Santulli Lab

BACKGROUND: Recent evidence suggests that inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), a key enzyme in cholesterol biosynthesis, has beneficial effects on lipid metabolism and blood pressure (BP), but detrimental consequences on glycemia. Nutraceuticals (NUTs) containing both Monacolin K (MK) and Morus alba have been shown to be more effective in lowering lipids compared to NUT formulations containing only MK. However, the effects of these NUTs on glucose homeostasis have not been fully determined.

METHODS: To evaluate the association between LDL-C-lowering therapy and glycemia in patients receiving NUT combinations with or without Morus alba, we analyzed data from a prospective, randomized, active-treatment controlled trial (NCT02898805), which enrolled 359 patients to compare the effects of a NUT combination containing MK alone (Formulation 1, F1; n = 170) versus one containing MK and Morus alba (Formulation 1, F2; n = 189).

RESULTS: Participants in the two treatment arms (F1 vs. F2) were comparable in terms of sex, age, metabolic parameters, and BP. After 3 months, both groups experienced significant reductions in LDL-C, fasting plasma glucose, HbA1c, and HOMA index. F2 treatment led to a significantly greater reduction in glycemic levels compared to F1 treatment (b = - 16, p < 0.001). Notably, a divergent trend emerged over time: an inverse relationship between LDL-C and glycemic levels was observed in the F1 group, while a significant direct association between LDL-C and glycemic levels was detected in the F2 group (b = 0.06, p = 0.002).

CONCLUSIONS: Taken together, our findings indicate that the treatment with a NUT combination containing Morus alba simultaneously reduces plasma levels of LDL-C and glucose.

Hypertension remains a major contributor to cardiovascular and renal complications in patients with diabetes mellitus, increasing the risk of macrovascular and microvascular disease. The 2025 AHA/ACC hypertension guidelines maintain a diagnostic and treatment threshold of 130/80 mmHg, emphasizing earlier and more intensive blood pressure control to reduce cardiovascular events, stroke, heart failure, and progression of diabetic nephropathy. Evidence from clinical trials and meta-analyses supports the benefits of tighter blood pressure targets, while acknowledging potential risks such as hypotension, electrolyte disturbances, and acute kidney injury. Management strategies combine pharmacologic therapy with lifestyle interventions including dietary modification, physical activity, weight management, and smoking cessation. Individualized blood pressure targets are recommended for older or frail patients to balance safety and benefit. Home and ambulatory blood pressure monitoring are highlighted for detecting masked or nocturnal hypertension, enhancing risk stratification, and supporting treatment titration. The guidelines also emphasize integrated risk assessment and multidisciplinary management. The 2025 AHA/ACC hypertension guidelines provide an evidence-based, patient-centered framework to optimize cardiovascular and renal outcomes in patients with diabetes, promoting early intervention, individualized therapy, and comprehensive risk reduction.

Fabry disease or Anderson-Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A (GLA), leading to systemic accumulation of globotriaosyl-ceramide (Gb3). Initially described in 1898 as a dermatological condition, Fabry disease is now recognized as a progressive multisystem disorder with significant cardiac involvement. Cardiomyopathy in Fabry disease arises from Gb3 accumulation in cardiac tissue, resulting in structural changes such as fibrosis and left ventricular hypertrophy (LVH), and functional impairments including diastolic dysfunction and heart failure. The deacylated derivative, lysoGb3, serves as a biomarker of cardiac involvement. Diagnosis relies on enzyme assays, genetic testing, and advanced cardiac imaging modalities like echocardiography and cardiac MRI. Management strategies are centered around enzyme replacement therapy, and prognosis varies due to phenotypic heterogeneity and severity of disease progression. Psychological and social burdens further complicate patient care. However, underdiagnosis remains a concerning issue, particularly in individuals with unexplained cardiomyopathies. Early recognition through increased clinical awareness and genetic screening is crucial for timely intervention. Ongoing research is essential to develop new therapies targeting the genetic and metabolic roots of the disease. This systematic review comprehensively examines current evidence regarding the mechanisms, diagnosis, treatment, and prognosis of cardiomyopathy associated with Fabry disease, providing insight that may enhance clinical practice and guide future research initiatives.

