Open questions — hypertensive heart disease¶
Last curated: 2026-08-31. IDs are stable handles for future audits. Tier 1 questions could change classification, screening, treatment, or clinical outcomes; Tier 2 questions refine mechanism, measurement, implementation, or subgroup translation. Every PMID was resolved by live PubMed E-utilities in this build.
Tier 1 — decision-changing questions¶
OQ-HHD-001 — What minimum definition should count as HHD?¶
Clinical remodeling phenotypes, causal attribution, administrative coding and GBD-modeled HHD are not interchangeable. A useful definition must specify hypertension exposure, cardiac phenotype, competing-cause evaluation and clinical stage, then demonstrate reproducibility across settings (Nwabuo 2020, PMID 32016791; Yang 2023, PMID 37698022).
Decisive study: international prospective cohort with a preregistered minimum dataset, adjudicated competing causes, cross-modality reproducibility, and externally tested outcome calibration.
OQ-HHD-002 — Does screening asymptomatic hypertension with echo, CMR or biomarkers improve outcomes?¶
ECG, echo, CMR, strain and biomarkers can stratify risk, but no strategy trial shows that systematic detection changes treatment and improves patient outcomes beyond high-quality risk-based BP care (Pewsner 2007, PMID 17726091; Sharp 2026, PMID 41771092).
Decisive study: cluster- or individual-randomized screening strategy with prespecified treatment actions, clinical outcomes, harms, anxiety and cost-effectiveness.
OQ-HHD-003 — Is remodeling regression a causal treatment target?¶
LVH regression is associated with lower events, and randomized drugs can change LV mass or fibrosis, but achieved BP, adherence and baseline risk confound mediation (Pierdomenico 2010, PMID 20414193; Lee 2025, PMID 40739095).
Decisive study: randomized treat-to-regression strategy versus identical BP target without serial imaging disclosure, powered for HF, stroke, AF and death.
OQ-HHD-004 — Can myocardial fibrosis be reversed in a way that prevents HF?¶
REVERSE-LVH demonstrated differential change in CMR interstitial volume at similar ambulatory SBP, but not clinical outcomes. Fibrosis measures are not interchangeable and may represent different tissue processes (González 2024, PMID 38084597; Lee 2025, PMID 40739095).
Decisive study: multicenter CMR-standardized trial linking a prespecified fibrosis change to HF prevention, with causal mediation analysis.
OQ-HHD-005 — Which BP target has the best net benefit in established HHD?¶
SPRINT and STEP support intensive control in selected populations, while ACCORD BP produced a neutral primary composite and more treatment-attributed serious adverse events. None selected participants by a standardized HHD phenotype (PMIDs: 26551272, 34491661, 20228401).
A STEP secondary analysis now anchors the achieved band out of office: versus achieved home systolic ≥135 mm Hg, adjusted HRs were 0.62 (95% CI 0.42–0.90) below 125 mm Hg and 0.66 (0.47–0.94) at 125–130 mm Hg, with stroke HR 0.36 (0.19–0.66) and no significant safety increase — but achieved BP is post-randomization, so this narrows the translation problem rather than answering the target question (Ji 2026, PMID 42660976).
Decisive study: phenotype-stratified target trial using standardized office plus ambulatory BP, patient-reported burden, renal harms and clinical events.
OQ-HHD-006 — Can biomarker staging guide treatment rather than only prognosis?¶
REMODEL’s NT-proBNP and hs-troponin T thresholds separated risk strongly, but were internally selected and can be distorted by age, CKD, AF and obesity (Sharp 2026, PMID 41771092; Obokata 2017, PMID 28381470).
PRECISE-HF shows the method is available even though the target condition differs: in 535,583 UK primary-care patients an NT-proBNP model conditioned on age, sex, ethnicity, eGFR, BMI, systolic BP, anaemia, loop diuretic and comorbidity reached AUROC 0.896 internally and outperformed universal ESC thresholds, with AUROC falling to 0.757 on Swedish external validation (Docherty 2026, PMID 42663089). REMODEL's fixed cutoffs have no equivalent covariate conditioning or external test.
Decisive study: assay-calibrated external validation followed by a randomized biomarker-guided intervention trial.
OQ-HHD-007 — Which pre-HF phenotype should enter a prevention trial?¶
Concentric LVH, impaired GLS, atrial dysfunction, fibrosis and biomarker elevation are plausible enrichers, but may select different pathways and event rates (Hwang 2025, PMID 40970541; Lertsiripatarajit 2026, PMID 41953289).
Decisive study: harmonized prospective platform cohort followed by an adaptive prevention trial across reproducible phenotypes.
