Targeting vasoactive peptides for managing calcific aortic valve disease

Figures & data

Table 1. Retrospective cohort studies of angiotensin converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) treatments in calcific aortic valve disease (CAVD).

Reference	Main method of patient classification	Study groups	Number of subjects	Age	Mean follow-up time	Conclusions	Notes
(6)	Echocardiography	No ACEi	109	69 ± 11	24 ± 18 mo.	ACEI not associated with CAVD progression	No effect found in all ACEI doses and types, or combination with statin
		ACEI	102	70 ± 10
(14)	Serial EBT	No ACEi	80	67 ± 98	2.5 years	ACEI use associated with lower rate of CAVD progression
		ACEI	43	69.3 ± 8.4
(21)	Echocardiography	Early-stage AS	157	71.1 ± 8.0	2.8 years	Nonuse of ARBs correlated with faster progression of early-stage CAVD
		Late-stage AS	399	74.7 ± 9.2
(23)	Valve histology		208N/A	69 ± 9	Duration of ACEI/ARB treatment unavailable	ARB treatment associated with lower valve remodelling score	Explanted end-stage valves used
(22)	Echocardiography	No hypertension, no RAS treatment	92	61 ± 18	6.2 ± 2.4 years	Use of ARBs but not ACEI associated with slower progression of CAVD	Use of ARBs but not ACEI also associated with reduced mortality
		Hypertension, no RAS treatment	77	73 ± 12
		Hypertension, ACEI treatment	113	71 ± 11
		Hypertension, ARB treatment	56	72 ± 11

AS: aortic stenosis; EBT: electron beam computed tomography; mo: months; RAS: renin–angiotensin system; N/A: not applicable.

Table 2. Clinical trials of renin–angiotensin system targeting treatments in calcific aortic valve disease (CAVD).

Study	Intervention	No of patients	Duration	CAVD status	Main outcome variables	Results	Reference/ Clinicaltrials.gov identifier
SCOPE-AS^a	Enalapril vs. placebo	56	1 month (3 month follow-up for selected patients)	Symptomatic severe	Development of hypertension, Borg dyspnea index, 6-min walk distance, off-target drug effects, NYHA-class changes, echocardiographic parameters	Improvement in NYHA class, Borg index and 6-min walk distance. Benefit greatest in patients with regurgitant valve lesions	(26)
Effects of angiotensin converting enzyme inhibitors in hypertensive patients with aortic valve stenosis: a drug withdrawal study^a	Various ACEIs, crossover design	20	Not reported (withdrawal study)	Asymptomatic AS	Hemodynamic and functional variables	Reduction in afterload, compensated by increase in transvalvular pressure gradient. Hemodynamic variables improved in most hypertensive patients.	(27)
Short-term hemodynamic effect of angiotensin-converting enzyme inhibition in patients with severe aortic stenosis^a	Trandolapril vs. placebo	44	8 weeks	Severe AS	Acute hemodynamic effects of ACEI, change in systemic BP, SAC, Zva, NT-proBNP, exercise capacity	Reduction in left ventricular end systolic volume and NT-proBNP	(28)
RIAS^a	Ramipril vs. placebo	100	1 year	Moderate or severe asymptomatic AS	LVM, systolic velocity, progression of CAVD by cardiac magnetic resonance	Reduction in LVM, preserved systolic pressure, non-significant reduction in progression of CAVD	(29)
ROCK-AS^a	Candesartan vs. placebo	51	5 months	Severe AS	Mortality, LV mass and function, 6-min walking test, Nt-proBNP		(24)
ACCESS^b	Captopril or trandolapril vs placebo	64	8 weeks	Severe AS	Hemodynamic and functional parameters		NCT00252317
ALFA^b	Fimasartan vs. placebo	100	1 year	Moderate to severe AS	Change of VmaxO2 in cardiopulmonary exercise test, various hemodynamic parameters, LVM, hospitalization, mortality		NCT01589380
BAV study^c	Telmisartan vs. placebo. Parallel arm tests atenolol vs. placebo.	85	5 years	BAV, no CAVD at baseline	Change from baseline in ascending aorta size, as evaluated by MRI; rate of change in ascending aorta size evaluated by (TEE)		NCT01202721
The effect of losartan in bicuspid aortic valve patients.^b	Losartan (open label, single group)	25	1 year	BAV, no CAVD at baseline	Inflammatory blood markers		NCT01390181

Status of the study ^acompleted, ^bunknown, and ^congoing.

AS: aortic stenosis; NYHA: New York Heart Association; BP: blood pressure; SAC: systemic aortic compliance; NT-proBNP: N-terminal pro-brain natriuretic peptide; Zva: valvuloarterial impedance; LVM: left ventricular mass; BAV: bicuspid aortic valve; MRI: magnetic resonance imaging; TEE: transthoracic echocardiography.

