Daily Cardiology Research Analysis
A large multicenter randomized trial in India found three commonly recommended dual antihypertensive combinations achieve similarly large reductions in 24-hour ambulatory and office blood pressure, informing first-line combination choices. A mechanistic study in the European Heart Journal identifies the hexosamine biosynthetic pathway–integrated stress response (HBP–ISR) axis as a driver of thoracic aortic aneurysm medial degeneration and shows pathway inhibition is protective in Marfan models.
Summary
A large multicenter randomized trial in India found three commonly recommended dual antihypertensive combinations achieve similarly large reductions in 24-hour ambulatory and office blood pressure, informing first-line combination choices. A mechanistic study in the European Heart Journal identifies the hexosamine biosynthetic pathway–integrated stress response (HBP–ISR) axis as a driver of thoracic aortic aneurysm medial degeneration and shows pathway inhibition is protective in Marfan models. A Circulation cohort of 460,544 UK Biobank participants links higher lipoprotein(a) to incident and progressive extracoronary atherosclerotic disease, supporting Lp(a) risk stratification.
Research Themes
- Optimization of first-line dual antihypertensive therapy
- Mechanistic targets in thoracic aortic aneurysm (HBP–ISR axis)
- Risk stratification using lipoprotein(a) for extracoronary atherosclerosis
Selected Articles
1. Comparison of dual therapies for hypertension treatment in India: a randomized clinical trial.
In a multicenter, single-blind RCT (n=1,981), three guideline-recommended dual combinations (amlodipine–perindopril, perindopril–indapamide, amlodipine–indapamide) produced similar, large reductions in 24-hour ambulatory (~14/8 mmHg) and office (~30/14 mmHg) BP over 6 months, with ~70% achieving control. Safety and secondary outcomes did not differ across regimens.
Impact: This pragmatic RCT directly informs first-line combination choices in a large South-Asian cohort, showing multiple dual regimens are equivalently effective and well tolerated.
Clinical Implications: Clinicians can prioritize availability, patient comorbidities, cost, and adherence when selecting initial dual therapy, as amlodipine–perindopril, perindopril–indapamide, and amlodipine–indapamide yield comparable BP reductions and control rates.
Key Findings
- All three dual combinations lowered 24-hour ambulatory BP by ~14/8 mmHg and office BP by ~30/14 mmHg at 6 months.
- Approximately 70% of participants achieved BP control (<140/90 mmHg) across all regimens.
- No significant differences in secondary outcomes or safety were observed among groups.
Methodological Strengths
- Multicenter randomized controlled, single-blind design with ambulatory BP primary endpoint
- Direct head-to-head comparison of three common dual regimens with high completion of ABPM
Limitations
- Single-blind design and conducted within one country (India), which may limit generalizability
- Six-month follow-up without hard cardiovascular outcomes
Future Directions: Evaluate long-term cardiovascular outcomes and cost-effectiveness across regimens and extend to other regions and high-risk subgroups (e.g., CKD, diabetes).
Evidence is lacking for guiding optimal combination hypertension therapy in South Asian patients. Here we investigated the blood pressure (BP)-lowering efficacy and safety of three commonly recommended antihypertensive dual combinations in a multicenter, single-blinded trial conducted in India. We randomized Indians aged 30-79 years (mean age, 52 years) with mean sitting systolic blood pressure (SBP) of 150-179 mmHg on no treatment or an SBP of 140-159 mmHg on monotherapy 1:1:1 to a single-pill combination of amlodipine-perindopril, perindopril-indapamide or amlodipine-indapamide. The primary outcome was the mean change in 24-hour ambulatory SBP at 6 months. Of the 1,981 participants (42% females) enrolled in the trial, 1,637 completed a 24-hour ambulatory BP measurement. All three drug combinations produced similar large reductions in the primary outcome, namely ambulatory (~14/8 mmHg) and office (~30/14 mmHg) BPs after 6 months, such that hypertension control rates (sitting BP < 140/90 mmHg) were achieved in approximately 70% of participants in all three groups. Furthermore, no significant differences in secondary outcomes, such as mean day and night ambulatory and office BPs and hypertension control rates, were observed among the study groups. Thus, in Indian patients, amlodipine-perindopril, perindopril-indapamide and amlodipine-indapamide were all equally well tolerated and equally highly effective in reducing 24-hour ambulatory and office BPs (ClinicalTrials.gov registration: NCT05683301 ).
2. Excessive glycosylation drives thoracic aortic aneurysm formation through integrated stress response.
Across Marfan and non-genetic TAAD models and human aortas, the hexosamine biosynthetic pathway is upregulated and promotes aortic dilatation and medial degeneration via vascular smooth muscle dysfunction and integrated stress response activation. Pharmacologic inhibition of HBP or ISR reversed disease features in Marfan models, nominating the HBP–ISR axis as a therapeutic target.
Impact: This work uncovers a unifying, targetable metabolic–stress pathway (HBP–ISR) in genetic and sporadic TAAD, advancing mechanistic understanding and therapeutic avenues beyond surgery.
Clinical Implications: Although preclinical, HBP/ISR inhibitors could complement or delay surgical intervention for TAAD if translated; biomarker development for HBP–ISR activation may enable risk stratification.
Key Findings
- HBP activation is elevated in Marfan and BAPN-induced TAAD models and in human MFS and sporadic TAAD aortas.
- Enhanced HBP activity drives vascular smooth muscle dysfunction and activates ISR, promoting aortic dilatation and medial degeneration.
- Pharmacologic inhibition of HBP or ISR reverses these pathogenic changes in Marfan mouse models.
