Oriental college of Pharmacy, Navi Mumbai.
CVD remains the main cause of death in the world and there is still a significant residual risk of cardiovascular disease despite the progress in standard pharmacologic and interventional treatment. The conventional treatment is mainly focused on the symptoms and risk factors but fails to effectively target the underlying disease developmental molecular pathways. New treatment options include RNA-based therapies, gene therapy, regenerative treatment, and next-generation pharmacology which provide new opportunities to alter cardiovascular disease on a biological level. RNA interference systems and genetic interventions on genes have shown positive outcomes in lowering lipids, remodeling myocardial, and genetic cardiomyopathies, and regenerative therapies are focused on repairing myocardial structure and myocardial function. Simultaneously, new pharmacologic therapies including PCSK9-inhibitors, SGLT2-inhibitors, GLP-1 receptor agonists, and anti-inflammatory treatments have provided additional ways to reduce cardiovascular risks, beyond the conventional ones. The present review indicates the changing role of these innovative therapies along with the incorporation of molecular and pharmacologic therapies into a precision medicine framework to enhance the long-term cardiovascular outcomes.
Huge contributors to the 17.9 million deaths that heart disease causes annually is heart disease and its rising prevalence in the third world and low and middle-income countries contribute 32 percent of all heart disease-related deaths on earth. The key gaps are the lack of telemedicine and other technology utilisation in the low-resource regions, limited access to specialised care, and inadequate adherence to the guidelines. The recent industry efforts have been on residual cardiovascular risks, which has shown that high-risk patients remain under the threat despite medicines.(1,2,3)
Pharmacologic therapies, such as as beta-blockers, ACE inhibitors and statins, assist in the symptoms by normalizing cholesterol, blood pressure, and cardiac workload. Nevertheless, these drugs have side effects such as sleepiness, electrolytes imbalance, and fatigue and they are not effective in repairing damaged tissue. Besides, they require their lifetime use. Although coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) are useful in restoring blood flow, they not only fail to deal with the underlying issue of heart muscle regeneration, but also they have little long-term success because the condition progresses, and cannot be used in complex patients as well as situations of large costs. Despite the fact that the symptoms are alleviated by the means of device implants, including a pacemaker, they are costly, and they fail to prevent the underlying disease.(4,5)
Innovative promise Cardiac disease has transformative promise in the novel medicines targeting the biological basis of pathogenesis, including RNA-based approaches, gene therapy, and precision pharmacology. These modalities address the inadequacies of conventional medicine in three ways; gene control, tissue healing, and personalised dosage.
RNA-Based Therapeutics in Cardiovascular Disease
Antisense oligonucleotides (ASOs) bind to target messenger RNA (mRNA) and can turn off genes that lower lipids, such as apolipoprotein B, by either breaking them down or stopping their translation. Inclisiran is a PCSK9 inhibitor and involves the process of knocking down specific sequences through the RNA interference (RNAi) pathway with small interfering RNAs (siRNAs). To make the networks more accurate, microRNA (miRNA) manipulation involves the use of inhibitors or mimics. As one example, miR-92a silencing activates vascular repair whereas miR-21 silencing suppresses fibrosis.(6,7)
PCSK9-inhibitory siRNA e.g. inclisiran demonstrates an LDL- C reduction of 50 percent following bi-annual dosing, licensed in hypercholesterolemia, and demonstrates reduced cardiovascular event risk. The phase 2/3 trials of lipoprotein(a) [Lp(a)] therapies such as olpasiran (siRNA) and zerlasiran reduce a remaining risk factor not eliminated by statins by over 70-90%. ANGPTL3 inhibitors, like siRNA (for example, zodasiran), lower triglycerides and LDL in genetic dyslipidaemias. Phase 3 results have confirmed their effectiveness.(6)
MiRNA modulation improves collagen degradation and preserves heart failure function in preclinical heart failure models by ameliorating fibrosis with miR-29 mirrors and hypertrophy with miR-133 silencers. The miR-208a modulators and miR-155 inhibitors are metabolic and macrophage activation targets respectively, which improves and suppresses cardiomyocyte energy balance and macrophage activation respectively.(7)
