Corin Variant Research Articles

Corin deficiency impairs cardiac function in mouse models of heart failure.

Corin is a protease in the natriuretic peptide system. Deleterious CORIN variants are associated with hypertension and heart disease. It remains unclear if and to what extent corin deficiency may contribute to heart failure (HF). Corin knockout (KO) mice were used as a model. Cardiac function was assessed by echocardiography and tissue analysis in Corin KO mice at different ages or subjected to transverse aortic constriction (TAC), which increased pressure overload. Heart and lung tissues were analyzed for cardiac hypertrophy and lung edema using wheat germ agglutinin, Sirius red, Masson's trichrome, and Prussian blue staining. Recombinant corin was tested for its effect on cardiac function in the TAC-operated Corin KO mice. Selected gene expression in the heart was examined by RT-PCR. ELISA was used to analyze factors in plasma. Corin KO mice had progressive cardiac dysfunction with cardiac hypertrophy and fibrosis after 9 months of age, likely due to chronic hypertension. When Corin KO mice were subjected to TAC at 10-12 weeks of age, cardiac function decreased more rapidly than in similarly treated wild-type mice. When the TAC-operated Corin KO mice were treated with recombinant corin protein, cardiac dysfunction, hypertrophy, and fibrosis were ameliorated. The corin treatment also decreased the gene expression associated with cardiac hypertrophy and fibrosis, increased plasma cGMP levels, lowered plasma levels of N-terminal pro-atrial natriuretic peptide, angiotensin II, and aldosterone, and lessened lung edema in the Corin KO mice subjected to TAC. Corin deficiency impairs cardiac function and exacerbates HF development in mice. Corin protein may be used to reduce cardiac hypertrophy and fibrosis, suppress the renin-angiotensin-aldosterone system, and improve cardiac function in HF.

Golden cats: A never‐ending story!

In the British feline breed a golden coat modification, called light‐gold, akita or copper, was reported by breeders during the 2010s. This modification restricted eumelanin to the tip of the tail and hairs showed a wideband modification. Pedigree analyses revealed an autosomal recessive inheritance pattern. A single candidate region was identified using a genome‐wide association study. Within that region, we identified CORIN (Corin, serine peptidase) as the strongest candidate gene, since two CORIN variants have previously been identified in Siberian cats with a golden phenotype. A homozygous CORIN:c.2425C>T nonsense variant was identified in copper British cats. Segregation of the variant was consistent with recessive inheritance. This nonsense CORIN:c.2425C>T variant, located in CORIN exon 19, was predicted to produce a truncated CORIN protein – CORIN:p.(Arg809Ter) – that would lack part of the scavenger receptor domain and the trypsine‐like serine protease catalytic domain. All 30 copper cats were T/T homozygous for the variant, which was also found in 20 C/T heterozygous British control cats but was absent in 340 cats from the 99 Lives dataset. Finally, genotyping of 218 cats from 12 breeds failed to identify carriers in cats from other breeds. We propose that this third CORIN:c.2425C>T variant represents the wb BSH (British recessive wideband) allele in the domestic cat.

Siberian cats help in solving part of the mystery surrounding golden cats.

Golden cats have been appreciated since the beginning of the cat fancy. Golden is a modification of the tabby coat. In the Siberian breed, a specific golden phenotype, named sunshine, has been described. Sunshine tabby cats exhibit a warm tone of tabby, a pink nose lacking the black lining and a large light cream area around the nose. Pedigree analyses revealed an autosomal recessive inheritance pattern. A single candidate region was identified by genome-wide association study (GWAS) and homozygosity mapping. Within that region, we identified CORIN (Corin, serine peptidase) as a strong candidate gene, since CORIN variants have been identified in mice and tigers with a golden phenotype and CORIN has been described as a modifier of the ASIP (Agouti Signaling Protein) pathway. A homozygous CORIN:c.2383C>T missense variant was identified in sunshine tabby cats. Segregation of the variant was consistent with recessive inheritance. The variant was also found in three Kurilian bobtail cats and in two ToyBob cats from the 99 Lives dataset but genotyping of 106 cats from 13 breeds failed to identify carriers in cats from other breeds. The CORIN:c.2383C>T variant was predicted to change an arginine to a cysteine at position 795 in the protein: CORIN:p.(Arg795Cys). Finally, hair observation in Siberian cats was consistent with elongated ASIP signaling as golden hair showed a large yellow band instead of the short subapical one usually observed in agouti hair. These results support an association of the Siberian sunshine modification with the CORIN:c.2383C>T variant. The Siberian cat has helped us to decipher one of the golden phenotypes observed in cats and we propose that the CORIN:c.2383C>T variant represents the wbSIB (Siberian recessive wideband) allele in the domestic cat.