OQ-HHD-008 — How much apparent essential HHD is missed primary aldosteronism or another secondary cause?¶
Primary aldosteronism carries excess cardiovascular and organ-damage risk, but screening practice and denominators vary. OSA, CKD, renovascular disease and drug/substance effects add overlapping pathways (Monticone 2018, PMID 29129575; Sarathy 2022, PMID 35227430).
Decisive study: systematic secondary-cause work-up in an unselected, clearly phenotyped HHD cohort with treatment-response follow-up.
OQ-HHD-009 — Does targeted primary-aldosteronism treatment reverse HHD and reduce events?¶
Biological plausibility and observational excess risk are strong; comparative cardiac-outcome evidence between surgery, MRA therapy and essential-hypertension care remains incomplete (Monticone 2018, PMID 29129575; Endocrine Society 2025, PMID 40658480).
Decisive study: prospective treatment-effect study with standardized biochemical phenotyping, CMR/echo endpoints and adjudicated clinical events.
OQ-HHD-010 — Will renal denervation prevent cardiovascular outcomes?¶
Sham-controlled and meta-analytic evidence supports BP lowering, and small AF studies suggest rhythm effects, but an adequately powered major-event trial is absent (Vukadinović 2024, PMID 39355923; Steinberg 2020, PMID 31961420).
Decisive study: sham-controlled event trial in persistent hypertension with adherence assessment and prespecified HHD/AF subgroups.
OQ-HHD-011 — Does aggressive hypertension treatment prevent AF through atrial reverse remodeling?¶
BP is associated with incident AF and LIFE analyses suggest reduced new AF with losartan-based therapy, but the mediated pathway through atrial structure/function is not established (Aune 2023, PMID 36626102; Wachtell 2005, PMID 15734615).
Decisive study: randomized BP/drug strategy with serial atrial strain/volume, continuous rhythm monitoring and formal mediation analysis.
OQ-HHD-012 — Which surveillance schedule changes outcomes?¶
Serial echo and CMR cohorts predict risk, but detection alone is not benefit. No validated HHD-specific repeat-imaging interval was identified (Hwang 2025, PMID 40970541; Lertsiripatarajit 2026, PMID 41953289).
Decisive study: randomized surveillance intervals with explicit action thresholds and patient-centered clinical outcomes.
OQ-HHD-013 — Can global treatment delivery prevent more HHD than phenotype-intensive care?¶
Village-doctor and home-based programs improve hypertension care in resource-constrained settings, while advanced imaging remains scarce. The comparative opportunity cost is unmeasured (Sun 2022, PMID 35500594; Siedner 2025, PMID 40888742).
Half-answered, 2026-08-31. CRHCP's 7-year report settles the durability half: a nonphysician-led intensive-target package in 326 villages and 33,995 adults sustained a −13.5/−5.4 mm Hg difference and a CVD composite HR of 0.76 (95% CI 0.72–0.81) over 7 years, and 0.79 (0.73–0.85) during the 3 post-trial years after free medication, extra training and performance incentives were withdrawn, at the cost of more hypotension (RR 1.58) and mild hypokalemia (RR 1.38) (Sun 2026, PMID 42666029). The delivery arm of the comparison is therefore no longer hypothetical. What remains unmeasured is the comparison itself: a live PubMed and ClinicalTrials.gov search repeated on 2026-08-31 identified no head-to-head study of a scalable delivery package versus a phenotype-intensive imaging/biomarker package for the same population and budget. CRHCP did not report cardiac phenotyping in its PubMed record.
Decisive study: implementation platform comparing scalable control packages, with nested low-cost organ-damage ascertainment and equity outcomes.
OQ-HHD-014 — What are the benefits and harms of telling an asymptomatic person they have “heart damage”?¶
Earlier imaging and biomarker staging create labels before symptoms, but direct evidence on anxiety, agency, adherence, discrimination and treatment burden is missing (Nwabuo 2020, PMID 32016791; Sharp 2026, PMID 41771092).
Decisive study: embedded randomized communication study plus longitudinal qualitative work in a phenotype cohort.
OQ-HHD-029 — What is the right blood-pressure target once HHD has produced atrial fibrillation?¶
Hypertension trials support monotonic "lower is better," but in established AF the relation splits. A dose-response meta-analysis of 23 studies from 17 cohorts (n=476,750) found systolic BP U-shaped for all-cause mortality with a nadir at 134 mm Hg (RR 0.92, 95% CI 0.86–0.98 versus 120 mm Hg) and diastolic J-shaped with a nadir at 83 mm Hg, while ischaemic stroke and especially intracranial haemorrhage rose monotonically with systolic BP (at 150 versus 120 mm Hg, RR 1.99 for intracranial haemorrhage against 1.14 for ischaemic stroke) (Shahmohamadi 2026, PMID 42663497). The observational nadir is vulnerable to reverse causation from advanced disease and to confounding by anticoagulant exposure, so it cannot be read as a target — but neither can a hypertension-trial target be transferred unexamined into an anticoagulated AF population.
