Aldosterone, mitochondria and regulation of cardiovascular metabolic disease.

Aldosterone is a mineralocorticoid hormone involved in controlling electrolyte balance, blood pressure, and cellular signaling. It plays a pivotal role in cardiovascular and metabolic physiology. Excess aldosterone activates mineralocorticoid receptors, leading to subsequent inflammatory responses, increased oxidative stress, and tissue remodeling. Various mechanisms have been reported to link aldosterone with cardiovascular and metabolic diseases. However, mitochondria, responsible for energy generation through oxidative phosphorylation, have received less attention regarding their potential role in aldosterone-related pathogenesis. Excess aldosterone leads to mitochondrial dysfunction, and this may play a role in the development of cardiovascular and metabolic diseases. Aldosterone has the potential to affect mitochondrial structure, function, and dynamic processes, such as mitochondrial fusion and fission. In addition, aldosterone has been associated with the suppression of mitochondrial DNA, mitochondria-specific proteins, and ATP production in the myocardium through mineralocorticoid receptor, nicotinamide adenine dinucleotide phosphate oxidase, and reactive oxygen species pathways. In this review, we explore the mechanisms underlying aldosterone-induced cardiovascular and metabolic mitochondrial dysfunction, including mineralocorticoid receptor activation and subsequent inflammatory responses, as well as increased oxidative stress. Furthermore, we review potential therapeutic targets aimed at restoring mitochondrial function in the context of aldosterone-associated pathologies. Understanding these mechanisms is vital, as it offers insights into novel therapeutic strategies to mitigate the impact of aldosterone-induced mitochondrial dysfunction, thereby potentially improving the outcomes of individuals affected by cardiovascular and metabolic disorders.

Evaluations of secondary hypertension and laboratory data in the elderly population.

Secondary hypertension in the elderly poses many challenges and requires a comprehensive diagnostic and management approach. This review explores the prevalence, diagnostic strategies, and treatment modalities for secondary hypertension in elderly patients, focusing on etiologies including primary aldosteronism, renal vascular disease, renal parenchymal disease, obstructive sleep apnea, thyroid disorders, Cushing's syndrome, pheochromocytomas and paragangliomas, and drug-induced hypertension. Key considerations include age-related changes in physiology and atypical presentations of underlying conditions necessitating thorough screening with a combination of clinical evaluation, laboratory tests, and imaging studies. Collaboration among healthcare providers is essential to ensure a timely diagnosis and personalized management tailored to the unique needs of elderly patients. Further research is needed to address knowledge gaps and optimize clinical strategies for managing secondary hypertension in this population.

Anticoagulation for Patients With Concomitant Atrial Fibrillation and End-Stage Renal Disease: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Concomitant atrial fibrillation and end-stage renal disease is common and associated with an unfavorable prognosis. Although oral anticoagulants have been well established to prevent thromboembolism, the applicability in patients under long-term dialysis remains debatable. The study aimed to determine the efficacy and safety of anticoagulation in the dialysis-dependent population. METHODS AND RESULTS: An updated network meta-analysis based on MEDLINE, EMBASE, and the Cochrane Library was performed. Studies published up to December 2022 were included. Direct oral anticoagulants (DOACs, dabigatran, rivaroxaban, apixaban 2.5/5 mg twice daily), vitamin K antagonists (VKAs), and no anticoagulation were compared on safety and efficacy outcomes. The outcomes of interest were major bleeding, thromboembolism, and all-cause death. A total of 42 studies, including 3 randomized controlled trials, with 185 864 subjects were pooled. VKAs were associated with a significantly higher risk of major bleeding than either no anticoagulation (hazard ratio [HR], 1.47; 95% CI, 1.34-1.61) or DOACs (DOACs versus VKAs; HR, 0.74 [95% CI, 0.64-0.84]). For the prevention of thromboembolism, the efficacies of VKAs, DOACs, and no anticoagulation were equivalent. Nevertheless, dabigatran and rivaroxaban were associated with fewer embolic events. There were no differences in all-cause death with the administration of VKAs, DOACs, or no anticoagulation. CONCLUSIONS: For dialysis-dependent populations, dabigatran and rivaroxaban were associated with better efficacy, while dabigatran and apixaban demonstrated better safety. No anticoagulation was a noninferior alterative, and VKAs were associated with the worst outcomes.