Function and regulation of corin in physiology and disease.

Atrial natriuretic peptide (ANP) is of major importance in the maintenance of electrolyte balance and normal blood pressure. Reduced plasma ANP levels are associated with the increased risk of cardiovascular disease. Corin is a type II transmembrane serine protease that converts the ANP precursor to mature ANP. Corin deficiency prevents ANP generation and alters electrolyte and body fluid homeostasis. Corin is synthesized as a zymogen that is proteolytically activated on the cell surface. Factors that disrupt corin folding, intracellular trafficking, cell surface expression, and zymogen activation are expected to impair corin function. To date, CORIN variants that reduce corin activity have been identified in hypertensive patients. In addition to the heart, corin expression has been detected in non-cardiac tissues, where corin and ANP participate in diverse physiological processes. In this review, we summarize the current knowledge in corin biosynthesis and post-translational modifications. We also discuss tissue-specific corin expression and function in physiology and disease.

A common CORIN variant in hypertension reduces corin intracellular trafficking by exposing an inhibitory N-terminus

Corin is a transmembrane serine protease that activates atrial natriuretic peptide, a cardiac hormone essential for normal blood pressure. Corin is synthesized as a zymogen and activated on the cell surface. In previous studies, we identified a CORIN variant allele with an adenine insertion in the 5′-end of the coding region in ∼5% of hypertensive individuals in a Chinese population. The protein, named insA, encoded by the CORIN variant allele has a shortened cytoplasmic tail and reduced atrial natriuretic peptide processing activity. It remains unknown how a shortened cytoplasmic tail impairs corin function. In this study, we expressed a series of corin mutants with different N-terminal sequences and analyzed them by Western blotting, flow cytometry, protein chase, and immunostaining. Our results revealed that a Gly-Asn sequence after the initiating Met at the newly generated N-terminus was responsible for delaying corin trafficking in the Golgi. Deletion of the N-terminal Gly and Asn residues increased the intracellular trafficking, cell surface expression, and activation cleavage of the insA variant. These results help to explain how the CORIN variant allele impairs corin structure and function as an underlying mechanism in hypertension.

Development of a novel, sensitive cell-based corin assay

Corin (atrial natriuretic peptide-converting enzyme, EC 3.4.21) is a transmembrane serine protease expressed in cardiomyocytes. Corin exerts its cardioprotective effects via the proteolytic cleavage and activation of pro-atrial natriuretic peptide (pro-ANP) to ANP. We recently described an ANP reporter cell line stably expressing the ANP receptor, a cGMP-dependent cation channel used as a real-time cGMP biosensor, and the Ca2+-sensitive photoprotein aequorin. Here, we describe the generation of a novel reporter cell line expressing the calcium biosensor GCaMP6 instead of aequorin. In contrast to the luminescence-based assay, ANP stimulation of our novel GCaMP6 reporter cell resulted in stable, long-lasting fluorescence signals. Using this novel reporter system, we were able to detect pro-ANP to ANP conversion by purified, soluble wildtype corin (solCorin), but not the active site mutant solCorin(S985A), resulting in left-shifted concentration-response curves. Furthermore, cellular pro-ANPase activity could be detected on HEK 293 cells after transient expression of wildtype corin. In contrast, corin activity was not detected after transfection with the inactive corin(S985A) variant. In supernatants from cardiomyocyte-derived HL-1 cells pro-ANP to ANP conversion could also be detected, while in HL-1 corin knockout cells no conversion was observed. These findings underline the role of corin as the pro-ANP convertase. Our novel fluorescence-based ANP reporter cell line is well-suited for the sensitive detection of corin activity, and may be used for the identification and characterization of novel corin modulators.

