33 compounds were read against these 3 conditions; 29 produced a graded row. The other 4 are named further down.

The ranking, and the key it uses

Ordered by the best rung the compound holds anywhere in this goal; then by what that study measured; then by how many graded rows it holds here, as a tie-break only; then by name. There is no blended score — one number mixing the rung and what was measured would invent a third scale nothing was graded against. Every rung links to the rubric that assigned it.

1. 01

   Adrenomedullin

   human RCT · direct outcome · 3 graded rows across 3 of 3 conditions

   Hypertension · Cardiovascular disease · Heart failure

   3 graded rows, 2 sources

   1. Hypertension

      human RCT Direct outcome Not approved for this condition

      Who was studied

      men aged 39-58 with uncomplicated essential hypertension, baseline 147/96 mmHg, n=8; two-hour infusions in a placebo-controlled crossover

      Blood pressure was measured in hypertensive men during intravenous adrenomedullin: the high dose (5.8 pmol/kg/min for 2 hours) lowered systolic by 24.6 mmHg and diastolic by 21.9 mmHg against vehicle, with a rise in heart rate and cardiac output. This is an acute infusion study of an endogenous peptide, not a treatment course; no trial of repeated or oral administration for hypertension is on file.

      Source PubMed 1 primary source read for this row

   2. Cardiovascular disease

      human case series Surrogate marker Not approved for this condition

      Who was studied

      7 patients with congestive heart failure and 7 healthy subjects given intravenous human adrenomedullin at 0.05 microg/kg/min in a single acute session, with a further 7 heart failure and 6 healthy subjects on placebo. The abstract does not describe randomisation or blinding

      The measurements were acute haemodynamic, renal and hormonal: mean arterial pressure, heart rate, cardiac index, pulmonary capillary wedge pressure, urine volume, urinary sodium and plasma aldosterone, over the course of one infusion in 7 heart failure patients. In those patients the blood-pressure fall was smaller than in healthy subjects (about 8 mmHg) and heart rate rose about 5 bpm. No study measured a cardiovascular outcome, symptom or event, and no chronic dosing trial is on file.

      Source PubMed 1 primary source read for this row

   3. Heart failure

      human case series Surrogate marker Not approved for this condition

      Who was studied

      patients with congestive heart failure, n=7 receiving adrenomedullin and n=7 receiving placebo, plus 7 and 6 healthy subjects respectively; single intravenous infusion at 0.05 mcg/kg/min, acute study, no follow-up; ejection fraction and heart failure type not reported in the source abstract

      A placebo-controlled acute infusion study (randomisation not stated in the source abstract) measured haemodynamics, not heart failure outcomes: in the heart failure group adrenomedullin lowered mean arterial pressure by 8 mmHg, raised cardiac index by 49%, lowered pulmonary capillary wedge pressure by 4 mmHg, and increased urine volume by 48% and sodium excretion by 42%. No study on file measured symptoms, hospitalisation or death, and the source does not say whether the patients had reduced or preserved ejection fraction.

      Source PubMed 1 primary source read for this row

2. 02

   Apelin

   human RCT · direct outcome · 3 graded rows across 3 of 3 conditions

   Hypertension · Cardiovascular disease · Heart failure

   3 graded rows, 1 source

   1. Hypertension

      human RCT Direct outcome Not approved for this condition

      Who was studied

      chronic heart failure patients NYHA II-III (n=18), patients undergoing diagnostic coronary angiography (n=6) and healthy volunteers (n=26); hypertension status of participants is not reported and no hypertensive cohort was enrolled

      Mean arterial pressure was measured in humans during systemic infusion of (Pyr1)apelin-13 in a randomised, double-blind, placebo-controlled study and fell in both heart failure patients and healthy controls, with peripheral and coronary vasodilatation and a rise in cardiac output. The trial was designed around heart failure: no hypertensive population was studied, and the infusions were acute, lasting minutes.

      Source PubMed 1 primary source read for this row

   2. Cardiovascular disease

      human RCT Surrogate marker Not approved for this condition

      Who was studied

      18 patients with NYHA class II-III chronic heart failure, 6 patients undergoing diagnostic coronary angiography, and 26 healthy volunteers; single-session acute studies. The peptides infused were (Pyr1)apelin-13 (intrabrachial, and systemic 30-300 nmol/min) and apelin-36 (intracoronary bolus), not apelin generically

      These were randomised, double-blind, placebo-controlled acute physiology studies measuring forearm blood flow by plethysmography, coronary blood flow by Doppler wire, left ventricular pressure by pressure wire, and cardiac output by bioimpedance. They record a haemodynamic response over minutes to hours in fewer than 20 heart failure patients: vasodilation, raised cardiac index, lowered mean arterial pressure. No study measured any cardiovascular outcome, symptom or event, and no trial of chronic dosing in heart failure is on file.

      Source PubMed 1 primary source read for this row

   3. Heart failure

      human RCT Surrogate marker Not approved for this condition

      Who was studied

      patients with NYHA class II-III chronic heart failure, n=18, alongside 6 patients undergoing coronary angiography and 26 healthy volunteers; acute single-session infusions, no follow-up; ejection fraction not reported in the source abstract

      Randomised, double-blind, placebo-controlled acute infusion studies measured vascular and haemodynamic variables only: (Pyr1)apelin-13 caused forearm vasodilatation, and systemic infusion raised cardiac index and lowered mean arterial pressure and peripheral vascular resistance in both heart failure patients and controls. No trial on file measured symptoms, hospitalisation, or mortality, and the source does not state whether the heart failure was of reduced or preserved ejection fraction.