Methodological Strengths
- Triangulation across multiple in vivo models (genetic and non-genetic) and human tissue
- Integrated transcriptomic/metabolomic profiling coupled with pharmacologic inhibition experiments
Limitations
- Preclinical study; human causal inference and therapeutic efficacy remain unproven
- Human sample sizes and clinical heterogeneity not fully detailed in the abstract
Future Directions: Develop and test selective HBP/ISR inhibitors in large-animal models; identify circulating markers of HBP–ISR activation; design early-phase clinical trials in heritable and sporadic TAAD.
BACKGROUND AND AIMS: Thoracic aortic aneurysms and dissections (TAADs) are depicted by aortic medial degeneration characterized by glycan-rich matrix accumulation. Marfan syndrome (MFS) is the most common inherited connective tissue disorder associated with TAAD. Although vascular smooth muscle cell metabolic dysfunction has emerged as a pathogenic driver of TAAD, surgical repair remains the mainstay of treatment. This study aimed to investigate the role of the hexosamine biosynthetic pathway (HBP) in sporadic and genetic TAAD pathophysiology. METHODS: Hexosamine biosynthetic pathway activation was analysed in aortas from an MFS mouse model, a β-aminopropionitrile-induced non-genetic TAAD model, and patients with sporadic TAAD using transcriptomic and metabolomic approaches. Aortic dilatation was monitored by ultrasound imaging. Pharmacological inhibition of HBP and integrated stress response (ISR) was performed to assess their therapeutic potential. RESULTS: Hexosamine biosynthetic pathway was up-regulated in both an MFS mouse model and β-aminopropionitrile-induced TAAD, as well as in aortic samples from MFS and sporadic TAAD patients. Enhanced HBP activity contributed to aortic dilatation and medial degeneration via vascular smooth muscle cell dysfunction and ISR activation. Inhibition of HBP or ISR reversed these effects in the MFS model. CONCLUSIONS: The HBP-ISR axis drives medial degeneration in TAAD. These findings identify HBP and ISR as a potential target in TAAD of both genetic and non-genetic origin.
3. Evaluation of Lipoprotein(a) as a Prognostic Marker of Extracoronary Atherosclerotic Vascular Disease Progression.
In 460,544 UK Biobank participants followed a median 13.6 years, higher Lp(a) was associated with incident PAD and carotid stenosis and with progression to major adverse limb events and stroke among those with prevalent disease. Risk per 75 nmol/L increase in Lp(a) was significant, supporting its role in extracoronary atherosclerotic risk stratification.
Impact: This very large, long-term cohort demonstrates that Lp(a) predicts not only coronary but extracoronary disease onset and progression, informing screening and emerging Lp(a)-lowering therapeutic strategies.
Clinical Implications: Measuring Lp(a) can refine risk stratification for PAD and carotid stenosis and identify candidates for intensified prevention and future Lp(a)-targeted therapies.
Key Findings
- Higher Lp(a) associated with incident PAD and carotid artery stenosis over a median 13.6 years.
- Among those with prevalent disease, higher Lp(a) predicted progression to first major adverse limb event and first stroke.
- Risk gradients evident: median Lp(a) levels were higher in incident/progressive disease than in those without disease.
Methodological Strengths
- Prospective cohort with very large sample size and long follow-up
- Standardized Lp(a) measurement and Cox modeling for multiple vascular outcomes
Limitations
- Predominantly European ancestry limits generalizability
- Observational design cannot prove causality
Future Directions: Evaluate Lp(a)-lowering therapies on extracoronary outcomes; validate risk thresholds across ancestries; integrate Lp(a) into poly-risk algorithms for PAD/carotid disease.
BACKGROUND: Despite current treatment strategies for atherosclerotic vascular disease focusing on lifestyle modification and lowering cholesterol, a significant residual risk of major atherosclerotic complication remains, prompting investigation into lipoprotein(a) (Lp(a)) as a potential predictive biomarker. The objective of this study was to determine the usefulness of Lp(a) in identifying patients at high risk of incident extracoronary atherosclerotic vascular disease and complications. METHODS: Data from 460 544 participants in the UK Biobank with prospectively measured Lp(a) concentrations were included in this analysis. Cox proportional hazards regressions modeled the associations of Lp(a) concentrations with incident peripheral artery disease (PAD) and incident carotid artery stenosis and progression to the first major adverse limb event and the first stroke, respectively. RESULTS: Of the study participants, the median [interquartile range] age at study enrollment was 58 [51-64] years, 54.2% were male, 94.4% were European, 5.5% had diabetes, and 10.5% were smokers. Over a median follow-up time of 13.6 [12.9-14.4] years, 6347 (1.4%) and 1972 (0.43%) developed the first incidence of PAD and carotid stenosis, respectively. Among participants with prevalent PAD and carotid stenosis at enrollment, 196 (2.7%) and 67 (1.9%) progressed to the first incidence of major adverse limb event and stroke, respectively. Median Lp(a) concentrations were significantly different in those without atherosclerotic vascular disease at 19.5 nmol/L [7.6-73.5] compared with incident PAD at 25.3 nmol/L [8.3-107.3], progression to major adverse limb event at 33.3 nmol/L [8.7-158.2], incident carotid stenosis at 29.5 nmol/L [8.5-116.3], and carotid stenosis progression to stroke at 37.8 nmol/L [11.1-158.3]. The risk estimate per 75 nmol/L Lp(a) for incident PAD (hazard ratio [HR], 1.18 [95% CI, 1.15-1.20]; CONCLUSIONS: High concentrations of Lp(a) are associated with both incident extracoronary atherosclerotic vascular disease and progression to major complications.