Association of rs2271037 and rs3749585 polymorphisms in CORIN with susceptibility to hypertension in a Chinese Han population: A case-control study

Corins are membrane-bound protease that regulates blood pressure by activating the natriuretic peptides. These pro-atrial natriuretic peptide convertases are essential for sodium homeostasis and normal blood pressure. CORIN variants have been identified in humans and other animals, but no studies of CORIN polymorphisms have been conducted in northeastern China. This study aims to investigate the association of 2 single nucleotide polymorphisms (SNPs) in CORIN (rs2271037 and rs3749585) with hypertension, as well as their potential interactions with some risk factors of hypertension in a Han population of northeastern China. A case-control study, including 402 patients with hypertension and 406 participants with normal blood pressure, was conducted in Liaoning province. SNP genotyping was carried out by high resolution melting (HRM) after polymerase chain reaction amplifications. Since rs3749585 is located in 3′ untranslated region (UTR) of CORIN, in silico analysis was used to predict target micro RNAs on TargetScan, miRanda, and DIANA-microT. As a result, mutant T allele in rs2271037 (odds ratio [OR], 1.693; 95% confidence [CI], 1.528-1.877; p < 0.001) and C allele in rs3749585 (OR, 1.114; 95% CI 1.011-1.227; p = 0.029) increased the risk of hypertension, comparing with wild G allele and T allele, respectively. Patients with genotype TT (OR, 10.209; 95% CI, 6.414-16.250; p < 0.001) and GT (OR, 1.730; 95% CI, 1.226-2.443; p = 0.002) have higher risk of hypertension than those with genotype GG. SNP rs2271037 was significantly associated with susceptibility to hypertension in all genetic models (dominant model: OR, 2.879; 95% CI, 2.080–3.986; p < 0.001; recessive model: OR, 7.159; 95% CI, 4.779–10.724; p < 0.001; additive model: OR, 1.535; 95% CI, 1.163–2.027; p = 0.002). SNP rs3749585 was significantly correlated with hypertension susceptibility only in dominant model (OR, 1.533; 95% CI, 1.073–2.189; p = 0.019), but not in recessive model (OR, 1.220; 95% CI, 0.906–1.644; p = 0.191) or additive model (OR, 0.915; 95% CI, 0.694–1.205; p = 0.527). After adjusting for age, gender, body mass index (BMI), smoking, low-density lipoprotein cholesterol, and serum sodium level in logistic models, the same statistical results were obtained. Interaction study showed the association between CORIN polymorphisms and hypertension could be changed by overweight (BMI ≥ 25 kg/m2). In silico analyses implicated hsa-miR-495 as a target miRNA that potentially interacts with the 3′ UTR of CORIN. In conclusion, polymorphisms of rs2271037 and rs3749585 in CORIN were significantly associated with hypertension in a Han population of northeastern China. The mutant-type T allele of rs2271037 and C allele of rs3749585 might increase the susceptibility to hypertension in this population.

Identification and functional analysis of CORIN variants in hypertensive patients.

