Cardiovascular & Haematological Disorders - Drug Targets - Volume 25, Issue 2, 2025

High blood glucose levels are a hallmark of Diabetes Mellitus (DM), which is classified as a metabolic disease. DM is closely associated with various Cardiovascular Disease (CVD) risk factors, and poor glycemic control is known to elevate the risk of developing CVD. Ranolazine, a novel anti-anginal medication, has demonstrated cardioprotective effects, making it an important agent in the management of heart-related complications in diabetic patients. The mechanism underlying the anti-ischemic effect of ranolazine primarily involves the blockade of the cardiac isoform of voltage-gated Sodium Channels (NaChs), specifically Nav1.5. By inhibiting the late Sodium Current (INa, late), ranolazine helps stabilize cardiac function and reduce ischemic episodes. Recent large Randomized Controlled Trials (RCTs) have shown that ranolazine significantly reduces levels of glycosylated hemoglobin (HbA1c), which is a critical marker for glycemic control. This dual action of ranolazine in improving both cardiac performance and glycemic control positions it as a valuable therapeutic option in the management of patients with DM and cardiovascular risk.

This review aims to provide a comprehensive overview of the preclinical and clinical research concerning ranolazine's potential as an antidiabetic agent. By examining existing studies, we explore the drug's mechanisms of action, its impact on glycemic control, and its role in managing DM-related cardiovascular complications. Through the available data, we highlight the emerging evidence supporting ranolazine's use beyond its traditional role as an anti-anginal medication, as well as its promising implications for DM management.

Using the terms ranolazine, DM, beta-cells, alpha cells, and preclinical and clinical trials, an EMBASE search for English language articles was conducted from 1979 to 2024.

Ranolazine has demonstrated a well-tolerated glucometabolic action and positively regulates glucose levels in individuals with DM. A meta-analysis has revealed that ranolazine effectively improves HbA1c levels without increasing the risk of hypoglycemia, offering significant advantages for patients with type 2 Diabetes Mellitus (T2DM) and stable angina. In addition to its effects on glycemic control, ranolazine has been shown to lower both baseline and postprandial glucagon levels in preclinical trials. This reduction in glucagon is associated with a decrease in hyperglycemia, suggesting that the blockade of Sodium Channels (NaChs) is integral to the glucose-lowering effects of ranolazine. Overall, these findings support the potential of ranolazine as a beneficial treatment option for managing glucose levels in diabetic patients, particularly those with concurrent cardiovascular conditions.

A novel approach for treating T2DM could involve selective Nav1.3 blockers, as ranolazine's unique mechanism of action distinguishes it from other approved antidiabetic medications. Targeting Nav1.3 channels may offer similar glycemic control benefits while minimizing side effects. This strategy could lead to innovative treatments that address both DM management and cardiovascular protection. Further research is needed to evaluate the efficacy and safety of these selective blockers in diabetic patients.

Casimiroa edulis La Llave (Rutaceae), commonly known as “zapote blanco”, is a tree widely distributed in Mexico's tropical and subtropical areas. The decoction of its leaves is traditionally used as a natural remedy to treat hypertension and anxiety.

The present study aimed to determine the vasorelaxant and antihypertensive effects of C. edulis extracts and evaluate the acute and sub-acute toxicity of one of the most active extracts.

The hydro-alcohol and organic (hexane, dichloromethane, and methanol) extracts, obtained from the leaves of C. edulis, were evaluated on isolated aorta rat rings in the presence and absence of endothelium to determine their vasorelaxant effect. Then, most active extracts were studied to evaluate the functional mechanism of their vasorelaxant action and antihypertensive effect on spontaneously hypertensive rats (SHR). The acute and sub-acute toxicity of dichloromethane extract was evaluated following the OECD 423 and 407 protocols.

The hexane (HE) and dichloromethane (DE) extracts from Casimiroa edulis induced significant vasorelaxant action on isolated rat aortic rings with (Emax 104.7 ± 1.4% and Emax 97.3 ± 6.7%, respectively) and without (Emax 94.9 ± 3.5% and Emax 67.4 ± 1.0%, respectively) endothelium, and this effect was partially endothelium-dependent. Their vasorelaxant action was modified by L-NAME (nitric oxide synthase inhibitor) and ODQ (soluble guanylyl cyclase inhibitor); however, indomethacin did not modify the effect. Also, both HE and DE significantly decreased the contraction induced by KCl in a concentration-dependent manner and the maximal effect induced by CaCl2. Moreover, DE showed a significant decrease in systolic and diastolic blood pressure in SHR at 7 hours and 15 days after treatment, respectively. Finally, the toxicity test of DE allowed classifying it in category 5, indicating it to be a non-toxic extract based on OECD guideline 423; the LD50 value was estimated to be greater than 2,000 mg/Kg and smaller than 5,000 mg/Kg in Wistar rats.

