A randomized, placebo-controlled, trial to assess the photosensitizing, phototoxic and carcinogenic potential of hydrochlorothiazide in healthy volunteers.

BACKGROUND AND AIMS: Pharmacovigilance reports, associating hydrochlorothiazide (HCT) with skin cancer, resulted in a significant decrease of HCT prescriptions for hypertension and heart failure. Whether HCT exhibits phototoxic properties thereby causing skin cancer remains unknown. This study aimed to examine the photosensitizing, phototoxic and carcinogenic potential of HCT in a randomized, placebo-controlled, double-blind trial in vivo and also in vitro . METHODS: The trial assigned 30 healthy, normotensive adult volunteers in a 2:1 ratio to either HCT 25 mg/day or placebo for 15 days. Photosensitivity of the skin with and without the effect of HCT treatment were assessed. Following whole-body ultraviolet A (UVA) and B (UVB, 311 nm) irradiation, phototoxic and carcinogenic reactions by measuring urinary excretion of pyrimidine dimers were evaluated. For the in-vitro studies, human keratinocytes (HaCaT) were incubated with HCT, irradiated with UVB, and analysed for markers of inflammation, apoptosis and carcinogenesis. RESULTS: Skin photosensitivity following exposure to UVA and UVB remained unchanged from baseline to 15-day follow-up in both groups (UVA change HCT 0.0 J/cm 2 vs. placebo 0.0 J/cm 2 ; P  = 0.99; UVB change HCT 0.0 J/cm 2 vs. placebo -0.2 J/cm 2 ; P  = 0.06). Pyrimidine dimers were not detected in either group. In vitro , combination of HCT and UVB irradiation did not induce the expression of oxidative stress marker proteins, inflammatory proteins, apoptotic proteins or activation of oncoproteins. CONCLUSION: HCT did not increase photosensitivity for UVA or UVB in healthy volunteers compared with placebo, and was not associated with phototoxic or carcinogenic reactions. In vitro , HCT was also not associated with phototoxicity or carcinogenesis (NCT04654312).

Photoinduced skin reactions of cardiovascular drugs-a systematic review.

This systemic review aims to provide a practical overview of the prevalence, clinical manifestation, and management of adverse photoinduced skin reactions caused by frequently used cardiovascular drugs and to assess their potential relevance for skin cancer development. Data search included PubMed, Web of Science, and the Cochrane Library. A systematic review of peer-reviewed studies reporting the photosensitizing and/or skin cancer-inducing properties of common cardiovascular drugs was performed and a guide to clinical management of photoinduced skin eruptions by cardiovascular drugs was provided. Study quality was assessed for major methodological biases. A total of 58 studies were identified (i.e. 23 case reports, 14 observational studies, 10 review articles, 10 experimental studies, and 1 meta-analysis). Most commonly, drug-associated adverse photoinduced cutaneous reactions were caused by phototoxic and photoallergic mechanisms. There is evidence suggesting that amiodarone and dronedarone, thiazide diuretics, thiazide-like diuretics, angiotensin receptor blockers, dihydropyridine-type calcium channel blockers, and certain angiotensin-converting enzyme inhibitors and statins may cause photoinduced adverse cutaneous reactions. Other drugs such as anticoagulants, antiplatelets, aldosterone antagonists, and fibrates have not been linked with photosensitizing reactions or adverse cutaneous reactions. Some drugs, i.e. thiazides and thiazide-like diuretics, were associated with an increased risk of non-melanoma skin cancers (basal cell carcinoma and squamous cell carcinoma). Certain commonly used cardiovascular drugs have been associated with adverse photoinduced cutaneous reactions. If they occur, further diagnosis and treatment might be needed, depending on the severity and progress. Whether photosensitizing drugs increase the risk of skin cancer remains elusive and further randomized controlled trials are required.

Mapping of an atrial tachycardia after Epicor™ high-intensity focused ultrasound ablation: A case report.

BACKGROUND: Surgical techniques, such as the application of high-intensity focused ultrasound (HIFU), can be used for pulmonary vein isolation (PVI). CASE SUMMARY: We report a case of a 73-year old patient, in whom HIFU failed to achieve PVI but promoted the occurrence of a scar-related atrial tachycardia (AT). Voltage mapping of the left atrium revealed multiple gaps along the ablation line. Coherent mapping with visualization of velocity vectors allowed the correct interpretation and the targeted ablation of the AT. DISCUSSION: Cardiac surgery can promote scar-related AT. The coherent mapping function could simplify the mapping of scar-related AT in the future.

Cardiovascular Outcomes According to Polypharmacy and Drug Adherence in Patients with Atrial Fibrillation on Long-Term Anticoagulation (from the RE-LY Trial).