Corin is a serine protease that activates atrial natriuretic peptide (ANP). CORIN gene variants have been reported in patients with hypertension. To date, however, the prevalence of CORIN variants in hypertensive patients remains unknown. To understand the prevalence and functional significance of CORIN variants in hypertension, we sequenced CORIN exons in 300 normal and 401 hypertensive individuals in a Chinese population and identified nine nonsynonymous variants, of which eight were not characterized previously. Among them, variants c.131A>G (p.Tyr13Cys), c.376G>T (p.Asp95Tyr), c.1094T>G (p.Leu334Trp), and c.1667G>A (p.Arg525His) occurred similarly in both normal and hypertensive individuals. Variants c1139G>A (p.Arg349His), c.2689C>T (p.Pro866Ser), and c.2864C>T (p.Thr924Met) were found once each in hypertensive individuals. Variant c.1683G>T (p.Arg530Ser) occurred preferentially in hypertensive individuals [10/401 (2.5%) vs. 1/300 (0.3%) in normal individuals; P=0.023], which was confirmed in another independent cohort [9/368 (2.44%) in hypertensive and 2/377 (0.53%) in normal individuals; P=0.033]. In biochemical and cell-based functional studies, variants p.Arg530Ser and p.Thr924Met, but not p.Tyr13Cys, p.Asp95Tyr, p.Leu334Trp, p.Arg349His, p.Arg525His, and p.Pro866Ser, exhibited reduced pro-ANP processing activity, which was caused by endoplasmic reticulum retention and poor zymogen activation, respectively. These results indicate that genetic variants impairing corin function are not uncommon in general populations and that such variants may be an important contributing factor in hypertension.

PCSK6-mediated corin activation is essential for normal blood pressure.

Hypertension is the most common cardiovascular disease, afflicting >30% of adults. The cause of hypertension in most individuals remains unknown, suggesting that additional contributing factors have yet to be discovered. Corin is a serine protease that activates the natriuretic peptides, thereby regulating blood pressure. It is synthesized as a zymogen that is activated by proteolytic cleavage. CORIN variants and mutations impairing corin activation have been identified in people with hypertension and pre-eclampsia. To date, however, the identity of the protease that activates corin remains elusive. Here we show that proprotein convertase subtilisin/kexin-6 (PCSK6, also named PACE4; ref. 10) cleaves and activates corin. In cultured cells, we found that corin activation was inhibited by inhibitors of PCSK family proteases and by small interfering RNAs blocking PCSK6 expression. Conversely, PCSK6 overexpression enhanced corin activation. In addition, purified PCSK6 cleaved wild-type corin but not the R801A variant that lacks the conserved activation site. Pcsk6-knockout mice developed salt-sensitive hypertension, and corin activation and pro-atrial natriuretic peptide processing activity were undetectable in these mice. Moreover, we found that CORIN variants in individuals with hypertension and pre-eclampsia were defective in PCSK6-mediated activation. We also identified a PCSK6 mutation that impaired corin activation activity in a hypertensive patient. Our results indicate that PCSK6 is the long-sought corin activator and is important for sodium homeostasis and normal blood pressure.

A corin variant identified in hypertensive patients that alters cytoplasmic tail and reduces cell surface expression and activity.

Corin is a membrane-bound protease that regulates blood pressure by activating the natriuretic peptides. CORIN variants have been associated with hypertension and heart disease in African Americans. In this study, we conducted targeted exome sequencing and identified an insertion variant, c.102_103insA, in exon 1 of the CORIN gene. Analysis of two independent cohorts showed that the variant was preferentially present in hypertensive patients (38/795 or 4.78% vs. 4/632 or 0.63% in normal individuals, p = 4.14E-6). The insertion shifted the reading frame, resulting in a corin variant with a truncated cytoplasmic tail. In cell-based studies, the corin variant exhibited poor trafficking in the Golgi, reduced cell surface expression and zymogen activation, and low natriuretic peptide processing activity. Compared with normal individuals with the wild-type allele, individuals with the variant allele had lower levels of plasma corin [0.59 ± 0.07 ng/mL (n = 25) vs. 0.91 ± 0.02 ng/mL (n = 215), p<0.001] and higher levels of plasma N-terminal pro-atrial natriuretic peptide (NT-pro-ANP) [2.39 ± 3.6 nmol/L (n = 21) vs. 0.87 ± 0.6 nmol/L (n = 48), p = 0.005]. These results indicate that the variant altered corin structure and impaired the natriuretic peptide processing activity in vivo. The results highlight corin defects as an important underlying mechanism in hypertension.