Hypoxia, a condition characterized by a temporary lack of oxygen, causes mitochondrial damage, which in turn leads to endothelial dysfunction. G-protein-coupled receptor kinase 2 (GRK2) plays a key role in vascular homeostasis and remodeling, influencing endothelial function through various pathways. GRK2 moves within the cellular compartments and is linked to mitochondrial function and biogenesis, promoting ATP production and protecting against oxidative stress and cell death. The present study examined how mitochondrial GRK2 accumulation affects vascular reactivity and endothelial function in transient hypoxic conditions. Using a cloning strategy, we employed a small peptide (10aa) TAT-conjugated based on the pleckstrin homology domain of GRK2 to redirect GRK2 from the plasma membrane to the mitochondria. Mitochondrial accumulation of GRK2 increases vasodilatory responses in isolated swine artery segments, indicating potential therapeutic applications for cardiovascular disorders. Furthermore, in endothelial cells, GRK2 accumulation within mitochondria protects membrane potential, mitochondrial mass and prevents oxidative damage and cell death caused by transient hypoxia. Our findings show that GRK2 accumulation in mitochondria represents a potential therapeutic target to prevent transient hypoxia-induced damage.

This study aimed to determine whether daily low-dose aspirin reduces the risk of type 2 diabetes (T2D) associated with COVID-19. A longitudinal cohort of 200,000 adults followed from 2018 to 2022 was analyzed, comparing T2D incidence between aspirin users and non-users. Propensity score matching was used to balance the groups. The incidence of T2D was substantially lower in the aspirin group, with Cox regression showing a 52% risk reduction. Kaplan-Meier analysis confirmed a significant divergence in cumulative T2D risk after two years. This protective effect was observed both before and during the COVID-19 pandemic, with a stronger association during the pandemic period. These findings indicate that daily low-dose aspirin significantly reduces the risk of COVID-19-associated new-onset T2D, highlighting the role of inflammation in the pathogenesis of T2D triggered or unmasked by COVID-19.

BACKGROUND: Recent studies based on hospital and outpatient clinic databases have reported a decline in cancer diagnoses during the COVID-19 pandemic, an observation that has been mainly attributed to halted screenings.

METHODS: We investigated the impact of COVID-19 on cancer incidence in the Campania Region (Italy) among adults followed by their primary care physicians over a 6-year period (2017-2022). Using a single-cohort design, we employed interrupted time series (ITS) analysis to compare cancer incidence rates during the 3 years preceding the pandemic (2017-2019) with those during the three pandemic years (2020-2022).

RESULTS: We analyzed data from 212,656 individuals and found that the incidence of new cancer diagnoses rose from 14.3 to 23.1 per 1000 person-years when comparing the pre-pandemic to the COVID-19 period. ITS analysis revealed a stable trend in cancer diagnoses before the pandemic, followed by a marked increase of  8 new cases per month beginning in January 2020, with a peak observed in August 2021. Notably, diagnoses of brain and skin cancers increased by 300% in 2022 compared to 2017.

CONCLUSIONS: Taken together, these findings highlight a concerning increase in cancer diagnoses in the Campania Region during the COVID-19 pandemic, contrasting with earlier reports that pointed to a decline in cases, mostly attributed to interrupted screening services. Several indirect factors might contribute to this trend, including heightened psychosocial stress and shifts in lifestyle behaviors, as well as profound disruptions in access to and continuity of healthcare delivery.

Doxorubicin is an anthracycline chemotherapeutic that is widely used for treating various malignancies, including breast cancer, lymphomas, and sarcomas. Despite its efficacy, its clinical utility is limited by a well-documented risk of cardiotoxicity, which may manifest acutely or chronically. Doxorubicin works by intercalating DNA and inhibiting topoisomerase II, leading to DNA damage and cell death. However, this mechanism is not selective to cancer cells and can adversely affect cardiac myocytes. The introduction of doxorubicin into oncologic practice has revolutionized cancer treatment, but its cardiotoxic effects remain a significant concern. This systematic review aims to comprehensively examine the multifaceted impact of doxorubicin on cardiac structure and function through both preclinical and clinical lenses.