      Source PubMed 1 primary source read for this row

3. 03

   Atrial Natriuretic Peptide (ANP)

   human RCT · direct outcome · 2 graded rows across 2 of 3 conditions

   Hypertension · Heart failure

   2 graded rows, 2 sources

   1. Hypertension

      human RCT Direct outcome Not approved for this condition

      Who was studied

      patients with essential hypertension, n=6, single intravenous injection; normotensive volunteers studied for comparison

      Arterial pressure was measured in humans after a 100 microgram intravenous injection of alpha-human atrial natriuretic peptide in a double-blind, placebo-controlled study: pressure fell within 2 minutes and had returned to placebo levels by 10 minutes, while urinary sodium excretion rose sixfold over 30 minutes. The blood pressure effect in the hypertensive patients was less sustained than the renal effect, and no trial of ANP given for the ongoing treatment of hypertension is on file.

      Source PubMed 1 primary source read for this row

   2. Heart failure

      human observational Direct outcome Approved for this condition

      Who was studied

      adults hospitalised with acute heart failure, predominantly Japanese, mean age 75-80, n approximately 2435 pooled across 6 studies published 2008-2025; ejection fraction not consistently reported in the included studies, so HFrEF and HFpEF cannot be separated

      Recombinant alpha-human ANP (carperitide) was approved for acute heart failure in Japan in 1995 by the Japanese regulator and is used there, but a 2025 systematic review and meta-analysis pooling 2 randomised trials and 3 observational studies found no difference against control in all-cause mortality (RR 1.02, 95% CI 0.63-1.66, I-squared 66%) or heart failure hospitalisation (RR 0.98, 95% CI 0.85-1.14). Tier is set at human_observational because the pooled evidence is mostly non-randomised. No regulator outside Japan has approved ANP for this condition, and no analysis on file reports outcomes by ejection fraction.

      Source NCBI 2 primary sources read for this row

4. 04

   C-Type Natriuretic Peptide (CNP)

   human RCT · direct outcome · 2 graded rows across 2 of 3 conditions

   Hypertension · Heart failure

   2 graded rows, 2 sources

   1. Hypertension

      human RCT Direct outcome Not approved for this condition

      Who was studied

      healthy normotensive volunteers, mean age 33, n=6; two one-hour infusions at 2 and 4 pmol/kg per minute

      Arterial pressure was measured in humans and did not move. Infusion raised plasma CNP from 1.17 to 41.52 pmol/L, four to ten times the levels seen in disease, with no effect on arterial pressure, cardiac output, cardiac volumes, renal haemodynamics, sodium excretion, plasma or urinary cGMP, renin or aldosterone. The authors conclude the result does not support CNP acting as a circulating hormone in humans. The population was normotensive, so this measures whether CNP lowers pressure at all rather than whether it treats hypertension, and no trial in a hypertensive population is on file. The animal record agrees rather than contradicting it: in hypertensive transgenic rats carrying an extra mouse renin gene (PubMed 8986453), atrial and brain natriuretic peptide each lowered blood pressure in one strain or the other and CNP lowered it in neither, alone or with a neutral endopeptidase inhibitor. Rung set from the study's own design wording, "random-order".

      Source PubMed 2 primary sources read for this row

   2. Heart failure

      human observational Mechanistic only Not approved for this condition

      Who was studied

      patients with chronic heart failure, n=11, and 11 age-matched healthy controls; graded intra-arterial infusions into the non-dominant brachial artery

      Recorded, and not evidence for this condition

      Forearm blood flow was measured by strain-gauge plethysmography during CNP infused into the arm. Systemic blood pressure and heart rate did not change during the study, which is the point of the technique: the dose is confined to one limb and measures local vessel response, not a treatment effect. No symptom, hospitalisation or mortality endpoint was measured, and no trial of systemic CNP given as a treatment for heart failure is on file. Rung set by review: eleven patients against eleven age-matched healthy controls, allocated by diagnosis rather than at random.

      Source PubMed 1 primary source read for this row

5. 05

   Endothelin-1

   human RCT · direct outcome · 2 graded rows across 2 of 3 conditions

   Hypertension · Heart failure

   2 graded rows, 1 source

   1. Hypertension

      human RCT Direct outcome Not approved for this condition

      Who was studied

      ten healthy male volunteers, studied on two occasions; systemic infusions of endothelin-1 at 0.75, 1.5 and 3 pmol/kg per minute for 30 minutes each against saline

      Vascular resistance was measured in humans and rose. Systemic vascular resistance went from 1156 to 1738 dyn.s.cm-5 and total pulmonary vascular resistance from 142 to 329, with dose-related falls in heart rate, stroke volume and cardiac output. This row records a compound that RAISES vascular resistance, the opposite of what a hypertension treatment does. It is on file because the measurement is a direct one in humans and because the finding is the reason endothelin receptor antagonists, not endothelin-1, are the drugs in this indication. No study has administered endothelin-1 to lower blood pressure. Rung set from the study's own design wording, "randomised, double-blind, placebo-controlled".

