Daily Cardiology Research Analysis
Three impactful cardiology studies stood out today: a secondary analysis from FINEARTS-HF shows finerenone reduces outpatient worsening heart failure events in HF with mildly reduced or preserved EF; a PNAS study introduces a spectral machine-learning method to reconstruct central aortic pressure waveforms from a simple brachial cuff; and a proteomics study identifies KLKB1 as a potentially causal, protective factor against aortic valve calcification. Together, these works span therapeutic, diag
Summary
Three impactful cardiology studies stood out today: a secondary analysis from FINEARTS-HF shows finerenone reduces outpatient worsening heart failure events in HF with mildly reduced or preserved EF; a PNAS study introduces a spectral machine-learning method to reconstruct central aortic pressure waveforms from a simple brachial cuff; and a proteomics study identifies KLKB1 as a potentially causal, protective factor against aortic valve calcification. Together, these works span therapeutic, diagnostic, and mechanistic advances.
Research Themes
- Therapeutic modulation of outpatient worsening heart failure in HFpEF/HFmrEF
- Noninvasive reconstruction of central aortic pressure via machine learning
- Proteomic mechanisms and causal targets in calcific aortic valve disease
Selected Articles
1. A spectral machine learning approach to derive central aortic pressure waveforms from a brachial cuff.
Using simultaneous invasive aortic catheter and brachial cuff signals in 115 subjects, the authors develop a spectral machine learning model that reconstructs central aortic pressure waveforms from a noninvasive cuff with high fidelity (mean normalized-RMS error 11.3%). The method captures dynamic oscillations in aortic systolic pressure and aligns beat-to-beat waveform magnitude and shape with invasive references.
Impact: This introduces a practical route to central blood pressure waveforms using standard cuff hardware plus spectral ML, potentially democratizing central hemodynamic assessment without tonometry or transfer functions.
Clinical Implications: If validated broadly, this approach could enable routine noninvasive central BP waveform analysis in clinics and trials, improving risk stratification, drug effect assessment on central hemodynamics, and personalized hypertension management.
Key Findings
- Developed a spectral ML model mapping brachial cuff wave components to central aortic waveforms.
- Validated against simultaneous invasive aortic catheter in 115 subjects with high fidelity (mean normalized-RMS error 11.3%).
- Captured dynamic oscillations in aortic systolic BP with strong correlation (r = 0.76).
Methodological Strengths
- Simultaneous invasive-reference validation (aortic catheter) in human subjects.
- Beat-to-beat waveform magnitude and shape correlation analysis providing granular performance assessment.
Limitations
- Single-device, single-laboratory development may limit generalizability across hardware and populations.
- No clinical outcome linkage; performance in arrhythmias, motion, and diverse pathologies remains to be shown.
Future Directions: External, multi-center validation across devices and populations, robustness testing in arrhythmias and ambulatory settings, and integration into cuff platforms with regulatory-grade calibration and clinical outcome studies.
Analyzing cardiac pulse waveforms offers valuable insights into heart health and cardiovascular disease risk, although obtaining the more informative measurements from the central aorta remains challenging due to their invasive nature and limited noninvasive options. To address this, we employed a laboratory-developed cuff device for high-resolution pulse waveform acquisition and constructed a spectral machine learning model to nonlinearly map the brachial wave components to the aortic site. Simultaneous invasive aortic catheter and brachial cuff waveforms were acquired in 115 subjects to evaluate the clinical performance of the developed wave-based approach. Magnitude, shape, and pulse waveform analysis on the measured and reconstructed aortic waveforms were correlated on a beat-to-beat basis. The proposed cuff-based method reconstructed aortic waveform contours with high fidelity (mean normalized-RMS error = 11.3%). Furthermore, continuous signal reconstruction captured dynamic aortic systolic blood pressure (BP) oscillations (r = 0.76,
2. Finerenone and Outpatient Worsening Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Secondary Analysis of the FINEARTS-HF Randomized Clinical Trial.