ACCESS: Acute Haemodynamic Effects of Treatment With Angiotensin Converting Enzyme (ACE)-Inhibitors in Patients With Symptomatic Aortic Stenosis; ALFA: A Randomized Trial of Angiotensin Receptor blocker, Fimasartan, in Aortic Stenosis; BAV: Beta Blockers and Angiotensin Receptor Blockers in Bicuspid Aortic Valve Disease Aortopathy; RIAS: A prospective, double-blind: randomized controlled trial of the angiotensin-converting enzyme inhibitor Ramipril In Aortic Stenosis; ROCK-AS: The Potential of Candesartan to Retard the Progression of Aortic Stenosis; SCOPEAS: Safety and efficacy of angiotensin-converting enzyme inhibitors in symptomatic severe aortic stenosis: Symptomatic Cardiac Obstruction-Pilot Study of Enalapril in Aortic Stenosis.

Figure 1. Vasoactive peptides in calcific aortic valve disease. A schematic illustration summarizing peptides involved in comprehensive shift in the balance of valvular RAS components towards activated ACE/AngII/AT₁-receptor-mediated fibrosis, proliferation and inflammation in AS. Black arrows show reported upregulated (↑), downregulated (↓) or unchanged (↔) gene expression in stenotic aortic valves.

Table 3. Expression of vasoactive peptides in calcified aortic valves (vs normal) and their localization in calcified valves/normal valves.

	Expression		Localization is stenotic valves
Factor	mRNA	Protein	Valvular endothelium	Neovessel endothelium	Myofibroblasts	Inflammatory cells	Reference
Prorenin	↓	N/A	N/A	N/A	N/A	N/A	(17)
Renin	↓	N/A	N/A	N/A	N/A	N/A	(17)
(P)RR	↓	↑	↓	↑	↑	↑	(17)
ACE	↑	↑	N/A	N/A	N/A	↑	(15)
ACE2	↓	N/A	↔	↔	↑	↑	(17)
AT1	↑	↑	N/A	N/A	N/A	N/A	(15)
AT2	↓	↔	↔	↔	↔	↔	(16)
Chymase	↑	↑	N/A	N/A	N/A	↑	(15)
Cathepsin G	↑	↑	N/A	N/A	N/A	↑	(30)
mas	↓	N/A	N/A	N/A	N/A	N/A	(17)
Apelin	↑	↑	↑	↑	N/A	↑	(16,71)
APJ	↑	N/A	N/A	N/A	N/A	N/A	(16,71)
ECE-1	↓	↓	↓	↔	↔	↔	(55)
ET-1	↔	↑	↑	↑	↑	N/A	(55)
ETA	↑	↑	↑	↑	N/A	N/A	(55)
ETB	↔	N/A	N/A	N/A	N/A	N/A	(55)
Corin	↔	N/A	N/A	N/A	N/A	N/A	(78)
Furin	↓	N/A	N/A	N/A	N/A	N/A	(78)
ANP	↔	N/A	N/A	N/A	N/A	N/A	(78,94)
BNP	↔	N/A	N/A	N/A	N/A	N/A	(78,94)
CNP	↓	↓	↓	↔	N/A	↔	(78,94)
GC-A	↓	N/A	N/A	N/A	N/A	N/A	(78,94)
GC-B	↓	N/A	N/A	N/A	N/A	N/A	(78,94)
NPR-C	↔	N/A	N/A	N/A	N/A	N/A	(78,94)
NEP	↑	↑	↑	N/A	↑	N/A	(50)
B1R	↑	↑	↑	↔	↑	N/A	(50)
B2R	↑	↔	↔	↔	↑	N/A	(50)

Upregulated (↑), downregulated (↓) or unchanged (↔) gene/protein expression in stenotic aortic valves compared to uncalcified valves. N/A, no studies performed to date.

Angiotensin converting enzyme (ACE) and type 2 (ACE2); angiotensin type 1 (AT₁) and type 2 (AT₂) receptor; APJ: apelin receptor; atrial (ANP) and B-type natriuretic peptide (BNP); bradykinin B1 (B1R) and B2 (B2R) receptor; CNP (C-type natriuretic peptide); ECE-1: endothelin converting enzyme 1; ET-1: endothelin-1; endothelin receptor A (ET_A) and B (ET_B); GC: guanylyl cyclase; NEP: neutral endopeptidase; natriuretic peptide receptor C (NPR-C); (P)RR: renin receptor.

Rosenhek R, Zilberszac R, Schemper M, Czerny M, Mundigler G, Graf S, et al. Natural history of very severe aortic stenosis. Circulation. 2010;121:151–6.

 PubMed Web of Science ®Google Scholar

O'Brien KD, Shavelle DM, Caulfield MT, McDonald TO, Olin-Lewis K, Otto CM, et al. Association of angiotensin-converting enzyme with low-density lipoprotein in aortic valvular lesions and in human plasma. Circulation. 2002;106:2224–30.

 PubMed Web of Science ®Google Scholar

Yamamoto K, Yamamoto H, Yoshida K, Kisanuki A, Hirano Y, Ohte N, et al. Prognostic factors for progression of early- and late-stage calcific aortic valve disease in Japanese: the Japanese Aortic Stenosis Study (JASS) Retrospective Analysis. Hypertens Res. 2010;33:269–74.