Decisive study: randomized BP-target trial enrolling anticoagulated AF patients, with prespecified separation of ischaemic and haemorrhagic stroke, mortality, and frailty/competing-risk stratification.
Tier 2 — mechanism, measurement and translation¶
OQ-HHD-015 — Which pressure exposure matters most?¶
Mean 24-hour pressure, nighttime BP, dipping, variability, central pressure and time in range may carry different remodeling information (Yang 2019, PMID 31386134; Zhang 2025, PMID 40249369). A participant-level pooling of TOPCAT-Americas, PARAGON-HF, DELIVER and FINEARTS-HF (17,788 patients) found median time in the 110–<130 mm Hg systolic band was only 38% of the first randomized year, and higher time in range was associated with fewer HF hospitalizations (P=0.007) but not with lower cardiovascular or all-cause death (Lu 2026, PMID 42669134).
OQ-HHD-016 — How should LV mass be indexed in obesity?¶
Body-surface area can conceal obesity-related hypertrophy, while height-based indexation changes prevalence and thresholds. The best decision-linked method is unsettled (Ismail 2023, PMID 37176563).
OQ-HHD-017 — Can HHD and hypertrophic cardiomyopathy be separated reliably in borderline cases?¶
CMR group differences do not guarantee accurate individual classification, particularly with coexisting hypertension and sarcomeric disease (Zhao 2024, PMID 39156132; Nemtsova 2023, PMID 37048689).
OQ-HHD-018 — Which fibrosis metric is most portable?¶
ECV fraction, absolute interstitial volume, LGE and circulating collagen-turnover markers reflect overlapping but nonidentical constructs (González 2024, PMID 38084597; Lee 2025, PMID 40739095).
OQ-HHD-019 — Does microvascular dysfunction cause the transition to HFpEF?¶
Hypertension, inflammation, fibrosis, impaired relaxation and coronary microvascular dysfunction form a coherent pathway, but temporal and interventional evidence is incomplete (Paulus 2013, PMID 23684677; Camici 2020, PMID 31999329).
OQ-HHD-020 — Are geometry transitions mechanistically distinct?¶
Concentric remodeling, concentric LVH, eccentric LVH and dilation predict differently, but transitions can reflect pressure load, obesity, ischemia, kidney disease or treatment (Nadruz 2015, PMID 24804791; Vasan 2021, PMID 34081212).
OQ-HHD-021 — Can strain thresholds be standardized?¶
GLS can detect subclinical dysfunction, but load, vendor, software, image quality and reference population impede universal cutoffs (Ismail 2023, PMID 37176563).
OQ-HHD-022 — What is the role of the right ventricle and pulmonary circulation?¶
The dominant HHD model is left-sided, yet clinical progression can involve pulmonary hypertension and right-heart dysfunction. Longitudinal HHD-specific evidence is thin (Nwabuo 2020, PMID 32016791).
OQ-HHD-023 — Which effects of obesity are independent of measured BP?¶
Obesity changes hemodynamics, LV indexing, natriuretic peptide levels and HFpEF phenotype; separation from BP-mediated effects is methodologically difficult (Obokata 2017, PMID 28381470; Redfield 2023, PMID 36917048).
OQ-HHD-024 — Does CKD alter the optimal remodeling strategy?¶
CKD raises risk, changes cardiac structure and biomarkers, and constrains RAAS/MRA therapy through renal and potassium safety boundaries (Kaesler 2023, PMID 38000021; Dobre 2024, PMID 38193308).
OQ-HHD-025 — Which sex differences are biological and which are measurement or attribution effects?¶
GBD analyses report sex differences in HHD burden, but exposure, survival, health-care access, coding, body-size indexation and biology can all contribute (Chan 2024, PMID 37607268; Khalid 2025, PMID 40565965).
OQ-HHD-026 — How should competing etiologies be represented?¶
Hypertension commonly coexists with coronary, valvular, infiltrative and genetic disease. A single-cause label can erase mixed causal structure (Nwabuo 2020, PMID 32016791; Zhao 2024, PMID 39156132).
OQ-HHD-027 — Which patient-reported outcomes belong in HHD trials?¶
BP and imaging trials rarely capture treatment burden, anxiety, function, financial cost or decisional regret, although severe hypertension and HFpEF studies show these matter (Hill 2026, PMID 42321603; Rubio 2025, PMID 40649089).
OQ-HHD-028 — Can salt-substitute benefits transfer safely across food systems?¶
SSaSS showed fewer strokes and deaths in rural China, but processed-food sodium, CKD prevalence, RAAS blockade and potassium surveillance differ elsewhere (Neal 2021, PMID 34459569; Yin 2022, PMID 35945000).