In 6001 patients with HF and LVEF ≥40%, outpatient oral diuretic intensification events were common, carried a poor prognosis (11.6 deaths/100 patient-years), and finerenone significantly reduced these events (HR 0.89) and an extended composite including CV death, HF hospitalization, and urgent HF visits (HR 0.85). Incorporating outpatient intensifications substantially increased event capture (1343 to 2238 patients).
Impact: This analysis reframes outpatient worsening HF as a clinically meaningful endpoint and demonstrates pharmacologic modification with finerenone in HFpEF/HFmrEF, informing future trial design and clinical management.
Clinical Implications: Clinicians should recognize outpatient diuretic intensifications as prognostically important and consider finerenone for patients with LVEF ≥40% to reduce worsening events alongside standard care, pending label and guideline alignment.
Key Findings
- Outpatient oral diuretic intensification was common (n=1250 first events) and associated with higher mortality (11.6 per 100 patient-years).
- Finerenone reduced outpatient diuretic intensification events (HR 0.89, 95% CI 0.80–0.98; P=0.02).
- Finerenone reduced an extended composite including CV death, HF hospitalization, urgent HF visit, and outpatient intensification (HR 0.85, 95% CI 0.78–0.92; P<.001).
Methodological Strengths
- Large, global, multicenter randomized dataset with centrally adjudicated endpoints.
- Prespecified analysis incorporating clinically relevant outpatient events.
Limitations
- Secondary analysis; randomization not stratified by outpatient event risk.
- Effect on hard clinical outcomes in isolation of outpatient intensification remains inferential.
Future Directions: Prospective trials incorporating outpatient diuretic intensification as an adjudicated endpoint; subgroup analyses to identify responders; pragmatic studies in real-world HFpEF/HFmrEF populations.
IMPORTANCE: Worsening heart failure (HF) is commonly managed in the outpatient setting with adjustments in oral diuretic therapy. The effect of the nonsteroidal mineralocorticoid receptor antagonist finerenone on outpatient worsening HF events in patients with mildly reduced or preserved ejection fraction is unknown. OBJECTIVE: To evaluate the effect of finerenone on outpatient worsening HF events requiring oral diuretic intensification among patients with HF with mildly reduced or preserved ejection fraction. DESIGN, SETTING, AND PARTICIPANTS: This is a secondary analysis of the Finerenone Trial to Investigate Efficacy and Safety Superior to Placebo in Patients With Heart Failure (FINEARTS-HF), a global, multicenter randomized clinical trial. Patients had HF and an ejection fraction of 40% or greater. Data analysis was conducted from September 1 to December 10, 2024. INTERVENTION: Participants were randomized 1:1 to finerenone or placebo. MAIN OUTCOMES AND MEASURES: Primary outcome events (cardiovascular death, HF hospitalization, and outpatient urgent HF visit requiring intravenous diuretic therapy) were centrally adjudicated. In this prespecified analysis, outpatient oral diuretic intensification events were defined as initiations of loop or thiazide diuretic or increases in loop diuretic dosage. The risk of all-cause death following each type of worsening HF event (HF hospitalization, urgent HF visit, or outpatient oral diuretic intensification) and the effect of finerenone on outpatient oral diuretic intensification alone or as part of an extended composite outcome with primary outcome events were evaluated. RESULTS: A total of 6001 participants (mean [SD] age, 72.0 [9.6] years; 2732 [46%] female) were enrolled. First worsening HF events included 664 HF hospitalizations, 87 urgent HF visits, and 1250 oral diuretic intensifications. Rates of death were higher following worsening HF: 27.7 (95% CI, 24.3-31.5) per 100 patient-years after HF hospitalization, 13.6 (95% CI, 8.8-21.1) per 100 patient-years after urgent HF visit, and 11.6 (95% CI, 10.2-13.1) per 100 patient-years after outpatient oral diuretic intensification compared with 4.5 (95% CI, 4.2-4.9) per 100 patient-years for patients without worsening HF. Adding outpatient oral diuretic intensification to the primary outcome increased the number of patients experiencing events from 1343 to 2238. Finerenone reduced outpatient oral diuretic intensification alone (hazard ratio [HR], 0.89 [95% CI, 0.80-0.98]; P = .02) and in an extended composite outcome that further included cardiovascular death, HF hospitalization, and urgent HF visit (HR, 0.85 [95% CI, 0.78-0.92]; P < .001). CONCLUSIONS AND RELEVANCE: Outpatient worsening HF events requiring oral diuretic intensification were common, associated with poor prognosis, and reduced by finerenone in patients with HF with mildly reduced or preserved ejection fraction. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04435626.