Corin in Natriuretic Peptide Processing and Hypertension

Corin is a serine protease originally isolated from the heart. Functional studies show that corin is the long-sought enzyme responsible for activating cardiac natriuretic peptides. In mice, lack of corin prevents natriuretic peptide processing, causing salt-sensitive hypertension. In humans, corin variants and mutations that reduce corin activity have been identified in patients with hypertension and heart failure. Decreased plasma levels of corin antigen and activity have been reported in patients with heart failure and coronary artery disease. Low levels of urinary corin also have been found in patients with chronic kidney disease. Most recent studies show that corin also acts in the uterus to promote spiral artery remodeling and prevent pregnancy-induced hypertension. Here, we review the role of corin in natriuretic peptide processing and cardiovascular diseases such as hypertension, heart disease, pre-eclampsia, and chronic kidney disease.

Corin Mutation R539C from Hypertensive Patients Impairs Zymogen Activation and Generates an Inactive Alternative Ectodomain Fragment

Corin is a cardiac transmembrane serine protease that regulates blood pressure by activating natriuretic peptides. Corin variants have been associated with African Americans with hypertension and heart disease. Here, we report a new mutation in exon 12 of the CORIN gene identified in a family of patients with hypertension. The mutation resulted in R539C substitution in the Fz2 (Frizzled-2) domain of the corin propeptide region. We expressed and characterized the corin R539C mutant in HEK293 cells. As determined by Western blot analysis, the R539C mutation did not alter corin expression in transfected cells but impaired corin zymogen activation. In a pro-atrial natriuretic peptide processing assay, the corin mutant had reduced activity and exhibited a dominant-negative effect on wild-type corin. In addition, the R539C mutation altered corin ectodomain shedding, producing an alternative ~75-kDa fragment that was biologically inactive. Using protease inhibitors and the catalytically inactive corin mutant S985A, we showed that the ~75-kDa fragment was generated by corin autocleavage. We constructed a series of mutants by replacing single or double Arg residues in the corin propeptide and identified Arg-530 in the Fz2 domain as the alternative autocleavage site. Our results show that the corin mutation R539C identified in hypertensive patients impairs corin zymogen activation and causes an alternative autocleavage that reduces corin activity. These data support that human CORIN gene mutations causing impaired corin activity may be an underlying mechanism in hypertension.

Heart Failure

See related article, pp 327–332 Atrial and brain natriuretic peptides (ANP and BNP) possess important regulatory cardiorenal functions, such as promoting natriuresis, diuresis, vasodilatation, and activation of antihypertrophic responses on pathophysiological stress. Release of ANP and BNP is significantly increased in response to atrial and ventricular stretch, respectively. Both ANP and BNP are produced and stored as prohormones and are present in the circulation as a mixture of propeptide and active 28- and 32-amino acid, carboxyl-terminal peptide hormones, respectively.1 Both ANP and BNP bind to the natriuretic peptide receptor-A, which is coupled to particulate guanylate cyclase to generate cGMP, the primary second messenger mediating downstream signaling cascades in target tissues. Despite stimulation of the same receptor, the physiological effects of ANP and BNP are somewhat different: ANP predominantly regulates sodium-water homeostasis and blood pressure, whereas BNP has more antihypertrophic effects, although there is substantial overlap.1 In theory, increases in generation of ANP and BNP in response to myocardial stretch should occur as part of compensatory mechanism(s) to restore homeostatic balance. However, the lusitropic, antihypertrophic, and natriuretic effects of ANP and BNP are significantly attenuated in congestive heart failure despite a considerable apparent increase in plasma concentrations. It is now increasingly accepted that the key reason for this discrepancy is because of variable activation/processing of natriuretic peptides, resulting in much greater proportion …

Salt-Sensitive Hypertension and Cardiac Hypertrophy in Transgenic Mice Expressing a Corin Variant Identified in Blacks

