Hypertension is the leading modifiable cardiovascular risk factor, yet long-term adherence to antihypertensive therapy remains suboptimal. RNA-based approaches targeting hepatic angiotensinogen (AGT) have emerged as an attractive strategy for upstream renin-angiotensin-aldosterone system suppression and warrant a timely, focused review of the field. PubMed/MEDLINE, ClinicalTrials.gov and the most relevant scientific and academic databases were searched up to February 2026 to draft a narrative review of peer-reviewed clinical trials, pivotal translational studies, contemporary hypertension guidelines, and official regulatory documents relevant to innovative antihypertensive treatments, such as antisense AGT suppression (zilebesiran), endothelin antagonism (aprocitentan), and aldosterone-synthase inhibition (baxdrostat). Zilebesiran demonstrated durable blood-pressure lowering in monotherapy (KARDIA-1: placebo-adjusted ambulatory systolic blood pressure (BP) - 16.7 mmHg at month 3) and as add-on therapy (KARDIA-2: greatest effect with indapamide background). KARDIA-3 extended evaluation to a higher-risk, heavily medicated population, in which the primary endpoint was not met. The ongoing ZENITH outcomes trial will determine whether AGT silencing reduces hard cardiovascular end-points. Aprocitentan reduced office and ambulatory systolic BP in resistant hypertension (PRECISION trial) and has received regulatory approval in the USA, EU, and UK, with specific monitoring requirements for fluid retention and hematological effects. Baxdrostat demonstrated selective aldosterone-synthase inhibition with meaningful BP reductions across two phase II trials. RNA interference targeting AGT represents one of the most advanced disease-modifying platforms in hypertension, alongside the already-approved endothelin antagonism and the emerging aldosterone synthase inhibition strategy. The available evidence supports cautious optimism and continued translational investment, but not premature adoption into routine practice.

Beta-blockers are among the most widely prescribed drugs in the management of both supraventricular and ventricular arrhythmias, and they are frequently regarded as a homogeneous pharmacological class. They are not. The agents in current use differ substantially in beta1-receptor selectivity, lipophilicity, half-life, route of administration, intrinsic sympathomimetic activity, and ancillary properties, and arrhythmias themselves differ in mechanism, adrenergic dependence, anatomical origin, and structural substrate. This narrative review examines whether these pharmacological differences translate into clinically meaningful differences in efficacy and utility, asking not only whether a beta-blocker should be used but which one should be used. Evidence was drawn from a targeted search of PubMed, Web of Science, Scopus, Ovid, Embase, and the Cochrane Library, with priority given to randomized controlled trials, meta-analyses, large registries, and contemporary society guidelines, and was synthesized qualitatively by arrhythmia type. A class effect is apparent for many indications, particularly rate control in atrial fibrillation and atrial flutter, where metoprolol, bisoprolol, and carvedilol perform broadly similarly and the choice is driven mainly by comorbidity and tolerability. Drug-specific differences emerge in three settings. In adrenergically mediated inherited syndromes, namely catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, nonselective agents and especially nadolol are clearly superior to beta1-selective agents, and the same principle appears to extend to ventricular electrical storm, in which propranolol has outperformed metoprolol in a randomized comparison. In acute care, pharmacokinetics dominate, and the ultra-short-acting agents esmolol and landiolol permit a degree of titration that longer-acting drugs cannot match. In patients with heart failure and reduced ejection fraction, carvedilol, metoprolol succinate, and bisoprolol should be preferred irrespective of arrhythmia subtype because of their established mortality benefit. Conversely, beta1-selective agents, including the highly selective agent nebivolol, improve tolerability in bronchospastic disease, although this reflects respiratory tolerability rather than any demonstrated antiarrhythmic advantage, and beta-blockers have little role in Brugada syndrome or in bradycardia-dependent acquired torsades de pointes. Beta-blockers should therefore not be treated as interchangeable. Selection should integrate arrhythmic mechanism, structural substrate, and patient characteristics, and head-to-head trials remain conspicuously scarce.

Cardiovascular-kidney-metabolic syndrome describes a complex interplay between cardiovascular disease, chronic kidney disease, and metabolic disorders. Recent randomized controlled trials have demonstrated beneficial effects of SGLT2 inhibitors in patients with this multifaceted condition. This review aims to critically evaluate the available evidence supporting the role of SGLT2 inhibitors in patients with cardiovascular-kidney-metabolic syndrome and familiarize healthcare providers with the evidence surrounding significant renal and cardiac benefits of SGLT2 inhibitors. A comprehensive narrative literature review was conducted using PubMed. Eligible studies included randomized controlled trials, systematic reviews, and meta-analyses published in English between 2018 and 2025, focusing on SGLT2 inhibitors in the context of cardio-renal syndrome and cardio-kidney-metabolic syndrome. Multiple landmark trials have shown that SGLT2 inhibitors significantly reduce the risk of chronic kidney disease progression, MACE, and hospitalization for HF. These benefits were seen in patients both with and without type 2 diabetes. Importantly, SGLT2 inhibitors such as canagliflozin, dapagliflozin, empagliflozin, and sotagliflozin were well tolerated, though caution is advised in volume-depleted patients or those at risk for genitourinary infections. Positive effects, ranging from glycemic control to renoprotective and cardioprotective properties, support SGLT2 inhibitors as first-line therapy in improving clinical outcomes and quality of life in patients affected by this interconnected disease spectrum.

