day orally for 3 weeks. Patients performed a 6-minute walking test (6MWT), and their Borg modified 0-10 rating of perceived exertion (BRPE) was assessed before starting and at the end of the treatment. Seventy-five patients receiving L-arginine, and 35 receiving placebo successfully completed the study. The 6MWT distance increased significantly in the L-arginine group compared with both baseline and placebo (P < 0.0001). Additionally, we observed a significant improvement in the BRPE in patients treated with L-arginine but not in the placebo group. Taken together, our data indicate that L-arginine potentiates the response to CR independently of age, sex, baseline functional capacity, and comorbid conditions. SIGNIFICANCE STATEMENT: This study shows for the first time that oral supplementation of L-arginine potentiates the response to cardiac rehabilitation after myocardial infarction and cardiac revascularization. Indeed, we observed a significant improvement in two fundamental parameters, namely, the 6-minute walking test and the Borg modified 0-10 rating of perceived exertion. Strikingly, the beneficial effects of L-arginine were independent of age, sex, comorbid conditions, and baseline functional capacity.

Combining L-Arginine with vitamin C improves long-COVID symptoms: The LINCOLN Survey.

INTRODUCTION: Recent evidence suggests that oxidative stress and endothelial dysfunction play critical roles in the pathophysiology of COVID-19 and Long-COVID. We hypothesized that a supplementation combining L-Arginine (to improve endothelial function) and Vitamin C (to reduce oxidation) could have favorable effects on Long-COVID symptoms. METHODS: We designed a survey (LINCOLN: L-Arginine and Vitamin C improves Long-COVID), assessing several symptoms that have been associated with Long-COVID to be administered nationwide to COVID-19 survivors; the survey also included effort perception, measured using the Borg scale. Patients receiving the survey were divided in two groups, with a 2:1 ratio: the first group included patients that received L-Arginine + Vitamin C, whereas the second group received a multivitamin combination (alternative treatment). RESULTS: 1390 patients successfully completed the survey. Following a 30-day treatment in both groups, the survey revealed that patients in the L-Arginine + Vitamin C treatment arm had significantly lower scores compared to patients who had received the multivitamin combination. There were no other significant differences between the two groups. When examining effort perception, we observed a significantly lower value (p < 0.0001) in patients receiving L-Arginine + Vitamin C compared to the alternative-treatment arm. CONCLUSIONS: Our survey indicates that the supplementation with L-Arginine + Vitamin C has beneficial effects in Long-COVID, in terms of attenuating its typical symptoms and improving effort perception.

Single systemic transfer of a human gene associated with exceptional longevity halts the progression of atherosclerosis and inflammation in ApoE knockout mice through a CXCR4-mediated mechanism.

AIMS: Here, we aimed to determine the therapeutic effect of longevity-associated variant (LAV)-BPIFB4 gene therapy on atherosclerosis. METHODS AND RESULTS: ApoE knockout mice (ApoE-/-) fed a high-fat diet were randomly allocated to receive LAV-BPIFB4, wild-type (WT)-BPIFB4, or empty vector via adeno-associated viral vector injection. The primary endpoints of the study were to assess (i) vascular reactivity and (ii) atherosclerotic disease severity, by Echo-Doppler imaging, histology and ultrastructural analysis. Moreover, we assessed the capacity of the LAV-BPIFB4 protein to shift monocyte-derived macrophages of atherosclerotic mice and patients towards an anti-inflammatory phenotype. LAV-BPIFB4 gene therapy rescued endothelial function of mesenteric and femoral arteries from ApoE-/- mice; this effect was blunted by AMD3100, a CXC chemokine receptor type 4 (CXCR4) inhibitor. LAV-BPIFB4-treated mice showed a CXCR4-mediated shift in the balance between Ly6Chigh/Ly6Clow monocytes and M2/M1 macrophages, along with decreased T cell proliferation and elevated circulating levels of interleukins IL-23 and IL-27. In vitro conditioning with LAV-BPIFB4 protein of macrophages from atherosclerotic patients resulted in a CXCR4-dependent M2 polarization phenotype. Furthermore, LAV-BPIFB4 treatment of arteries explanted from atherosclerotic patients increased the release of atheroprotective IL-33, while inhibiting the release of pro-inflammatory IL-1ß, inducing endothelial nitric oxide synthase phosphorylation and restoring endothelial function. Finally, significantly lower plasma BPIFB4 was detected in patients with pathological carotid stenosis (>25%) and intima media thickness >2 mm. CONCLUSION: Transfer of the LAV of BPIFB4 reduces the atherogenic process and skews macrophages towards an M2-resolving phenotype through modulation of CXCR4, thus opening up novel therapeutic possibilities in cardiovascular disease.

Ibrutinib in relapsed hairy cell leukemia variant: A case report and review of the literature.

Hairy cell leukemia variant (HCLv) is a provisional disease in the 2016 WHO classification of lymphomas, characterized by unfavorable prognosis and early relapse following conventional purine analog-based regimens. In this study, we report 2 patients with relapsed HCLv treated with ibrutinib. The first patient achieved a partial response following ibrutinib treatment and received the drug for 16 months, without severe adverse events. However, at disease progression venetoclax was not clinically active. The second patient discontinued the drug early due to intolerance. Ibrutinib was active in our patients with HCLv and deserve further investigations.