2024 Guidelines of the Taiwan Society of Cardiology for the Diagnosis and Treatment of Heart Failure with Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is a multi-organ systemic syndrome that involves cardiac and extra-cardiac pathophysiological abnormalities. Its growing prevalence causes a major public concern worldwide. HFpEF is usually associated with multiple comorbidities, and non-cardiovascular death is common in patients with HFpEF. In Asia, patients with HFpEF has a younger age, higher prevalence of diabetes and chronic kidney disease than Western countries. A 2-step diagnostic algorithm is recommended in this guideline. In the first step, the diagnosis of HFpEF can be made if patients have symptoms and/or signs of heart failure, left ventricular ejection fraction ≥ 50%, increased natriuretic peptide, and objective evidence of left atrial or left ventricular abnormalities or raised left ventricular filling pressure. If diagnosis is still uncertain, invasive or noninvasive stress test can be performed in the second step. Comorbidities need to be controlled in HFpEF. Weight reduction for obesity and supervised exercise training are recommended for HFpEF. For pharmacological therapy, diuretic is used to relieve congestion and sodium-glucose cotransporter 2 inhibitor, empagliflozin or dapagliflozin, is recommended to improve prognosis of HFpEF. The research on HFpEF is advancing at a rapid pace. It is expected that newer modalities for diagnosis and management of HFpEF could appear in the near future.

Helicobacter pylori CagA protein induces gastric cancer stem cell-like properties through the Akt/FOXO3a axis.

The presence of Helicobacter pylori (H. pylori) infection poses a substantial risk for the development of gastric adenocarcinoma. The primary mechanism through which H. pylori exerts its bacterial virulence is the cytotoxin CagA. This cytotoxin has the potential to induce inter-epithelial mesenchymal transition, proliferation, metastasis, and the acquisition of stem cell-like properties in gastric cancer (GC) cells infected with CagA-positive H. pylori. Cancer stem cells (CSCs) represent a distinct population of cells capable of self-renewal and generating heterogeneous tumor cells. Despite evidence showing that CagA can induce CSCs-like characteristics in GC cells, the precise mechanism through which CagA triggers the development of GC stem cells (GCSCs) remains uncertain. This study reveals that CagA-positive GC cells infected with H. pylori exhibit CSCs-like properties, such as heightened expression of CD44, a specific surface marker for CSCs, and increased ability to form tumor spheroids. Furthermore, we have observed that H. pylori activates the PI3K/Akt signaling pathway in a CagA-dependent manner, and our findings suggest that this activation is associated with the CSCs-like characteristics induced by H. pylori. The cytotoxin CagA, which is released during H. pylori infection, triggers the activation of the PI3K/Akt signaling pathway in a CagA-dependent manner. Additionally, CagA inhibits the transcription of FOXO3a and relocates it from the nucleus to the cytoplasm by activating the PI3K/Akt pathway. Furthermore, the regulatory function of the Akt/FOXO3a axis in the transformation of GC cells into a stemness state was successfully demonstrated.

Post-exercise left atrial conduit strain predicted hemodynamic change in heart failure with preserved ejection fraction.

OBJECTIVES: Left ventricle function directly impacts left atrial (LA) conduit function, and LA conduit strain is associated with exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF). Pulmonary capillary wedge pressure (PCWP) before and during exercise is the current gold standard for diagnosing HFpEF. Post-exercise ΔPCWP can lead to worse long-term outcomes. This study examined the correlation between LA strain and post-exercise ΔPCWP in patients with HFpEF. METHODS: We enrolled 100 subjects, including 74 with HFpEF and 26 with non-cardiac dyspnea, from November 2017 to December 2020. Subjects underwent echocardiography, invasive cardiac catheterization, and expired gas analysis at rest and during exercise. Arterial blood pressure, right atrial pressure, pulmonary artery pressure, and PCWP were recorded during cardiac catheterization. Cardiac output, stroke volume, pulmonary vascular resistance, pulmonary artery compliance, systemic vascular resistance, and LV stroke work were calculated using standard formulas. RESULTS: Exercise LA conduit strain significantly correlated with both post-exercise ΔPCWP (r = - 0.707, p < 0.001) and exercise PCWP (r = - 0.659; p < 0.001). Exercise LA conduit strain differentiated patients who did and did not meet the 2016 European Society of Cardiology HFpEF criteria with an area under the curve of 0.69 (95% confidence interval, 0.548-0.831) using a cutoff value of 14.25, with a sensitivity of 0.64 and a specificity of 0.68. CONCLUSIONS: Exercise LA conduit strain significantly correlates with post-exercise ΔPCWP and has a comparable power to identify patients with HFpEF. Additional studies are warranted to confirm the ability of LA conduit strain to predict long-term outcomes among patients with HFpEF. CLINICAL RELEVANCE STATEMENT: Exercise left atrial conduit strain was highly associated with the difference of post-exercise pulmonary capillary wedge pressure and may indicate increased mortality risk in patients with heart failure with preserved ejection fraction, and also has comparable diagnostic ability. KEY POINTS: • Left atrial conduit strain is associated with exercise intolerance in patients with heart failure with preserved ejection fraction. • Left atrial conduit strain during exercise can identify patients with heart failure with preserved ejection fraction. • Exercise left atrial conduit strain significantly correlates with the difference of pulmonary capillary wedge pressure during and before exercise which might predict the long-term outcomes of heart failure with preserved ejection fraction patients.