      Source PubMed 1 primary source read for this row

   2. Heart failure

      human RCT Surrogate marker Not approved for this condition

      Who was studied

      ten healthy male volunteers; the same crossover infusion study, with left and right ventricular diastolic filling and inotropic indices measured by pulsed-wave Doppler

      Ventricular function was measured in humans and worsened. Endothelin-1 significantly impaired left and right ventricular diastolic filling, including at the low dose that produced no systemic or pulmonary pressor effect, and impaired electromechanical and Doppler indices of inotropic state; the authors describe it as a negatively inotropic agent. These are imaging surrogates in healthy men over 90 minutes, not symptoms or hospitalisation in heart failure patients. No trial has administered endothelin-1 to anyone with heart failure as a treatment, and the finding here is a reason nobody would. Rung set from the study's own design wording, "randomised, double-blind, placebo-controlled".

      Source PubMed 1 primary source read for this row

6. 06

   Dulaglutide

   human RCT · direct outcome · 1 graded row across 1 of 3 conditions

   Cardiovascular disease

   1 graded row, 1 source

   1. Cardiovascular disease

      human RCT Direct outcome Approved for this condition

      Who was studied

      adults aged 50 or over with type 2 diabetes, most without prior cardiovascular events, n=9901, median 5.4 years (REWIND, subcutaneous dulaglutide 1.5 mg weekly)

      REWIND met superiority on its primary composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death: hazard ratio 0.88 (95% CI 0.79-0.99), p=0.026, with events in 12.0 percent against 13.4 percent on placebo. It is the one trial in this group whose population was mostly primary prevention rather than established cardiovascular disease, which is the reason its absolute event reduction is small even though the relative result reached superiority.

      Source PubMed 1 primary source read for this row

7. 07

   Exenatide

   human RCT · direct outcome · 1 graded row across 1 of 3 conditions

   Cardiovascular disease

   1 graded row, 1 source

   1. Cardiovascular disease

      human RCT Direct outcome Not approved for this condition

      Who was studied

      adults with type 2 diabetes, 73.1 percent with previous cardiovascular disease, n=14752, median 3.2 years (EXSCEL, exenatide extended-release 2 mg weekly; the corpus record's approved brand BYETTA is the twice-daily formulation of the same peptide)

      EXSCEL met non-inferiority and did not meet superiority. The primary composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke gave a hazard ratio of 0.91 (95% CI 0.83-1.00), p<0.001 for non-inferiority but p=0.06 for superiority. The finding is that exenatide did not increase cardiovascular risk, which is a different claim from reducing cardiovascular events; no cardiovascular indication is on the label.

      Source PubMed 1 primary source read for this row

8. 08

   Liraglutide

   human RCT · direct outcome · 1 graded row across 1 of 3 conditions

   Cardiovascular disease

   1 graded row, 1 source

   1. Cardiovascular disease

      human RCT Direct outcome Approved for this condition

      Who was studied

      adults with type 2 diabetes at high cardiovascular risk, n=9340, median 3.8 years (LEADER, subcutaneous liraglutide up to 1.8 mg daily)

      LEADER was a regulator-mandated non-inferiority safety trial that went on to meet superiority on its primary composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke: hazard ratio 0.87 (95% CI 0.78-0.97), p<0.001 for non-inferiority and p=0.01 for superiority, with events in 13.0 percent on liraglutide against 14.9 percent on placebo. The population was people with type 2 diabetes and established cardiovascular disease or high risk; there is no trial of this size in people without diabetes on file.

      Source PubMed 1 primary source read for this row

9. 09

   Lixisenatide

   human RCT · direct outcome · 1 graded row across 1 of 3 conditions

   Cardiovascular disease

   1 graded row, 1 source

   1. Cardiovascular disease

      human RCT Direct outcome Not approved for this condition

      Who was studied

      adults with type 2 diabetes and a myocardial infarction or hospitalisation for unstable angina within the previous 180 days, n=6068, median 25 months (ELIXA, subcutaneous lixisenatide daily)

      ELIXA met non-inferiority and showed no benefit. The primary composite was four-point: cardiovascular death, myocardial infarction, stroke or hospitalisation for unstable angina, and the hazard ratio was 1.02 (95% CI 0.89-1.17) against a pre-specified non-inferiority margin of 1.3. The trial establishes that lixisenatide did not increase cardiovascular events after an acute coronary syndrome; it does not show any reduction in them.

      Source PubMed 1 primary source read for this row

10. 10

    Nesiritide

    human RCT · direct outcome · 1 graded row across 1 of 3 conditions

    Heart failure

    1 graded row, 1 source

    1. Heart failure

       human RCT Direct outcome Approved for this condition

       Who was studied

       adults hospitalised with acute decompensated heart failure (dyspnoea at rest or on minimal exertion), n=7141, infusion 24-168 hours, follow-up 30 days; no ejection fraction criterion, so both reduced and preserved ejection fraction were enrolled and results are not reported separately by heart failure type

       ASCEND-HF measured the condition directly and did not find a benefit: dyspnoea improvement at 6 and 24 hours did not meet the prespecified significance threshold (44.5% vs 42.1%, P=0.03; 68.2% vs 66.1%, P=0.007), and 30-day rehospitalisation for heart failure or death from any cause was 9.4% with nesiritide versus 10.1% with placebo (P=0.31), with no difference in worsening renal function and more hypotension. FDA approved nesiritide in 2001 for acute decompensated heart failure, but the approval is historical in practice: Drugs@FDA lists the sole product, NATRECOR under NDA 020920, as Discontinued, and DailyMed carries no current nesiritide label. The trial did not stratify by ejection fraction, so nothing on file speaks to HFrEF versus HFpEF separately.