BACKGROUND: The long-term risk of cardiovascular (CV) events in individuals who develop new-onset type 2 diabetes (T2D) after having received statin therapy in primary prevention is mostly unknown.

METHODS: We designed a population-based cohort study in individuals without T2D and atherosclerotic CV disease (ASCVD), divided in two groups according to the presence or not of statin therapy. We also balanced the study groups for demographic and clinical factors using propensity score matching.

RESULTS: 119307 individuals without T2D and ASCVD were divided in statin users (N = 90906) or not (N = 28401) and followed-up for 70.1 ± 61.3 months. Yearly incidence of T2D rate was 0.3% in the control group and 2.2% in the statin treated group. A Cox regression analysis confirmed the association between incident T2D and statin therapy. In normotensive individuals, the presence of statin therapy led to a 2-fold risk to develop incident T2D with a HR 2.61 (95% CI 2.11-3.22, p < 0.001) which was also that of statin untreated hypertensive patients. In the hypertensive population statin therapy was associated with a HR of incident T2D of 4.62 (95% CI 3.75-5.69, p < 0.001). CV events rate, including coronary and cerebrovascular fatal and non-fatal events, was 1.9% in the statin group vs. 0.7% in the control group and a multiple regression analysis demonstrated an association between statin therapy and CV events. A further Cox regression performed only in the statin treated population revealed a significant association of CV events with age, serum creatinine levels, and incident T2D. Of note, the increased rate of new-onset T2D associated with statin use does not modify the class of CV risk of this population. All these findings were confirmed at the propensity score matched analysis.

CONCLUSIONS: Statin therapy in primary prevention is associated with a higher risk of incident T2D, especially in hypertensive patients. However, since the final CV risk of those who develop T2D during statin treatment was lower than the one required for statin prescription according to the ESC guidelines, indicating that this phenomenon does not impair the benefit in CV prevention associated with the lipid lowering effect of statins.

BACKGROUND: Delirium may develop in association with an underlying cardiovascular or cerebrovascular disease and complicates one out of three medical admissions representing a significant economic burden for healthcare systems. However, a clear relationship between delirium onset and diabetes mellitus has not been clarified. The purpose of this study was to explore the association between DM and delirium with the following aims: (a) to assess the incidence of delirium among DM patients (b) to assess the risk of delirium onset in patients with DM (c) to assess the role of anti-diabetic drugs on delirium onset.

METHODS: MEDLINE, Scopus, and Web of Science and ClinicalTrials.gov were searched from inception up to 30th of December 2024. Studies reporting the incidence of delirium in diabetic patients, delirium events in diabetic patients compared to non- diabetic patients, and the role of antidiabetic drugs on delirium development were considered.

RESULTS: The pooled incidence of delirium resulted 29% (95% CI 26.0%- 33.0% I2 = 99.6%). The OR for developing delirium resulted: 1.78 (95% CI 1.59-1.99 i2 = 88.3%) Intranasal insulin administration compared to placebo groups was characterized by a RR = 0.34 (95% CI 0.23-0.52). Metformin use compared to non-metformin use in diabetic patients was characterized by lower RR for delirium: pooled RR = 0.71 (95% CI 0.59-0.85, I2 = 84.8%).

CONCLUSIONS: The incidence of delirium in patients with diabetes is about 29% and patients with diabetes have higher odds of delirium. Chronic use of metformin, and intranasal insulin administration before surgery may offer benefits in the prevention of delirium. These findings are characterized by significant heterogeneity which hampers their interpretation. Future research for developing diabetes-specific delirium screening protocols, and evidence-based preventive interventions is needed.