Aldosteronism is associated with more severe cerebral small vessel disease in hypertensive intracerebral hemorrhage.

Primary aldosteronism is associated with various types of cardiovascular and cerebrovascular damage independently of hypertension. Although chronic hypertension and related cerebral arteriosclerosis are the main risk factors for intracerebral hemorrhage, the effects of aldosteronism remain poorly understood. We enrolled 90 survivors of hypertensive intracerebral hemorrhage, 21 of them with aldosteronism and 69 with essential hypertension as controls in this study. Clinical parameters and neuroimaging markers of cerebral small vessel disease were recorded, and its correlations with aldosteronism were investigated. Our results showed that the aldosteronism group (55.2 ± 9.7 years, male 47.6%) had similar hypertension severity but exhibited a higher cerebral microbleed count (interquartile range) (8.5 [2.0‒25.8] vs 3 [1.0‒6.0], P = 0.005) and higher severity of dilated perivascular space in the basal ganglia (severe perivascular space [number >20], 52.4% vs. 24.6%, P = 0.029; large perivascular space [>3 mm], 52.4% vs. 20.3%, P = 0.010), compared to those with essential hypertension (53.8 ± 11.7 years, male 73.9%). In multivariate models, aldosteronism remained an independent predictor of a higher (>10) microbleed count (odds ratio = 8.60, P = 0.004), severe perivascular space (odds ratio = 4.00, P = 0.038); the aldosterone-to-renin ratio was associated with dilated perivascular space (P = 0.043) and large perivascular space (P = 0.008). In conclusions, survivors of intracerebral hemorrhage with aldosteronism showed a tendency towards more severe hypertensive arteriopathy than the essential hypertension counterparts independently of blood pressure; aldosteronism may contribute to dilated perivascular space around the deep perforating arteries. Aldosteronism is associated with more severe cerebral small vessel disease in hypertensive intracerebral hemorrhage.

Reversal of arterial stiffness in medically and surgically treated unilateral primary aldosteronism.

OBJECTIVE: Hyperaldosteronism has adverse effects on cardiovascular structure and function. Laparoscopic adrenalectomy is the gold standard for patients with unilateral primary aldosteronism. For unilateral primary aldosteronism patients unable or unwilling to undergo surgery, the effects of mineralocorticoid receptor antagonists (MRAs) on the reversibility of arterial stiffness and other clinical data remain unclear. We aimed to compare the reversibility of arterial stiffness using pulse wave velocity (PWV) and other clinical parameters between surgically and medically treated unilateral primary aldosteronism patients. METHODS: We prospectively enrolled 306 unilateral primary aldosteronism patients, of whom 247 received adrenalectomy and 59 received medical treatment with MRAs. Detailed medical history, basic biochemistry and PWV data were collected in both groups before treatment and 1 year after treatment. After propensity score matching (PSM) for age, sex, SBP and DBPs, 149 patients receiving adrenalectomy and 54 patients receiving MRAs were included for further analysis. RESULTS: After PSM, the patients receiving adrenalectomy had a greater reduction in blood pressure, increase in serum potassium, and change in PWV (ΔPWV, -53 ±â€Š113 vs. -10 ±â€Š140 cm/s, P  = 0.028) than those receiving MRAs 1 year after treatment. Multivariable regression analysis further identified that surgery (compared with MRA treatment), baseline PWV, baseline DBP, the change in DBP and the use of diuretics were independently correlated with ΔPWV. CONCLUSION: Adrenalectomy is superior to MRA treatment with regards to vascular remodeling when treating unilateral primary aldosteronism patients.

How should anti-hypertensive medications be adjusted before screening for primary aldosteronism?

Anti-hypertensive medications may affect plasma renin activity and/or plasma aldosterone concentration, misleading the interpretation of the aldosterone-to-renin ratio when screening for primary aldosteronism. The Task Force of Taiwan PA recommends that, when necessary, using α-adrenergic receptor blocking agents, centrally acting α-adrenergic agonists, and/or non-dihydropyridine calcium channel blockers should be considered to control blood pressure before screening for PA. We recommend temporarily holding ß-adrenergic receptor blocking agents, mineralocorticoid receptor antagonists, dihydropyridine calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and all diuretics before screening for PA. Further large-scale randomized controlled studies are required to confirm the recommendations.