The results demonstrated hexane and dichloromethane extracts to exert a vasorelaxant effect through endothelium-dependent NO release and cGMP increase, as well as by calcium channel blockade. Also, dichloromethane extract showed efficacy and security as a potential antihypertensive agent.

POEMS syndrome is a rare multisystem disorder associated with plasma cell dyscrasia and abnormal cytokine production, including vascular endothelial growth factor (VEGF). The mandatory criterion for its diagnosis includes polyneuropathy and monoclonal plasma cell disorder, along with other major and minor criteria. This case highlights the diagnostic and therapeutic challenges of POEMS syndrome by depicting the case of a 61-year-old male with progressive sensory-motor polyneuropathy, lymphadenopathy, and splenomegaly.

The patient presented with a year-long history of bilateral limb weakness and sensory disturbances, accompanied by abdominal distention, weight loss, and other systemic symptoms. Clinical examination revealed skin hyperpigmentation, splenomegaly, and a right axillary lymph node enlargement. Neurological evaluation showed distal limb hypotonia, absent reflexes, and sensory deficits. Diagnostic investigations, including nerve conduction studies, imaging, and bone marrow biopsy, confirmed POEMS syndrome based on polyneuropathy, monoclonal IgG lambda plasma cells, Castleman disease, sclerotic bone lesions, elevated VEGF, and minor criteria, such as endocrinopathy and skin changes. The treatment comprised lenalidomide and dexamethasone, resulting in significant improvement at the three-month follow-up, including normalized VEGF levels and resolution of ascites.

This case highlights the necessity of identifying the many presentations of POEMS syndrome for prompt diagnosis and treatment. Despite its rarity and diagnostic complexity, prompt treatment can significantly improve clinical outcomes. POEMS syndrome should be considered in patients with unexplained neuropathy and systemic features, enabling better outcomes through targeted therapies.

Autoimmune hemolytic anemia (AIHA) is a rare disorder in hematology, with an incidence of 1-3 per 100,000 per year. The current data available on open-heart procedures in patients with AIHA is limited. Despite presenting periprocedural challenges, multidisciplinary efforts enabled the successful performance of surgical atrial septal defect (ASD) closure in a patient with warm-reactive AIHA.

A 56-year-old woman with a large elliptical ASD was planned for surgical closure. The patient has never received a blood transfusion or experienced any previous hematological issues. During the surgical preparation, the patient's immunoglobulin G Coombs test result was positive for the presence of immunoglobulin G. The patient was diagnosed with a remission state of warm AIHA. A challenge arose when surgical ASD closure needed a cardiopulmonary bypass (CPB), which increased the risk of hemolysis. The patient also needed to be hypothermic to reduce metabolism, which may interact with the pathophysiology of AIHA. Several approaches were taken, and the procedure was conducted successfully without noteworthy obstacles.

A successful surgical ASD closure was performed in a patient with complete remission of warm-reactive AIHA. Considering the different hemolytic mechanisms between CPB and AIHA, determining whether AIHA is cold or warm reactive is crucial for managing temperature in the heart-lung machine. Several approaches, such as utilizing a roller pump, a heparin-coated circuit, and administering steroids, can be implemented to prevent hemolysis.

Hematohidrosis is an extremely rare condition characterized by the spontaneous exudation of blood through intact skin, often linked to emotional stress and sympathetic nervous system activation. Due to its rarity, many aspects of its pathophysiology remain poorly understood. This case highlights the importance of considering hematohidrosis in the differential diagnosis of unexplained bleeding and emphasizes the role of psychological assessment in its management.

A 7-year-old girl from a low-income background presented with a two-month history of recurrent blood oozing from the sweat glands at her elbows, knee joints, and forehead. The episodes, lasting 5-10 minutes, were more frequent during periods of emotional distress. Physical examination revealed no signs of trauma, purpura, or underlying skin lesions. Routine laboratory investigations, including hemogram, platelet count, clotting time, prothrombin time, and activated partial thromboplastin time, were within normal limits. Microscopic analysis of the secreted fluid confirmed the presence of erythrocytes, supporting the diagnosis of hematohidrosis. Given the suspected psychogenic trigger, the patient was referred for psychiatric evaluation and stress management therapy, leading to a gradual reduction in symptom frequency over a four-month follow-up period.

This case reinforces the multidisciplinary approach required for diagnosing and managing hematohidrosis, which lacks definitive diagnostic markers. Early psychological intervention is crucial in mitigating symptom severity, as evidenced by this patient’s clinical improvement. Increased awareness of hematohidrosis among clinicians can prevent unnecessary invasive testing, facilitate timely recognition, and optimize patient outcomes.