       Source PubMed 3 primary sources read for this row

11. 11

    Relaxin

    human RCT · direct outcome · 1 graded row across 1 of 3 conditions

    Heart failure

    1 graded row, 1 source

    1. Heart failure

       human RCT Direct outcome Not approved for this condition

       Who was studied

       adults hospitalised for acute heart failure with dyspnoea, radiographic congestion, raised natriuretic peptides, mild-to-moderate renal impairment and systolic blood pressure at least 125 mmHg; n=6545 analysed of 6600 randomised, 48-hour infusion, follow-up 180 days; no ejection fraction criterion, so HFrEF and HFpEF were both enrolled and results are not reported separately by type

       RELAX-AHF-2 tested serelaxin, the recombinant human relaxin-2 form, and did not find a benefit on either primary endpoint: cardiovascular death at 180 days occurred in 8.7% versus 8.9% with placebo (hazard ratio 0.98, 95% CI 0.83-1.15, P=0.77) and worsening heart failure at day 5 in 6.9% versus 7.7% (hazard ratio 0.89, 95% CI 0.75-1.07, P=0.19), with no difference in all-cause death, rehospitalisation, or length of stay. This confirmatory trial did not reproduce the earlier phase 3 RELAX-AHF result, and no regulator has approved serelaxin for heart failure. Entry required raised natriuretic peptides and systolic blood pressure at least 125 mmHg, so lower-blood-pressure patients were excluded.

       Source PubMed 2 primary sources read for this row

12. 12

    Semaglutide

    human RCT · direct outcome · 1 graded row across 1 of 3 conditions

    Cardiovascular disease

    1 graded row, 1 source

    1. Cardiovascular disease

       human RCT Direct outcome Approved for this condition

       Who was studied

       adults with type 2 diabetes, n=3297, 104 weeks (SUSTAIN-6, subcutaneous semaglutide 0.5 or 1.0 mg weekly); and adults aged 45 or over with established cardiovascular disease and BMI 27 or above but no diabetes, n=17604, mean 39.8 months (SELECT, semaglutide 2.4 mg weekly)

       SELECT was a superiority trial and met it: the primary composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke occurred less often on semaglutide, hazard ratio 0.80 (95% CI 0.72-0.90, p<0.001), in people with cardiovascular disease and overweight or obesity but no diabetes. The earlier SUSTAIN-6 was designed and powered as a non-inferiority safety trial in type 2 diabetes and met non-inferiority (p<0.001); its hazard ratio of 0.74 (95% CI 0.58-0.95) also crossed the superiority threshold, but that test was not what the trial was sized for. FDA has since added a cardiovascular indication to the semaglutide 2.4 mg label on the strength of SELECT.

       Source PubMed 2 primary sources read for this row

13. 13

    Soy Peptides

    human RCT · direct outcome · 1 graded row across 1 of 3 conditions

    Hypertension

    1 graded row, 1 source

    1. Hypertension

       human RCT Direct outcome Not approved for this condition

       Who was studied

       adults with untreated systolic 130-159 mmHg and/or diastolic 80-99 mmHg (prehypertension to stage 1 hypertension), n=100, 8 weeks

       Office blood pressure was measured in humans: 4.5 g of black soy peptides daily for 8 weeks was followed by a systolic fall of -9.69 +/- 12.37 mmHg against -2.91 +/- 13.29 mmHg on placebo, alongside changes in malondialdehyde, superoxide dismutase and nitric oxide. The enrolled population was hypertensive rather than normotensive. No regulator has approved soy peptides for hypertension.

       Source PubMed 1 primary source read for this row

14. 14

    Testosterone

    human RCT · direct outcome · 1 graded row across 1 of 3 conditions

    Cardiovascular disease

    1 graded row, 1 source

    1. Cardiovascular disease

       human RCT Direct outcome Not approved for this condition

       Who was studied

       men aged 45-80 with hypogonadism (testosterone below 300 ng/dL) and pre-existing or high-risk cardiovascular disease, n=5246, mean treatment 21.7 months and mean follow-up 33.0 months (TRAVERSE, transdermal testosterone gel)

       TRAVERSE was a cardiovascular SAFETY trial, designed and powered for non-inferiority with an upper limit of 1.5, and it met that: hazard ratio 0.96 (95% CI 0.78-1.17) for the composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke. This is a finding that testosterone replacement in hypogonadal men did not raise cardiovascular event rates. It is not evidence that testosterone treats or prevents cardiovascular disease, and no trial testing that question is on file. Testosterone is approved for replacement in male hypogonadism only, and carries no cardiovascular indication.