It is challenging to enhance cardiac/vascular targeting with lipid nanoparticles (LNPs) and GalNAc conjugates; however, this administration technique poses the risk of immune reaction. Chemical derivations, including 2'-O-methyl may decrease the off-target effects. This, however, depends upon the persistence of these effects which may take between three and twelve months. At present, the experiments are in progress to maximise the safety of phase 2 and 3.(6,7)
Gene Therapy in Heart Disease
Multifactorial complications such as ischaemic heart failure have multiple pathways that can be corrected using medicines that increase contractility or vascularization, but monogenic conditions such as familial hypertrophic cardiomyopathy (e.g., MYBPC3 mutations) are treated by gene replacement or editing. Gene therapy is long-term change compared to medication which requires day to day administration. This modification can also reverse remodelling and minimize death in advanced cases. (8,9)
Adeno-associated viral (AAV) vectors, particularly cardiotropic AAV1 or chimeric capsid (such as those of AB-1002) used as intracoronary vectors, have very low immunogenicity, and years of long-term expression in preclinical animals, leading to high cardiac tropism. Examples of non-viral technologies that can potentially bypass immune reactions include lipid nanoparticles and electroporation; however, they are less effective and have temporary effects, so they are not the best options when it comes to CRISPR-based editing research.(9)
Heart failure treatments target contractility, such as I-1c in AB-1002, or calcium. Phase 1 results showed that these drugs improved LVEF and did not hurt HF patients who did not have ischaemia. Arrhythmia syndromes can reactivate ion channel activity in preclinical Long QT models through KCNH2 or SCN5A regulation. Inherited cardiomyopathies, however, necessitate mutation-specific strategies, including allele-specific silencing.( 10)
The immunogenicity of AAV pre-existing antibodies that prevent 30-50% of people can be reduced by using capsid engineering or immunosuppression. Risks of insertional mutagenesis are mild that are strictly followed through long-term follow-ups and its longevity is between 6 to 24 months. Ethical issues that can be addressed through the stepwise study include fair access, banning of germline editing and provision of informed consent to undergo permanent changes through the FDA and the EMA.(8)
Regenerative Approaches in Cardiovascular Medicine
Mesenchymal stem cells (MSCs) enhance cardiac performance by neovascularisation, paracrine signalling and anti-inflammatory mechanisms in models of myocardial infarction (MI). Preclinical studies have indicated that induced pluripotent stem cells (iPSCs) could enhance ventricular activity and tissue repair in patients when they are transplanted although teratomas should be eliminated prior to transplantation.(11,12)
In the absence of the dangers of pluripotency, direct reprogramming can make fibroblasts into cardiomyocyte-like cells in vivo, which enhances heart performance following myocardial infarction and reduces fibrosis. Electrical stimulation has improved the contractility and shape of the bioengineered cardiac tissues and thus is a good candidate to be used in heart patches.(13)
Exosomes secreted by stem cells can have paracrine effects, including reduced apoptosis, inflammation, and fibrosis, through microRNAs which can interact with signaling pathways such as NF- 2. They have the possibility of use as treatment to avoid heart damage due to ischemia-reperfusion injury, enhance autophagy, and recover functionality without issues related to cell engraftment.(14,15)
The success rates of engraftment are usually below 5 percent due to the inability of cells to retain and survive in ischaemic conditions, which inhibits efficiency. The lack of a complete development and integration of electrophysiology may contribute to arrhythmogenic issues such as the instability or ectopic beating. The scale of the problem of scalability is contributed to the production process itself, quality assurance, and regulatory needs of the clinical-grade products.(16,17,18,19,20)
In addition to the traditional antihypertensives and statins, the next-generation pharmacotherapeutic agents are expected to reduce the frequency of cardiovascular events by acting on inflammation, fibrosis, lipids, and glucose metabolism. Areas where the drugs have demonstrated promising results in the clinical studies include atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), and cardiometabolic protection.(21,22)
Monoclonal antibodies, like evolocumab, stop LDL receptors from going down and lower LDL-C levels by 50–60% by binding to PCSK9. Inclisiran, a siRNA-containing drug, inhibits the PCSK9 synthesis through GalNAc conjugation, and both inclisiran and ORION-4 outcomes are expected in 2026 and both drugs prevent ASCVD.(23)
These agents are favourable to HF with ejection fractions by reducing hospitalisations in natriuresis, preload drop, and RAAS modulation. They preserve kidney and heart functions by reducing tubular hypoxia, inhibiting fibrosis and inflammation with no effects on glucose levels. Two of the mechanisms include increments in haematocrit and energy efficiency.(24)