Lipoprotein(a) [Lp(a)] is a genetically determined, low-density lipoprotein-like particle that has emerged as an important and independent contributor to atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Elevated Lp(a) concentrations, defined as approximately 125 nmol/L (≥ 50 mg/dL) by most consensus thresholds, affect an estimated 20% of the general population and confer lifelong inherited cardiovascular risk that is not adequately captured by standard lipid panels. Epidemiological, observational and genetic studies consistently show that elevated Lp(a) concentrations are associated with increased risk of coronary heart disease, myocardial infarction, ischemic stroke, peripheral artery disease and calcific aortic valve stenosis. Unlike low-density lipoprotein (LDL) cholesterol, Lp(a) levels remain relatively stable throughout life and are only minimally influenced by lifestyle interventions or most conventional lipid-lowering therapies. This creates a clinically relevant therapeutic gap, particularly in patients with premature cardiovascular disease, recurrent events despite optimal LDL cholesterol control, or otherwise unexplained residual risk. Traditional lipid-lowering strategies remain essential to reduce global cardiovascular risk, but they have limited ability to directly modify Lp(a)-mediated risk. PCSK9 inhibitors and inclisiran produce modest (approximately 20-30%) Lp(a) reductions, and lipoprotein apheresis may be useful in highly selected patients, but none represents a broadly applicable Lp(a)-specific therapy. Recent advances have changed this landscape. Antisense oligonucleotides, small interfering RNA therapies and oral small-molecule inhibitors have demonstrated profound and durable Lp(a) reductions, frequently exceeding 80-100% with small interfering RNA (siRNA)-based agents (olpasiran, zerlasiran, lepodisiran), up to 80% with the antisense oligonucleotide pelacarsen, and up to 85% with the oral small-molecule muvalaplin, in phase 1 and phase 2 clinical trials. However, the central question remains whether pharmacological Lp(a) lowering translates into fewer cardiovascular events. Current evidence supports strong biological efficacy, but definitive proof of clinical benefit awaits ongoing randomized cardiovascular outcomes trials, including Lp(a)HORIZON (pelacarsen), OCEAN(a)-Outcomes (olpasiran) and ACCLAIM-Lp(a) (lepodisiran). This narrative review summarizes the biology and epidemiological relevance of Lp(a), quantifies its association with cardiovascular events, reviews the effect of traditional lipid-lowering therapies on Lp(a) and critically discusses emerging Lp(a)-targeted treatments and future directions.

This report describes vutrisiran (Amvuttra[®]), a novel double-stranded small interfering ribonucleic acid (siRNA)-N-acetylgalactosamine (GalNAc) conjugate. A narrative literature review was conducted using a secondary database, PubMed, from 2018 to 2025. Articles were limited to those written in English. Inclusion criteria consisted of randomized controlled trials and systematic reviews that analyzed the use of vutrisiran to treat amyloidosis. Other drug information resources, including the package inserts and UpToDate, were also utilized for general information. Two phase 3 publications were included in this report. Vutrisiran significantly improved neuropathy, quality of life, and functional measures in patients with hereditary transthyretin amyloidosis with polyneuropathy. Additionally, vutrisiran reduced the risk of death and recurrent cardiovascular events, preserved functional capacity and quality of life, and slowed New York Heart Association (NYHA) class progression compared with placebo. A favorable safety profile was also found in landmark trials. Vutrisiran is a therapeutic option for amyloidosis, directly targeting the underlying pathogenic mechanism through RNA interference. Clinical trials have demonstrated a reduction in transthyretin protein levels, slowing neuropathic and cardiac disease progression, and improving functional and quality-of-life outcomes. Ongoing research on long-term outcomes is still to be elucidated.

Zilebesiran is an investigational RNA interference therapeutic that lowers blood pressure by silencing hepatic angiotensinogen, thereby offering sustained antihypertensive activity with infrequent dosing in selected ambulatory populations. This profile is attractive for long-term blood pressure control, but it also raises an unresolved clinical question: how should acute illness be managed when upstream renin-angiotensin system suppression cannot be rapidly attenuated? In this Current Opinion, we place that question in perspective using available trial data, cardiorenal physiology, and acute-care literature. Early-phase studies established that zilebesiran produces sustained angiotensinogen suppression and blood pressure reduction, while also showing that the antihypertensive response is modulated by dietary sodium intake and background renin-angiotensin-aldosterone system blockade. Phase 2 studies then confirmed antihypertensive efficacy in clinically stable outpatient populations, and KARDIA-3 extended evaluation to patients with uncontrolled hypertension and established or high cardiovascular risk receiving multiple antihypertensive agents; however, the study did not meet its prespecified multiplicity-adjusted threshold for statistical significance at month 3. The concern is not that harm has been demonstrated, but that prolonged angiotensinogen silencing may reduce short-term therapeutic flexibility during sepsis, perioperative stress, acute heart failure, marked volume depletion, or hyperkalemia-settings in which clinicians often rely on temporary adjustment of oral renin-angiotensin-aldosterone system inhibitors. Early reversal strategies are conceptually important, but current approaches appear better suited to planned de-escalation than emergency rescue. Future work should define vulnerable phenotypes, clarify whether acute-care pathways require protocol adaptation, and determine how reversibility can be operationalized as phase 3 development advances.