       Source PubMed 1 primary source read for this row

15. 15

    Tirzepatide

    human RCT · direct outcome · 1 graded row across 1 of 3 conditions

    Cardiovascular disease

    1 graded row, 1 source

    1. Cardiovascular disease

       human RCT Direct outcome Not approved for this condition

       Who was studied

       adults with type 2 diabetes and atherosclerotic cardiovascular disease, mean age 64.1 years, 29 percent women, n=13299 randomised (6586 tirzepatide, 6579 dulaglutide in the modified intention-to-treat analysis), median treatment about 46.9 months (SURPASS-CVOT)

       SURPASS-CVOT was an active-comparator non-inferiority trial against dulaglutide, not a placebo trial. Tirzepatide met non-inferiority on the primary composite of cardiovascular death, myocardial infarction or stroke, hazard ratio 0.92 (95.3% CI 0.83-1.01) against a margin of 1.05, p=0.003 for non-inferiority; superiority over dulaglutide was not met, p=0.09. No placebo-controlled cardiovascular outcome trial of tirzepatide is on file, and there is no cardiovascular indication on the label.

       Source PubMed 1 primary source read for this row

16. 16

    Vasopressin

    human RCT · direct outcome · 1 graded row across 1 of 3 conditions

    Cardiovascular disease

    1 graded row, 1 source

    1. Cardiovascular disease

       human RCT Direct outcome Not approved for this condition

       Who was studied

       adults with out-of-hospital cardiac arrest, n=1186 analysed (589 vasopressin, 597 epinephrine), survival to hospital admission and to discharge

       Survival was measured. Two injections of 40 units of vasopressin were compared with 1 mg of epinephrine during cardiopulmonary resuscitation. Hospital admission rates did not differ in ventricular fibrillation (46.2% versus 43.0%) or pulseless electrical activity (33.7% versus 30.5%). In the asystole subgroup, admission (29.0% versus 20.3%) and discharge (4.7% versus 1.5%) were higher on vasopressin. Cerebral performance was similar between groups. The subgroup result is the basis for the drug's continued mention in resuscitation practice; the overall comparison was not positive, and no regulator has approved vasopressin for cardiac arrest. Rung set from the study's own design wording, "randomly assigned".

       Source PubMed 1 primary source read for this row

17. 17

    Estradiol

    human RCT · surrogate marker · 1 graded row across 1 of 3 conditions

    Cardiovascular disease

    1 graded row, 1 source

    1. Cardiovascular disease

       human RCT Surrogate marker Not approved for this condition

       Who was studied

       healthy postmenopausal women, n=643, median 5 years, randomised to oral 17-beta-estradiol 1 mg daily or placebo and stratified by time since menopause: early (under 6 years) or late (10 years or more) (ELITE)

       ELITE measured the rate of change in carotid-artery intima-media thickness, an imaging surrogate, not cardiovascular events. Progression was slower on estradiol in the early-postmenopause stratum (0.0044 vs 0.0078 mm/year, p=0.008) but not in the late stratum (0.0100 vs 0.0088 mm/year, p=0.29), interaction p=0.007 - the timing hypothesis. The cardiac CT endpoints pointed the other way: coronary-artery calcium, total stenosis and plaque did not differ from placebo in either stratum. No cardiovascular event outcome was measured, estradiol has no cardiovascular indication, and its label carries a boxed warning covering cardiovascular disorders.

       Source PubMed 1 primary source read for this row

18. 18

    SS-31

    human RCT · surrogate marker · 1 graded row across 1 of 3 conditions

    Heart failure

    1 graded row, 1 source

    1. Heart failure

       human RCT Surrogate marker Not approved for this condition

       Who was studied

       patients with stable heart failure with reduced ejection fraction, LVEF 40% or below by echocardiography at screening (mean 31% plus or minus 7%), aged 40-80, n=71, 24% female, once-daily subcutaneous elamipretide 4 mg or 40 mg or placebo for 28 days

       PROGRESS-HF measured left ventricular end-systolic volume by cardiac MRI, an imaging surrogate rather than a symptom or event, and found no difference from placebo at 4 weeks (4 mg versus placebo: difference of means -0.3, 95% CI -4.6 to 4.0, P=0.90; 40 mg versus placebo: 2.3, 95% CI -1.9 to 6.5, P=0.28), with no difference in ejection fraction either. Elamipretide holds an FDA approval as FORZINITY (NDA 215244) for a different indication, Barth syndrome, which is not an approval for heart failure. The trial enrolled only HFrEF; no HFpEF trial of elamipretide is on file.

       Source PubMed 2 primary sources read for this row

19. 19

    Urocortin

    human RCT · surrogate marker · 1 graded row across 1 of 3 conditions

    Heart failure

    1 graded row, 1 source

    1. Heart failure

       human RCT Surrogate marker Not approved for this condition

       Who was studied

       patients with acute decompensated heart failure, n=53, urocortin-2 5 ng/kg/min or placebo infused for 4 hours as adjunct to conventional therapy, measurements to 24 hours; ejection fraction and heart failure type not reported in the source abstract

       The UNICORN study measured haemodynamic and neurohormonal variables rather than heart failure outcomes: urocortin-2 raised cardiac output (2.1 l/min versus -0.1 l/min with placebo, P<0.001) and lowered systolic blood pressure by 16 mmHg, while falls in pulmonary artery and wedge pressures did not differ from placebo and urine volume and creatinine clearance fell transiently during infusion. No trial on file measured symptoms beyond 24 hours, hospitalisation or death, and the population is not resolved into HFrEF or HFpEF.