Prevalence of atrial fibrillation (AF) increases with age, along with comorbidities and, thus, polypharmacy. Non-adherence is associated with polypharmacy. This study aimed to identify patients at risk for cardiovascular events according to their pharmacological treatment intensity and adherence. Patients (n = 18,113) with a mean age of 71.5 ± 8.7 years, at high cardiovascular risk were followed between December 2005 until December 2007 for a median time of 2 years. The association between polypharmacy and adherence and their impact on cardiovascular and bleeding events were explored. Adherence was defined as a study drug intake of ≥80%. Patients with more co-medications had a higher body mass index, higher prevalence of hypertension, coronary heart disease, heart failure, and diabetes mellitus (all p < 0.0001) compared to ≤4 or 5-8 co-medications, but no differences in history of stroke (p = 0.68) or transient ischemic attack (p = 0.065). Across all treatments, the adjusted hazard ratios (HRs) increased in patients with more co-medications (≥9 vs ≤4) for all-cause death (HR 1.30; 1.06-1.59), major bleeding (HR 1.65; 1.33-2.05), and all bleeding events (HR 1.44; 1.31-1.59). Yearly event rates were higher in non-adherent than adherent patients for stroke and systemic embolism (SSE) (3.14 vs 1.00), all-cause death (7.76 vs 2.66), major bleeding (6.21 vs 2.65), and all bleeding (28.71 vs 19.05; all p < 0.0001). After an event the patients were more likely to become non-adherent (adherence after SSE 30.3%, after major bleeding 33.4%, after all bleeding 66.7%; all p < 0.0001). The treatment effects were consistent to the overall group in the different polypharmacy groups. In conclusion, polypharmacy and non-adherence are risk indicators for increased adverse cardiovascular and bleeding events. Dabigatran is safe to use across the full spectrum of AF patients, independent of the number of co-medications and adherence. Patients with co-medications and comorbidities require special attention and encouragement to adhere to oral anticoagulation.

Effects of edoxaban and warfarin on vascular remodeling: Atherosclerotic plaque progression and collateral artery growth.

BACKGROUND AND PURPOSE: Oral anticoagulation prevents thromboembolism in atrial fibrillation. Factor Xa inhibitors, like edoxaban, are known to reduce inflammation and proliferation of smooth muscle cells, while vitamin K antagonism can cause vascular calcific damage. The influence of edoxaban compared to warfarin on vascular remodeling, atherosclerosis and arteriogenesis is unknown. EXPERIMENTAL APPROACH: Apolipoprotein E knockout (ApoE -/-) mice were fed cholesterol-rich diet alone (control, co), with warfarin+vitamin K1 (warf) or with edoxaban (Edo) for 8 weeks. After 6 weeks, femoral artery ligation was performed. KEY RESULTS: There was no difference in hind-limb perfusion restoration between the three groups after 14 days (Co 0.36 ± 0.05 vs. Warf 0.39 ± 0.09 (p = .39), Co vs. Edo 0.51 ± 0.06 (p = .089), Warf vs. Edo (p = .83)) after ligation. Immuno-histologically, there was no difference in smooth muscle cell count in both hindlimbs between the three groups or in the amount of perivascular macrophages in collateral-bearing hindlimb tissue. Edoxaban showed the lowest amount of plaque tissue in the aortic sinus tissue (Co 74 ± 11% vs. Edo 62 ± 12% (p = .024), Co vs. Warf 69 ± 14% (p = .30), Edo vs. Warf (p = .14)) as well as the least amount of fibrosis (Co 3.1 ± 0.9% vs. Edo 1.7 ± 0.6% (p = .027), Co vs. Warf 4.1 ± 0.7% (p = .081), Edo vs. Warf (p < .001)). No difference in mRNA content of inflammatory cytokines in muscle tissue or spleen was detected between the three groups. CONCLUSION AND IMPLICATIONS: These data suggest that treatment with edoxaban unlike warfarin prevents vascular maladaptive remodeling, which may be clinically important.

Exercise promotes collateral artery growth mediated by monocytic nitric oxide.

OBJECTIVE: Collateral artery growth (arteriogenesis) is an important adaptive response to hampered arterial perfusion. It is unknown whether preventive physical exercise before limb ischemia can improve arteriogenesis and modulate mononuclear cell function. This study aimed at investigating the effects of endurance exercise before arterial occlusion on MNC function and collateral artery growth. APPROACH AND RESULTS: After 3 weeks of voluntary treadmill exercise, ligation of the right femoral artery was performed in mice. Hindlimb perfusion immediately after surgery did not differ from sedentary mice. However, previous exercise improved perfusion restoration ≤7 days after femoral artery ligation, also when exercise was stopped at ligation. This was accompanied by an accumulation of peri-collateral macrophages and increased expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) in hindlimb collateral and in MNC of blood and spleen. Systemic monocyte and macrophage depletion by liposomal clodronate but not splenectomy attenuated exercise-induced perfusion restoration, collateral artery growth, peri-collateral macrophage accumulation, and upregulation of iNOS. iNOS-deficient mice did not show exercise-induced perfusion restoration. Transplantation of bone marrow-derived MNC from iNOS-deficient mice into wild-type animals inhibited exercise-induced collateral artery growth. In contrast to sedentary controls, thrice weekly aerobic exercise training for 6 months in humans increased peripheral blood MNC iNOS expression. CONCLUSIONS: Circulating mononuclear cell-derived inducible nitric oxide is an important mediator of exercise-induced collateral artery growth.

Therapeutic approaches in the stimulation of the coronary collateral circulation.

Arteriogenesis as a way to restore blood flow after arterial occlusion has been under investigation for the treatment of coronary artery disease (CAD) for decades. Therapeutic approaches so far have included delivery of cytokines and growth factors as well as mechanical stimulation such as external counterpulsation. As knowledge on the mechanisms of arteriogenesis expanded, new therapeutic approaches have emerged. This review summarizes recent attempts to stimulate the growth of the coronary vasculature and discusses their potential in clinical application. This article also delivers an overview of current studies and trials on coronary arteriogenesis.