Besides SGLT2i, GLP-1 receptor and dual agonists (including tirzepatide) minimize the risks of myocardial infarction, acute coronary syndrome (ACS), and renal disease. New anti-inflammatory agents like canakinumab (IL-1 2 ), colchicine, and IL-6 inhibitors reduce the number of recurrent episodes by targeting adherent inflammation. SRC/TGF inhibitors can reverse myofibroblast activation in preclinical models of fibrosis.(25,26,27,28)
Figure 1. Overview of Key Cardiometabolic Therapeutic Strategies
Integration of Molecular and Pharmacologic Therapies
With regard to cardiovascular care, precision medicine is concerned with integrating pharmacologic drugs with molecular interventions such as RNA and gene editing to provide individualised care. Biomarkers and imaging can be used to select patients and measure response, which improves patient outcomes in CVD.(29,30)
In order to stratify patients and discover risk assessable biomarkers in ACS and HF, precision methods utilize genomes, transcriptomics, and AI/ML. Such biomarkers are natriuretic peptides and troponins. Patient selection algorithms based on genetic profiles to predict medication response can be used to give examples of biomarker panels that have attained 96% CVD diagnostic accuracy.(31)
In Mendelian and acquired CVD, the gene is targeted by RNA (siRNA, ASOs, mRNA); the strategies can be used together with drugs, including PCSK9 inhibitors to treat atherosclerosis or HF. With the integration of gene editing technology such as CRISPR and pharmacologics we can fight inflammation and fibrosis without the challenges of nanoparticles or AAV delivery.(32)
Besides clinical evaluation, high-sensitivity troponins, NT-proBNP, and inflammatory markers can be applied to prognose and offer therapeutic recommendations. Molecular imaging can follow the pathogenesis of HF and the treatment success, including the reversal of fibrosis, and intracoronary ultrasound and optical coherence tomography (IVUS/OCT) enhance percutaneous coronary intervention (PCI).(33)
Challenges, Limitations, and Future Directions
Regenerative and pharmacologic ameliorations to cardiovascular therapy have numerous barriers, including high prices and translation barriers. Nevertheless, this can be overcome through customized methods. The solution of these problems would enhance the effectiveness and fairness of the patient treatment.
Stem cells, gene editors, PCSK9 blockers and the rest are not accessible to a large population especially in regions with limited funds, and it is broadening health disparities. The failure to represent the different people in the trials and the deficiency of the required facilities in developing countries such as India are factors that perpetuate the inequity disparities.
There are things to be concerned with, such as immunogenicity, off-target effects in RNA/gene therapies, and late arrhythmogenesis or cancer in stem cell therapies. Most of the advantages also wear off after one or two years and thus continuous medication or repeated disposition is required; the effects of it are not known.
Adaptive studies and real-world evidence are speeding up orphan indication approvals even though FDA/EMA pathways require robust phase III data of hard endpoints.Two challenges to the development of customised treatments are the vector safety and the standardisation of cell potency testing.
Examples of bench-to-bedside challenges include poor preclinical models which do not reflect human retention/survival (less than 5% engraftment) and variable responses in patients. In order to seal loopholes to personalize the therapy, future studies must examine organoids, biomarkers that are driven by artificial intelligence, and combination drugs.(34)
CONCLUSION
Innovations in RNA-based therapeutics, gene therapy, regenerative medicine and next-generation pharmacology are a paradigm shift in managing cardiovascular diseases as opposed to merely controlling the symptoms but actually intervening at the mechanism level. Although these innovations have a great potential, there are still issues concerning the cost, accessibility, safety, and long-term durability. The future of cardiovascular care is likely to be characterized by the integration of the molecular therapies and the well-established pharmacologic therapies based on precision diagnostics and biomarkers. It will be necessary to continue research, implement these improvements with equal measure, and generate evidence in the field to ensure these improvements are translated into sustainable improvements in the outcomes of global cardiovascular.
REFERENCES
Vishal Pednekar, Vikas Gupta, Sayali Jadhav, Nameerah Rakhe, Emerging Therapies in Heart Disease: RNA-Based Approaches, Gene Therapy, and Precision Pharmacology, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 2, 3537-3544. https://doi.org/10.5281/zenodo.18723925
10.5281/zenodo.18723925