       Source PubMed 1 primary source read for this row

20. 20

    Angiotensin I

    human observational · direct outcome · 1 graded row across 1 of 3 conditions

    Hypertension

    1 graded row, 1 source

    1. Hypertension

       human observational Direct outcome Not approved for this condition

       Who was studied

       healthy men of ACE genotype DD (n=8) and II (n=8); incremental intravenous infusion of angiotensin I titrated to a 25 mmHg rise in diastolic and in systolic pressure

       Blood pressure was measured in humans and rose, which is the intended effect of the infusion rather than a side effect. The infusion is titrated upwards until diastolic pressure has risen by 25 mmHg, and the dose needed is the result being reported: a geometric mean of 2.53 micrograms per minute in II subjects and 2.67 in DD, a ratio of 0.95 with a confidence interval from 0.44 to 2.02, despite serum converting-enzyme activity differing nearly fourfold between the genotypes. A second infusion study in ten normotensive men (PubMed 10826400) found the pressor and aldosterone responses fell in proportion to the reduction in angiotensin II formation under ACE inhibition, while the renal response was inhibited substantially less than expected — read by its authors as angiotensin I being converted to angiotensin II inside the kidney rather than only in the lung. Angiotensin I raises blood pressure, so it is the opposite of a hypertension treatment, and this row exists to record that fact with a measurement behind it. It is a research probe of converting-enzyme activity, nothing in the record proposes it as a therapy, and neither study followed a clinical outcome beyond the session. Rung set by review: sixteen healthy men in two groups compared by ACE genotype — a comparison nobody can randomise.

       Source PubMed 2 primary sources read for this row

21. 21

    Hexarelin

    human observational · surrogate marker · 2 graded rows across 2 of 3 conditions

    Cardiovascular disease · Heart failure

    2 graded rows, 2 sources

    1. Cardiovascular disease

       human observational Surrogate marker Not approved for this condition

       Who was studied

       patients with coronary artery disease undergoing bypass surgery under general anaesthesia, mean age 59.5 years, mean baseline left ventricular ejection fraction 57.2 per cent; single intravenous dose of 2.0 micrograms/kg, compared against growth hormone-releasing hormone, recombinant human growth hormone and placebo

       Cardiac performance was measured intraoperatively by transoesophageal echocardiography with pulmonary and systemic catheterisation. Hexarelin raised ejection fraction, cardiac index and cardiac output within ten minutes and lowered wedge pressure, with the effect lasting to 90 minutes; end-diastolic volume and systemic vascular resistance index did not change. Growth hormone-releasing hormone, recombinant growth hormone and placebo produced no haemodynamic effect, which is what separates a direct cardiac action from a growth hormone effect. This is one intravenous dose measured over 90 minutes in an operating theatre: no study on file gives hexarelin repeatedly or measures a clinical event. Rung set by review: the same paper, indexed a Controlled Clinical Trial rather than a randomised one.

       Source PubMed 1 primary source read for this row

    2. Heart failure

       human case series Surrogate marker Not approved for this condition

       Who was studied

       8 patients with dilated cardiomyopathy (mean ejection fraction 16.7 per cent) and 5 with ischaemic cardiomyopathy (22.6 per cent), compared with 7 normal subjects and 7 patients with severe growth hormone deficiency studied previously by the same method; single intravenous dose

       A negative result in the group with the worse ventricle. Ejection fraction, measured by radionuclide angiography, rose after hexarelin in ischaemic cardiomyopathy but was unchanged in dilated cardiomyopathy, even though growth hormone rose similarly in both and baseline ejection fraction was comparable. Other haemodynamic parameters did not move in any group. The historical comparison groups were studied earlier rather than concurrently, the exposure is a single dose, and no controlled trial has given hexarelin to patients with heart failure over time. In rodents the picture is more favourable: hexarelin was one of four peptides that improved left ventricular function in pressure-overload heart failure in rats, though that report gives no separate effect size for hexarelin. Rung set by review: thirteen patients given a single dose, compared against groups studied earlier by the same method — historical controls are not a control group.

       Source PubMed 2 primary sources read for this row

22. 22

    GHRH (Growth Hormone-Releasing Hormone)

    human observational · surrogate marker · 1 graded row across 1 of 3 conditions

    Cardiovascular disease

    1 graded row, 1 source

    1. Cardiovascular disease

       human observational Surrogate marker Not approved for this condition

       Who was studied

       patients with coronary artery disease undergoing bypass surgery under general anaesthesia, mean age 59.5 years, mean baseline left ventricular ejection fraction 57.2 per cent; single intravenous dose of GHRH at 2.0 micrograms/kg, alongside hexarelin, recombinant human growth hormone and placebo arms

       A negative result, and the study was designed so that it would show. Cardiac performance was measured intraoperatively by transoesophageal echocardiography with systemic and pulmonary catheterisation. GHRH produced no haemodynamic effect at all, as did recombinant growth hormone and placebo, while hexarelin in the same protocol raised ejection fraction, cardiac index and cardiac output within ten minutes. GHRH did raise growth hormone. The reading the authors take from it is that the cardiac effect of hexarelin runs through cardiovascular growth hormone secretagogue receptors rather than through growth hormone, and that GHRH does not reach them. The exposure was one intravenous dose measured over 90 minutes; nothing here speaks to repeated dosing. Rung set by review: indexed a Controlled Clinical Trial, which is the term MeSH uses for a controlled study that was NOT randomised.