Blacks represent a high-risk population for salt-sensitive hypertension and heart disease, but the underlying mechanism remains unclear. Corin is a cardiac protease that regulates blood pressure by activating natriuretic peptides. A corin gene variant (T555I/Q568P) was identified in blacks with hypertension and cardiac hypertrophy. In this study, we tested the hypothesis that the corin variant contributes to the hypertensive and cardiac hypertrophic phenotype in vivo. Transgenic mice were generated to express wild-type (WT) or T555I/Q568P variant corin in the heart under the control of α-myosin heavy chain promoter. The mice were crossed into a corin knockout (KO) background to create KO/TgWT and KO/TgV mice that expressed WT or variant corin, respectively, in the heart. Functional studies showed that KO/TgV mice had significantly higher levels of proatrial natriuretic peptide in the heart compared with that in control KO/TgWT mice, indicating that the corin variant was defective in processing natriuretic peptides in vivo. By radiotelemetry, corin KO/TgV mice were found to have hypertension that was sensitive to dietary salt loading. The mice also developed cardiac hypertrophy at 12 to 14 months of age when fed a normal salt diet or at a younger age when fed a high-salt diet. The phenotype of salt-sensitive hypertension and cardiac hypertrophy in KO/TgV mice closely resembles the pathological findings in blacks who carry the corin variant. The results indicate that corin defects may represent an important mechanism in salt-sensitive hypertension and cardiac hypertrophy in blacks.

Corin Variant Associated With Hypertension and Cardiac Hypertrophy Exhibits Impaired Zymogen Activation and Natriuretic Peptide Processing Activity

Corin is a cardiac serine protease that acts as the pro-atrial natriuretic peptide (ANP) convertase. Recently, 2 single-nucleotide polymorphisms (SNPs) (T555I and Q568P) in the human corin gene have been identified in genetic epidemiological studies. The minor I555/P568 allele, which is more common in African Americans, is associated with hypertension and cardiac hypertrophy. In this study, we examined the effect of T555I and Q568P amino acid substitutions on corin function. We found that corin frizzled-like domain 2, where T555I/Q568P substitutions occur, was required for efficient pro-ANP processing in functional assays. Mutant corin lacking this domain had 30+/-5% (P<0.01) activity compared to that of wild type. Similarly, corin variant T555I/Q568P had a reduced (38+/-7%, P<0.01) pro-ANP processing activity compared to that of wild type. The variant also exhibited a low activity (44+/-15%, P<0.05) in processing pro-brain natriuretic peptide (BNP). We next examined the biochemical basis for the loss of activity in T555I/Q568P variant and found that the zymogen activation of the corin variant was impaired significantly, as indicated by the absence of the activated protease domain fragment. This finding was confirmed in human embryonic kidney (HEK)293 cells and murine HL-1 cardiomyocytes. Thus, our results show that the corin gene SNPs associated with hypertension and cardiac hypertrophy impair corin zymogen activation and natriuretic peptide processing activity. Our data suggest that corin deficiency may be an important mechanism in hypertensive and heart diseases.