HSP70/HSF1 axis, regulated via a PI3K/AKT pathway, is a druggable target in chronic lymphocytic leukemia.

Considering the role played by the heat shock protein of 70 kDa (HSP70) in cancer, we characterized this protein and its major regulator, the heat shock factor 1 (HSF1), in chronic lymphocytic leukemia (CLL). We found both HSP70 and HSF1 overexpressed in CLL patients, correlated to poor prognosis and abnormally localized in the nucleus of leukemic B cells. The two proteins were strictly correlated each other and their levels decreased consensually in those patients responding to in vivo therapeutic regimens. HSP70 and HSF1 inhibition was proved to be effective in inducing a dose-dependent in vitro apoptosis of CLL B cells. Considering that HSF1 is finely regulated by kinases belonging to pathways triggered by rat sarcoma (RAS), we benefited from a previous proteomic study performed in CLL patients aiming to assess the activation/expression of key signaling proteins. We found that patients showing high levels of HSP70 also expressed high Akt-Ser473, thus activating HSF1. Inhibition of PI3K, which activates AKT, reduced the expression of HSF1 and HSP70. By contrast, HSP70-low patients displayed high activation of MEK1/2 and ERK1/2, known to negatively regulate HSF1. These data demonstrate that the HSP70 expression is regulated by the modulation of HSF1 activity through the activation of RAS-regulated pathways and suggest the HSP70/HSF1 interplay as an interesting target for antileukemic therapies. Finally, inhibition of PI3K, that activates AKT, reduced the expression of HSF1 and HSP70.

Anticancer Drug-Related Nonvalvular Atrial Fibrillation: Challenges in Management and Antithrombotic Strategies.

Cancer patients may experience nonvalvular atrial fibrillation (AF) as a manifestation of cardiotoxicity. AF may be a direct effect of a neoplasm or, more often, appear as a postsurgical complication, especially after thoracic surgery. AF may also develop as a consequence of anticancer therapy (chemotherapy or radiotherapy), a condition probably underestimated. Cancer patients with AF require a multidisciplinary approach involving oncologists/hematologists, cardiologists, and coagulation experts. An echocardiogram should be performed to detect possible abnormalities of left ventricular systolic and diastolic function, as well as left atrial dilation and the existence of valvular heart disease, to determine pretest probability of sinus rhythm restoration, and identify the best treatment. The choice of antiarrhythmic treatment in cancer patients may be difficult because scanty information is available on the interactions between anticancer agents and antiarrhythmic drugs. A careful evaluation of the antithrombotic strategy with the best efficacy/safety ratio is always needed. The use of vitamin K antagonists (VKAs) may be problematic because of the unpredictable therapeutic response and high bleeding risk in patients with active cancer who are undergoing chemotherapy and who may experience thrombocytopenia and changes in renal or hepatic function. Low molecular weight heparins (in particular for short and intermediate periods) and non-VKA oral anticoagulants (NOACs) should be preferred. However, the possible pharmacological interactions of NOACs with both anticancer and antiarrhythmic drugs should be considered. Based on all these considerations, antiarrhythmic and anticoagulant therapy for AF should be tailored individually for each patient.

Effects of a new nutraceutical combination on cognitive function in hypertensive patients.

BACKGROUND: Chronic increased arterial blood pressure has been associated with executive dysfunction, slowing of attention and mental processing speed, and later with memory deficits. Due to the absence of a concrete therapeutic approach to this pathophysiological process, in the last decades there has been an increasing interest in the use of nutraceuticals, especially those with antioxidant properties, which own strong neuroprotective potential, that may help to improve cognitive function and to delay the onset of dementia. RESULTS: We evaluated the effects of the treatment with a new nutraceutical preparation containing different molecules with potent antioxidant properties (AkP05, IzzeK®) and placebo on a cohort of thirty-six hypertensive patients. At baseline, neuropsychological evaluation, arterial stiffness and biochemical parameters of the subjects were comparable. After 6 months of treatment, there was a significant reduction of the augmentation index in the AkP05-treated group. Moreover, the measurement of cognitive function, evaluated with MoCA test and Word Match Testing, showed a significant improvement in patients receiving the active treatment. In addition, the group treated with nutraceutical reached a better Stroop test score, while subjects that received placebo did not showed any improvement. Finally, a positive relationship between SBP variation and the psychometric assessment with the EQ-VAS scale was observed only in the active treatment group. CONCLUSIONS: In this study, we demonstrated that the therapy with a new nutraceutical preparation is able to significantly increase the scores of important neuropsychological tests in hypertensive patients already on satisfactory blood pressure control. Although future studies are needed to better characterize the molecular mechanisms involved, these results candidate the new nutraceutical combination as a possible therapeutic strategy to support the cerebrovascular functions and delay the onset of dementia in hypertensive patients.