       Source PubMed 1 primary source read for this row

23. 23

    Angiotensin (1-7)

    human case series · surrogate marker · 3 graded rows across 3 of 3 conditions

    Hypertension · Cardiovascular disease · Heart failure

    3 graded rows, 2 sources

    1. Hypertension

       human case series Surrogate marker Not approved for this condition

       Who was studied

       patients with essential hypertension (n=8) and normotensive controls (n=8); intra-arterial infusion into the brachial artery, 5 minutes per dose, not randomised and not placebo-controlled

       What was measured was forearm blood flow by venous occlusion plethysmography, which rose dose-dependently by about 32% in the hypertensive patients and about 29% in the controls; systemic blood pressure was not the outcome, and a local vasodilator response in one limb is not a blood pressure result. No study on file measured office, ambulatory or home blood pressure in people given angiotensin-(1-7).

       Source PubMed 1 primary source read for this row

    2. Cardiovascular disease

       human case series Mechanistic only Not approved for this condition

       Who was studied

       8 patients with heart failure already treated with an ACE inhibitor; angiotensin-(1-7) infused into the brachial artery, alone and with bradykinin, in a single acute session. The abstract does not describe randomisation or blinding

       Recorded, and not evidence for this condition

       What was measured was forearm blood flow by venous occlusion plethysmography in 8 people - a local vascular response, not a cardiovascular outcome. Angiotensin-(1-7) produced no vasodilation on its own and did not alter the response to bradykinin; the authors concluded it was biologically inactive in this circulation. No study measured cardiovascular disease itself - no events, no symptoms, no cardiac function endpoint - so the link to the condition is an argument from mechanism rather than a result.

       Source PubMed 1 primary source read for this row

    3. Heart failure

       human case series Mechanistic only Not approved for this condition

       Who was studied

       patients with heart failure already treated with an ACE inhibitor, n=8, single-session intrabrachial infusion; ejection fraction, NYHA class and heart failure type not reported in the source

       Recorded, and not evidence for this condition

       The only human heart failure intervention study on file measured forearm blood flow by venous occlusion plethysmography, which is a vascular measurement and not a heart failure outcome, and it found nothing: angiotensin-(1-7) had no effect alone and no effect on the response to bradykinin, while bradykinin alone caused profound vasodilatation. The authors concluded angiotensin-(1-7) is biologically inactive in the forearm circulation of these patients, in contrast to preclinical work. No study on file measured symptoms, hospitalisation or death in heart failure. Regraded from human_rct: the same paper is the sole source for the cardiovascular-disease row, which records that the abstract describes neither randomisation nor blinding. A single-arm 8-patient infusion session is a case series under the published rubric, and one study cannot hold two rungs.

       Source PubMed 2 primary sources read for this row

24. 24

    Neurotensin

    animal in vivo · direct outcome · 1 graded row across 1 of 3 conditions

    Hypertension

    1 graded row, 1 source

    1. Hypertension

       animal in vivo Direct outcome Not approved for this condition

       Who was studied

       anaesthetised normotensive rats; intrathecal administration, 0.5 micromolar to 3 millimolar, acute recording only

       Mean arterial pressure was measured directly in anaesthetised rats and fell dose-dependently, to about -25 mmHg at 3 mM, with bradycardia and reduced sympathetic nerve activity. The animals were normotensive and the peptide was placed into the intrathecal space rather than given systemically, so this is spinal cardiovascular physiology; no study measured blood pressure in a hypertensive animal model or in any human given neurotensin.

       Source PubMed 1 primary source read for this row

25. 25

    Wheat Peptides

    animal in vivo · direct outcome · 1 graded row across 1 of 3 conditions

    Hypertension

    1 graded row, 1 source

    1. Hypertension

       animal in vivo Direct outcome Not approved for this condition

       Who was studied

       spontaneously hypertensive rats; group sizes, dose and dosing duration are not stated in the abstract and the full text is paywalled

       Systolic, diastolic and mean arterial pressure were measured in living spontaneously hypertensive rats and fell after wheat oligopeptides; the same paper reports 77% ACE inhibition at 2.5 mg/mL in a test tube, which is a separate in vitro result. No study measuring blood pressure in humans given wheat-derived peptides was located: the registered trial NCT02197910 posted no results and no publication was found, so the human blood-pressure claim remains a named gap and this row is rat evidence only.

       Source PubMed 1 primary source read for this row

26. 26

    GHRP-6

    animal in vivo · surrogate marker · 2 graded rows across 2 of 3 conditions

    Cardiovascular disease · Heart failure

    2 graded rows, 2 sources

    1. Cardiovascular disease

       animal in vivo Surrogate marker Not approved for this condition

       Who was studied

       rats with a non-reperfusion myocardial infarct produced by permanent left descending coronary artery ligation, treated from immediately after surgery for 7 days; sham, infarct plus saline and infarct plus GHRP-6 groups

       Echocardiography and histology at day 7 showed less myocardial tissue loss and improved left ventricular physiology against saline. The dose had been set beforehand at 0.4 mg/kg as the minimum effective dose for inotropy in healthy rats. The mechanism offered — upregulated fatty acid beta-oxidation and mitochondrial reprogramming from a proteomic analysis of six healthy animals — is put forward by the authors themselves as a proposal rather than a demonstration. Seven days in a rodent is not a clinical course, and no human study of GHRP-6 after myocardial infarction exists. Rung set from the population studied, "rats".