Issue Highlights

HomeCirculationVol. 112, No. 16Issue Highlights Free AccessIn BriefPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessIn BriefPDF/EPUBIssue Highlights Originally published18 Oct 2005https://doi.org/10.1161/circ.112.16.2377Circulation. 2005;112:2377CORIN GENE MINOR ALLELE DEFINED BY 2 MISSENSE MUTATIONS IS COMMON IN BLACKS AND ASSOCIATED WITH HIGH BLOOD PRESSURE AND HYPERTENSION, by Dries et al.Natriuretic peptides play a fundamental role in blood pressure regulation. Recent work has emphasized the importance of corin, an enzyme that cleaves pro-natriuretic peptides to their active forms. In this issue of Circulation, Dries and colleagues relate a single nucleotide polymorphism of the corin gene (that is common in blacks but rare in whites) to hypertension prevalence and blood pressure levels in black patients in the Dallas Heart Study sample. The presence of the corin I555 allele was associated with 63% higher odds of prevalent hypertension and higher systolic blood pressure (relative to those without the variant). Two additional features of this study are noteworthy. First, the authors addressed potential confounding by population stratification: If subjects are sampled from 2 or more subpopulations or from recently admixed populations (such as blacks), for which the frequencies of disease-susceptibility alleles differ, spurious associations may arise. Therefore, the authors genotyped more than 2000 single nucleotide polymorphisms highly informative of ancestry and adjusted for “estimated ancestry” in multivariable analyses. The association of the corin variant with hypertension remained robust upon adjustment for ancestry. Second, recognizing the importance of validating genotype-phenotype associations to minimize false positive findings, they replicated their findings in 2 other cohorts. See p 2403.ANGIOTENSIN RECEPTOR BLOCKADE AND EXERCISE CAPACITY IN ADULTS WITH SYSTEMIC RIGHT VENTRICLES: A MULTICENTER, RANDOMIZED, PLACEBO-CONTROLLED CLINICAL TRIAL, by Dore et al.It is unknown whether pharmacological blockade of the renin-angiotensin system has beneficial effects in patients with complex congenital heart disease in whom the morphological right ventricle supports the systemic circulation. Dore and colleagues performed a multicenter, randomized, double-blind, placebo-controlled crossover trial to assess the effects of losartan on exercise capacity and neurohormonal levels in 29 patients with systemic right ventricles due to D-transposition of the great arteries with a Mustard baffle or congenitally corrected transposition. Despite impairments in baseline functional testing, adult patients with a systemic right ventricle did not improve their exercise capacity with losartan therapy. Minimal baseline activation of the renin-angiotensin system may explain this lack of benefit. Caution is warranted in extrapolating results from studies assessing effects of inhibition of the renin-angiotensin system on the failing left ventricle without independent validation on the systemic right ventricle. See p 2411.EFFECT ON SURVIVAL AND HOSPITALIZATION OF INITIATING TREATMENT FOR CHRONIC HEART FAILURE WITH BISOPROLOL FOLLOWED BY ENALAPRIL, AS COMPARED WITH THE OPPOSITE SEQUENCE: RESULTS OF THE RANDOMIZED CARDIAC INSUFFICIENCY BISOPROLOL STUDY (CIBIS) III TRIAL, by Willenheimer et al.Clinicians managing patients with heart failure frequently prescribe an ACE inhibitor as one of the first drugs and titrate the dose up to the maximum tolerated. Other drugs shown to be helpful in heart failure that are started subsequently may not be titrated as aggressively. The CIBIS III investigators randomized 1010 patients with mild to moderate heart failure to 6 months of therapy with either bisoprolol or enalapril to determine if initiation of a β-blocker first would yield outcomes comparable to those achieved by initiation of an ACE inhibitor first. Noninferiority of bisoprolol-first therapy was shown in an intention-to-treat analysis, which suggests that physicians now have data to support a customized approach to management of heart failure with initiation of either a β-blocker or an ACE inhibitor first, according to clinical circumstances. The CIBIS III trial was presented at a Hotline Session of the ESC Congress 2005 and published online simultaneously in Circulation. This print version of the paper is accompanied by an editorial to help place the findings in perspective. See pp 2380 and 2426.Visit http://www.circ.ahajournals.org:Images in Cardiovascular MedicineCulprit Lesion Atherothrombectomy During Acute Myocardial Infarction: Extraction of an Acute Coronary Plaque Rupture. See p e267.Delayed Contrast-Enhanced Magnetic Resonance Imaging in Pulmonary Arterial Hypertension. See p e268.Anterolateral Papillary Muscle Rupture Complicated by the Obstruction of a Single Diagonal Branch. See p e269. Download figureDownload PowerPointCorrespondenceSee p e271. Previous Back to top Next FiguresReferencesRelatedDetails October 18, 2005Vol 112, Issue 16 Advertisement Article InformationMetrics https://doi.org/10.1161/circ.112.16.2377 Originally publishedOctober 18, 2005 PDF download Advertisement