Cardiac fibrosis and remodeling are critical contributors to heart failure, particularly in the context of diabetes, where hyperglycemia (HG) exacerbates pathological fibroblast activity. Despite the known cardiovascular benefits of canagliflozin (CANA), its specific effects on human cardiac fibroblasts (HCFs) under HG conditions remain unexplored. We investigated whether CANA could mitigate HG-induced detrimental responses in HCFs. Dose-response assays revealed that 100 nM CANA significantly reduced HG-induced proliferation and migration of HCFs. Furthermore, CANA attenuated mitochondrial reactive oxygen species (ROS) production, a key driver of myofibroblast differentiation, and suppressed HG-induced expression of SMAD2, a critical activator of cardiac fibroblasts. Additionally, HG disrupted calcium (Ca2+) homeostasis, which was ameliorated by CANA treatment. These findings collectively demonstrate that CANA exerts protective effects on HCFs by improving mitochondrial function, restoring Ca2+ handling, and reducing fibroblast proliferation, migration, and activation under HG conditions.

Prevention of dementia represents a public health priority. Hypertension is a risk factor for mild cognitive impairment (MCI), a precursor to progressive dementia. A great effort is underway to develop accurate and sensitive tools to detect the MCI condition in hypertensive patients. To investigate the potential association of subclinical left ventricular dysfunction expressed by the global longitudinal strain (GLS) with the MCI, defined by the Italian version of the quick mild cognitive impairment (Qmci-I). This multi-centric study included 180 consecutive hypertensive patients without medical diseases and/or drugs with known significant effects on cognition but with a not negligible comorbidity burden to avoid a possible "hyper-normality bias". The study cohort was classified into two main groups concerning the median value of the GLS. A weighted logistic regression model was employed after an inverse probability of treatment weighting (IPTW) analysis to characterize a potential association between GLS and MCI. Almost 41,1% of the whole study population was female. The mean age was 65,6 ± 7,2. 39 patients (21,7%) showed MCI. After IPTW, the GLS was significantly associated with the study endpoint (OR, 1,22; 95% CI: 1,07-1,39, P = 0.003). Our results highlight that the GLS is a potential predictor of MCI and, therefore, a valuable tool for establishing preventive strategies to arrest the progression toward a cognitive decline in hypertensive patients.

OBJECTIVE: This article presents the design, development, and implementation of a novel and innovative virtual reality (VR) simulation aimed at increasing nursing skills in identifying, managing, and deescalating workplace violence (WPV) incidents and mitigating the effects after critical incidents.

BACKGROUND: The ANA reports that 1 in 4 nurses in the United States experience workplace assault annually, highlighting the novel role of VR simulations in educating and preparing nurses to recognize, address, and minimize the impact of WPV.

METHODS: A multidisciplinary team designed and implemented a VR simulation based on real WPV incidents reported by nurses in an urban health system, enlisting a film and video company's expertise to bring scenarios to life, addressing a critical gap.

CONCLUSIONS: This article discusses the collaborative creation of simulations using VR as a novel strategy for educating nurses on identification, management, and deescalation of incidents of WPV and mitigating the effects of WPV after critical incidents.

Mitochondria serve an essential metabolic and energetic role in cellular activity, and their dysfunction has been implicated in a wide range of disorders, including cardiovascular conditions, neurodegenerative disorders, and metabolic syndromes. Mitochondria-targeted therapies, such as Elamipretide (SS-31, MTP-131, Bendavia), have consequently emerged as a topic of scientific and clinical interest. Elamipretide has a unique structure allowing for uptake in a variety of cell types and highly selective mitochondrial targeting. This mitochondria-targeting tetrapeptide selectively binds cardiolipin (CL), a lipid found in the inner mitochondrial membrane, thus stabilizing mitochondrial cristae structure, reducing oxidative stress, and enhancing adenosine triphosphate (ATP) production. Preclinical studies have demonstrated the protective and restorative efficacy of Elamipretide in models of heart failure, neurodegeneration, ischemia-reperfusion injury, metabolic syndromes, and muscle atrophy and weakness. Clinical trials such as PROGRESS-HF, TAZPOWER, MMPOWER-3, and ReCLAIM elaborate on preclinical findings and highlight the significant therapeutic potential of Elamipretide. Further research may expand its application to other diseases involving mitochondrial dysfunction as well as investigate long-term efficacy and safety of the drug. The following review synthesizes current knowledge of the structure, mechanisms of action, and the promising therapeutic role of Elamipretide in stabilizing mitochondrial fitness, improving mitochondrial bioenergetics, and minimizing oxidative stress.