TABLE 1.

HF therapies and agents with the potential to modulate receptors present on cardiac fibroblasts or extracellular collagen processing in clinical testing for LV and RV overloaded conditions.

Cardiac condition	Target	Study	Agent	Patients (n)	Findings
LV overload	RAAS	(178)	ACE inhibitor lisinopril	35	Administration of lisinopril, but not hydrochlorothiazide for 6 months decreased CVF in endomyocardial biopsies of hypertensive patients
		(179)	ARB losartan	19	Administration of losartan for 12 months decreased CVF in endomyocardial biopsies of hypertensive patients with severe fibrosis, but not in patients with non-severe fibrosis
		(226)	ARB losartan	37	Administration of losartan but not amlodipine for 12 months decreased CVF in endomyocardial biopsies and serum biomarker PIP in patients with hypertensive heart disease
		RAAM-PEF	Aldosterone antagonist eplerenone	44	Administration of eplerenone for 6 months reduced biomarkers of collagen turnover in HFpEF patients with a history of hypertension
		Aldo-DHF	MR antagonist spironolactone	422	Administration of spironolactone for 12 months improved diastolic function but did not improve HF symptoms in HFpEF patients, mostly with a history of hypertension
		TOPCAT	MR antagonist spironolactone	3,445	Administration of spironolactone for 3.3 years decreased hospitalization for HF, but not death from cardiovascular causes, aborted cardiac arrest, or hospitalization for any reason in HFpEF patients, mostly with a history of hypertension
		(186)	MR antagonist spironolactone	40	Administration of spironolactone for 6 months decreased the rate of extracellular expansion but did not change myocardial extracellular volume measured by MRI in HFpEF patients
	Extracellular collagen processing	(26)	Diuretic torsemide	20	Administration of torsemide but not furosemide for 8 months decreased LOX protein expression and collagen cross-linking in endomyocardial biopsies of chronic HF patients
		(41)	Diuretic torsemide	36	Administration of torsemide but not furosemide for 8 months decreased CVF in endomyocardial biopsies and serum biomarker PIP of class II to IV chronic HF patients
		(131)	Diuretic torsemide	22	Administration of torsemide but not furosemide for 8 months decreased CVF and PCP activation in endomyocardial biopsies and serum biomarker PICP of chronic HF patients
		TORAFIC	Diuretic torsemide	155	Administration of torsemide or furosemide for 8 months had no effect on serum biomarker PICP in hypertensive patients with mild chronic HF
	TGFβ inhibitors	PIROUETTE	TGFβ inhibitor pirfenidone	80	Administration of pirfenidone for 52 weeks decreased ECV measured by MRI in HFpEF patients, mostly with hypertension
	ET-1 inhibitors	(205)	Dual ET A/B receptor antagonist enrasentan	72	Administration of enrasentan for 6 months increased LV-EDVI in asymptomatic patients with LV dysfunction
		EARTH	ET antagonist darusentan	485	Administration of darusentan for 6 months did not change LV-ESV at, measured by MRI in patients with LV systolic dysfunction
RV overload	RAAS	STAR-HF	MR antagonist spironolactone	30 estimated	Ongoing; administration of spironolactone for 12 weeks will be assessed by biomarkers of fibrosis and T1 weighted MRI in patients with right HF

ACE, angiotensin converting enzyme; CVF, collagen volume fraction; ARB, angiotensin receptor blocker; HFpEF, Heart Failure with preserved ejection fraction; MR, mineralocorticoid receptor; MRI, magnetic resonance imaging; LOX, lysil oxidase; PIP/PICP, procollagen type I carboxy-terminal peptide (biomarker of collagen type I fiber synthesis); TGFβ, Transforming Growth Factor-β1; ET, endothelin-1; LV-EDVI, left ventricular end diastolic volume index; LV-ESV left ventricular end-systolic volume.