 PubMed Web of Science ®Google Scholar

Cote N, Couture C, Pibarot P, Despres JP, Mathieu P. Angiotensin receptor blockers are associated with a lower remodelling score of stenotic aortic valves. Eur J Clin Invest. 2011;41:1172–9.

 PubMed Web of Science ®Google Scholar

Capoulade R, Clavel MA, Mathieu P, Cote N, Dumesnil JG, Arsenault M, et al. Impact of hypertension and renin-angiotensin system inhibitors in aortic stenosis. Eur J Clin Invest. 2013;43:1262–72.

 PubMed Web of Science ®Google Scholar

Chockalingam A, Venkatesan S, Subramaniam T, Jagannathan V, Elangovan S, Alagesan R, et al. Safety and efficacy of angiotensin-converting enzyme inhibitors in symptomatic severe aortic stenosis: symptomatic cardiac obstruction-pilot study of enalapril in aortic stenosis (SCOPE-AS). Am Heart J. 2004;147:E19.

 PubMed Web of Science ®Google Scholar

Jimenez-Candil J, Bermejo J, Yotti R, Cortina C, Moreno M, Cantalapiedra JL, et al. Effects of angiotensin converting enzyme inhibitors in hypertensive patients with aortic valve stenosis: a drug withdrawal study. Heart. 2005;91:1311–18.

 PubMed Web of Science ®Google Scholar

Dalsgaard M, Iversen K, Kjaergaard J, Grande P, Goetze JP, Clemmensen P, et al. Short-term hemodynamic effect of angiotensin-converting enzyme inhibition in patients with severe aortic stenosis: a placebo-controlled, randomized study. Am Heart J. 2014;167:226–34.

 PubMed Web of Science ®Google Scholar

Bull S, Loudon M, Francis JM, Joseph J, Gerry S, Karamitsos TD, et al. A prospective, double-blind, randomized controlled trial of the angiotensin-converting enzyme inhibitor ramipril in aortic stenosis (RIAS trial). Eur Heart J Cardiovasc Imaging. 2015;16:834–41.

 PubMed Web of Science ®Google Scholar

Helske-Suihko S, Laine M, Lommi J, Kaartinen M, Werkkala K, Kovanen PT, et al. Is blockade of the Renin-Angiotensin system able to reverse the structural and functional remodeling of the left ventricle in severe aortic stenosis? J Cardiovasc Pharmacol. 2015;65:233–40.

 PubMed Web of Science ®Google Scholar

Peltonen T, Napankangas J, Ohtonen P, Aro J, Peltonen J, Soini Y, et al. (Pro)renin receptors and angiotensin converting enzyme 2/angiotensin-(1-7)/Mas receptor axis in human aortic valve stenosis. Atherosclerosis. 2011;216:35–43.

 PubMed Web of Science ®Google Scholar

Helske S, Lindstedt KA, Laine M, Mayranpaa M, Werkkala K, Lommi J, et al. Induction of local angiotensin II-producing systems in stenotic aortic valves. J Am Coll Cardiol. 2004;44:1859–66.

 PubMed Web of Science ®Google Scholar

Peltonen T, Napankangas J, Vuolteenaho O, Ohtonen P, Soini Y, Juvonen T, et al. Apelin and its receptor APJ in human aortic valve stenosis. J Heart Valve Dis. 2009;18:644–52.

 PubMed Web of Science ®Google Scholar

Helske S, Syvaranta S, Kupari M, Lappalainen J, Laine M, Lommi J, et al. Possible role for mast cell-derived cathepsin G in the adverse remodelling of stenotic aortic valves. Eur Heart J. 2006;27:1495–504.

 PubMed Web of Science ®Google Scholar

Yuan ZS, Zhou YZ, Liao XB, Luo JW, Shen KJ, Hu YR, et al. Apelin attenuates the osteoblastic differentiation of aortic valve interstitial cells via the ERK and PI3-K/Akt pathways. Amino Acids. 2015;47:2475–82.

 PubMed Web of Science ®Google Scholar

Peltonen T, Taskinen P, Napankangas J, Leskinen H, Ohtonen P, Soini Y, et al. Increase in tissue endothelin-1 and ETA receptor levels in human aortic valve stenosis. Eur Heart J. 2009;30:242–9.

 PubMed Web of Science ®Google Scholar

Peltonen TO, Taskinen P, Soini Y, Rysa J, Ronkainen J, Ohtonen P, et al. Distinct downregulation of C-type natriuretic peptide system in human aortic valve stenosis. Circulation. 2007;116:1283–9.

 PubMed Web of Science ®Google Scholar

Peltonen T, Ohtonen P, Näpänkangas J, Ohukainen P, Ruskoaho H, Taskinen P. Statin treatment and gene expression of anti-atherogenic factor C-type natriuretic peptide system in stenotic aortic valves. J Heart Valve Dis. 2011;205:545–51.

 Google Scholar

Helske S, Laine M, Kupari M, Lommi J, Turto H, Nurmi L, et al. Increased expression of profibrotic neutral endopeptidase and bradykinin type 1 receptors in stenotic aortic valves. Eur Heart J. 2007;28:1894–903.

 PubMed Web of Science ®Google Scholar