       Source PubMed 1 primary source read for this row

    2. Heart failure

       animal in vivo Surrogate marker Not approved for this condition

       Who was studied

       male rats with pressure-overload chronic heart failure from abdominal aortic banding; 100 micrograms/kg subcutaneously twice daily for 3 weeks starting 9 weeks after banding; GHRP-6 was one of four peptides compared against saline

       Left ventricular ejection fraction and end-systolic pressure rose and end-diastolic pressure and dimension fell against saline, with less cardiac cachexia and lower plasma catecholamines, renin, angiotensin II, aldosterone and endothelin-1. GHRP-1, GHRP-2, GHRP-6 and hexarelin were reported together and no separate effect size for GHRP-6 is given, so this compound's own contribution is not on file. No human heart-failure study of GHRP-6 exists. Rung set from the study's own design wording, "rats".

       Source PubMed 1 primary source read for this row

27. 27

    Elabela

    animal in vivo · surrogate marker · 1 graded row across 1 of 3 conditions

    Heart failure

    1 graded row, 1 source

    1. Heart failure

       animal in vivo Surrogate marker Not approved for this condition

       Who was studied

       mice with pressure-overload-induced heart failure and mice given angiotensin II; continuous ELABELA peptide infusion, with APJ knockout mice as a mechanistic control; no human study on file

       In mice, continuous ELABELA infusion suppressed pressure-overload-induced cardiac hypertrophy, fibrosis and impaired contractility, and the effect was lost in APJ knockout mice. These are rodent measurements of cardiac structure and function in a surgical model, not measurements in people; no human trial of ELABELA in heart failure is on file, and the compound record itself is marked preclinical only.

       Source DOI 1 primary source read for this row

28. 28

    GHRP-1

    animal in vivo · surrogate marker · 1 graded row across 1 of 3 conditions

    Heart failure

    1 graded row, 1 source

    1. Heart failure

       animal in vivo Surrogate marker Not approved for this condition

       Who was studied

       male rats with pressure-overload chronic heart failure induced by abdominal aortic banding; treatment began 9 weeks after banding, 100 micrograms/kg subcutaneously twice daily for 3 weeks; GHRP-1 was one of four peptides compared against saline in the same experiment

       GHRP-1 appears in one animal experiment that measured cardiac function directly: left ventricular ejection fraction and end-systolic pressure rose and end-diastolic pressure and dimension fell against saline, alongside reduced cardiac cachexia and lower plasma catecholamines, renin, angiotensin II, aldosterone and endothelin-1. The four peptides were reported together and the paper does not separate GHRP-1's effect size from those of GHRP-2, GHRP-6 and hexarelin, so how much of the result belongs to this compound is not on file. No human study of GHRP-1 in heart failure exists. GHRP-1 is not approved in any jurisdiction and its remaining literature is doping-control assay development and single-dose growth hormone release in sheep. Rung set from the study's own design wording, "rats".

       Source PubMed 1 primary source read for this row

29. 29

    GHRP-2

    animal in vivo · surrogate marker · 1 graded row across 1 of 3 conditions

    Heart failure

    1 graded row, 1 source

    1. Heart failure

       animal in vivo Surrogate marker Not approved for this condition

       Who was studied

       male rats with pressure-overload chronic heart failure from abdominal aortic banding; 100 micrograms/kg subcutaneously twice daily for 3 weeks starting 9 weeks after banding; GHRP-2 was one of four peptides compared against saline

       Left ventricular ejection fraction and end-systolic pressure rose and end-diastolic pressure and dimension fell against saline, with less cardiac cachexia, lower plasma catecholamines, renin, angiotensin II, aldosterone and endothelin-1, and less cardiomyocyte apoptosis. The report pools GHRP-1, GHRP-2, GHRP-6 and hexarelin and does not give a separate effect size for GHRP-2, so this compound's own contribution is not on file. No human heart-failure study of GHRP-2 exists. Rung set from the study's own design wording, "rats".

       Source PubMed 1 primary source read for this row

Checked, and nothing on file

4 compounds were read against these conditions and produced no gradeable row. They are named here rather than left off, because a list of 29 reads identically whether 29 survived 33 or 29 were all anyone thought of.

1. Brain Natriuretic Peptide (BNP) on heart failure

   No rung — nothing on file to grade Not approved for this condition

   Recorded to mark a distinction, not as evidence. BNP and NT-proBNP are measured in blood to diagnose heart failure and to gate trial entry - RELAX-AHF-2, for example, required BNP at or above 500 pg/mL - and that diagnostic use is not an indication for administering BNP. The therapeutic form of human B-type natriuretic peptide given to patients is nesiritide, which is graded on its own row; endogenous BNP itself has no graded therapeutic row here.

2. CRH (Corticotropin-Releasing Hormone) on hypertension

   No rung — nothing on file to grade Not approved for this condition

   A CRH test transiently raises cortisol and can raise blood pressure. It is never given to lower it and no trial has tried.

3. Enfuvirtide on cardiovascular disease

   No rung — nothing on file to grade Not approved for this condition

   No trial has measured a cardiovascular outcome for enfuvirtide. Lipid parameters in the TORO substudy were a safety measure and did not differ between groups.

4. Urotensin II

   No rung — nothing on file to grade

   Checked against heart failure. No study meeting the rubric was found for any of them.

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