3. Plasma Proteomic Assessment of Calcific Aortic Valve Disease in Older Adults.
Aptamer-based proteomics (~5000 proteins) in CHS identified proteins associated with AVC; CXCL12, KLKB1, and leptin replicated in AGES-RS. Mendelian randomization supported a causal, protective association of higher KLKB1 with lower AVC, nominating KLKB1 as a potential therapeutic target for calcific aortic valve disease.
Impact: This work bridges population proteomics, replication, and genetic causality to propose KLKB1 as a modifiable pathway in valve calcification, addressing a major unmet need in AS prevention.
Clinical Implications: While not yet a clinical test, KLKB1 pathway modulation could be explored as a preventive strategy for CAVD; proteins like CXCL12 and leptin refine risk biology and may inform biomarker panels.
Key Findings
- Six proteins were significantly associated with AVC in CHS; CXCL12, KLKB1, and leptin replicated in AGES-RS.
- Mendelian randomization supported a causal association: higher KLKB1 linked to lower AVC (protective).
- CXCL6 showed a significant positive association with incident AS; CXCL12 and KLKB1 associations highlighted novel biology.
Methodological Strengths
- Two large, independent older-adult cohorts with orthogonal imaging endpoints (echo and CT).
- Genetic causal inference via 2-sample Mendelian randomization using cis-pQTLs.
Limitations
- Aptamer-based proteomics may have platform-specific biases; limited functional validation.
- Observational cohorts with residual confounding; MR limited to available instruments and outcomes.
Future Directions: Mechanistic studies of KLKB1 in valvular interstitial cells and animal models; drug discovery/repurposing targeting kallikrein pathways; prospective validation of proteomic panels for CAVD risk.
BACKGROUND: Calcific aortic valve disease (CAVD), and ensuing severe aortic stenosis (AS), is the foremost valvular disorder of aging, yet preventive therapies are lacking. A better understanding of the molecular underpinnings of aortic valve calcification (AVC) is necessary to develop pharmacologic interventions. METHODS AND RESULTS: We undertook large-scale plasma proteomics in a cohort study of adults ≥65 years old, the CHS (Cardiovascular Health Study), to identify individual proteins associated with echocardiographic AVC and incident moderate/severe AS. Proteomics measurements were performed with the aptamer-based SomaLogic platform of ~5000 proteins. Significant proteins were validated in a second cohort, the AGES-RS (Age, Gene/Environment Susceptibility-Reykjavik Study), which assessed AVC and AS by computed tomography. The potential causal associations of replicated proteins were tested in 2-sample Mendelian randomization using identified cis protein quantitative trait loci in consortia having computed tomography-quantified AVC or AS as outcomes. Six proteins showed Bonferroni-corrected significant relationships with AVC in CHS. Three of these, CXCL-12 (C-X-C chemokine ligand 12), KLKB1 (kallikrein), and leptin, replicated in AGES-RS, of which the former 2 are novel. Only 1 protein, CXCL6, which showed a near-significant association with AS in the replication cohort, was significantly (positively) associated with incident AS. Mendelian randomization analysis was conducted for KLKB1, CXCL12, and CXCL6, which supported a causal relationship for higher KLKB1 with lower AVC (beta=-0.25, CONCLUSIONS: This study of older adults newly identified and largely replicated associations of 3 circulating proteins with calcific aortic valve disease, of which the relationship of plasma KLKB1 may have a causal basis. Additional investigation is necessary to determine if KLKB1 could be harnessed for calcific aortic valve disease therapeutics.