OQ-HHD-030 — Does clinically assigned HHD attribution agree with modeled HHD attribution in the same population?¶
THESUS-HF II clinically assigned aetiology in 1,578 acute-HF presentations across 17 African countries and identified HHD as the leading cause at 36.5%, ahead of cardiomyopathy and ischaemic heart disease (Sliwa 2026, PMID 42669305). GBD partitions HHD inside a modeled HF envelope with a different denominator and a different causal machinery (Chen 2025, PMID 39774847). A live PubMed and ClinicalTrials.gov search repeated on 2026-08-31 identified no study applying both constructs to one population, so their agreement and direction of difference remain unknown.
Dots not yet connected¶
| # | Dot A | Dot B | Missing junction | Powers |
|---|---|---|---|---|
| 1 | Lower BP prevents events | LVH/fibrosis can regress | Randomized proof that regression mediates event reduction | Treat-to-regression trial with identical BP target and blinded imaging arm |
| 2 | REMODEL biomarkers predict high risk | HF therapies improve outcomes after syndrome onset | Evidence that biomarker-triggered pre-HF treatment helps | External validation followed by biomarker-guided platform trial |
| 3 | CMR distinguishes phenotypes | Global HHD burden is concentrated where CMR is scarce | Minimum low-cost phenotype with calibrated accuracy | Paired ECG/echo/biomarker/CMR cohort across resource settings |
| 4 | Primary aldosteronism causes excess injury | HHD cohorts often use “essential hypertension” | Prevalence and reversibility of missed aldosteronism in HHD | Systematic screening cohort with targeted-treatment follow-up |
| 5 | Nighttime BP predicts risk | Serial imaging detects remodeling change | Which nocturnal exposure drives reversible tissue change | Repeated ABPM plus standardized echo/CMR longitudinal study |
| 6 | Hypertension increases AF risk | Renal denervation may reduce BP and AF recurrence | Whether atrial benefit is BP-mediated or neural | Sham-controlled trial with continuous rhythm and atrial imaging |
| 7 | Obesity suppresses natriuretic peptides | Biomarker staging uses fixed thresholds | Obesity-calibrated thresholds and decision utility | Stratified calibration plus randomized threshold-guided care |
| 8 | CKD increases HHD risk | Intensive treatment causes more AKI/electrolyte events | Net-benefit frontier by kidney phenotype | CKD-stratified target trial with renal and cardiovascular estimands |
| 9 | Salt substitution prevents events | Hyperkalemia risk varies by kidney function and medicines | Scalable safety algorithm | Pragmatic cluster trial with potassium-risk triage |
| 10 | Community health-worker programs improve control | Advanced phenotyping stratifies risk | Whether simple phenotyping improves community allocation | Cluster trial adding low-cost ECG/echo/biomarker triage |
| 11 | “Heart damage” may motivate prevention | Labeling can create anxiety and burden | Net patient effect of early HHD disclosure | Randomized communication study with qualitative process evaluation |
| 12 | HFpEF is heterogeneous | Hypertension is a common upstream exposure | Reproducible hypertension-dominant treatment-response phenotype | Prospective phenomapping embedded in multi-arm HFpEF trials |
| 13 | LV mass and GLS both predict outcomes | Mass-to-strain ratio is a new candidate | Incremental decision value and portability | Multivendor external validation with decision-curve analysis |
| 14 | Guidelines disagree on thresholds/targets | Measurement protocols differ | Harmonized crosswalk grounded in outcomes | Individual-participant calibration across office, home and ABPM |
| 15 | Lower BP prevents stroke in hypertension | Mortality is U-shaped against systolic BP in established AF | Whether the AF nadir is causal or reverse-caused | Randomized BP target in anticoagulated AF, splitting ischaemic from haemorrhagic stroke |
| 16 | Nonphysician delivery sustains event reduction after subsidy withdrawal | Phenotype-intensive imaging stratifies risk | Head-to-head comparison at equal budget | Implementation trial randomizing delivery package versus phenotype package |
| 17 | Clinical assignment makes HHD the leading acute-HF cause in the THESUS-HF II aggregate cohort | GBD models HHD as a partition of an HF envelope | Whether the two constructs agree on one population | Parallel clinical and modeled attribution in a shared cohort |
Maintenance rules¶
- Promote a Tier 2 question to Tier 1 when a plausible answer would change a clinical decision.
- Retire a question only when replicated evidence answers the decision, not when a single association is published.
- Add negative and neutral trials; avoid “breakthrough-only” maintenance.
- Preserve stable OQ IDs and append rather than renumber.
- Link each resolved question to the page and source that resolved it.