Impact of aldosterone receptor blockade on the deleterious cardiac effects of adrenergic activation in hypertensive rats.

Although in hypertension beta-adrenoreceptor activation promotes the transition from cardiac hypertrophy to pump dysfunction, the use of beta-blockers is controversial. As adrenergic activation may mediate adverse effects on the heart through the renin-angiotensin-aldosterone system, we evaluated the effects of the aldosterone receptor blocker, spironolactone (SPIRO), on isoproterenol (ISO)-induced changes in left ventricular cavity size and pump function and the determinants thereof in spontaneously hypertensive rats (SHR). ISO administered for 4.5 months resulted in increases in left ventricular dimensions and a decrease in pump function in SHR but not in normotensive rats, changes that, without affecting blood pressure, were abolished by SPIRO. In SHR, 4-5 days of ISO increased myocardial matrix metalloproteinase-2 activity, which was associated with matrix metalloproteinase-2 but not tissue inhibitor of MMP expression; persisted at 4.5 months; and was prevented by SPIRO. Moreover, after 4.5 months, ISO increased non-cross-linked myocardial collagen concentrations in SHR, which was abolished by SPIRO. Although after 4.5 months, ISO was not associated with increased cardiomyocyte apoptosis, an early (4-5 days) ISO-induced apoptotic effect was noted, which was prevented by SPIRO. Hence, aldosterone receptor blockade may be sufficient to prevent those adverse effects of beta-adrenoreceptor activation responsible for the transition from concentric cardiac hypertrophy to pump dysfunction in hypertension.

The G-308A polymorphism of the TNF-alpha gene does not predict changes in cardiac function in response to medical therapy for idiopathic dilated cardiomyopathy.

The G-308A polymorphism of the tumour necrosis factor-alpha (TNF-alpha) gene, a variant that influences TNF-alpha transcription, may contribute to non-ischaemic dilated cardiomyopathy. To evaluate whether TNF-alpha genotyping may assist in identifying a subset of patients who could potentially benefit from immunomodulatory therapy, we assessed the relationship between the G-308A polymorphism of the TNF-alpha gene and changes in left ventricular (LV ) chamber dimensions and systolic function in patients with idiopathic dilated cardiomyopathy (IDC) before and six months after diuretic, digoxin and angiotensin-converting enzyme inhibitor (ACEI) therapy. In 331 patients with IDC and 349 controls, the TNF-2 (A) allele (odds ratio = 1.509, 95% CI = 1.130-2.015, p < 0.01) and the TNF-12/22 (AG/GG) genotype (odds ratio = 1.620, 95% CI = 1.159-2.266, p < 0.01) were associated with IDC. However, in 122 patients with IDC, the TNF-alpha genotype was not associated with plasma TNF-alpha concentrations. In 133 patients with IDC, the TNF-alpha genotype failed to predict either the severity of pump dysfunction and cardiac dilatation at baseline, or changes in pump function and cardiac dimensions after six months of medical treatment. We conclude therefore that although the TNF-alpha gene G-308A polymorphism may contribute to the development of IDC, it does not influence pump function or adverse cardiac remodelling in patients with IDC. Genotyping for this variant is therefore unlikely to assist in identifying patients with heart failure who may be particularly susceptible to novel immunomodulatory therapeutic strategies.

Functional variants of the angiotensinogen gene determine antihypertensive responses to angiotensin-converting enzyme inhibitors in subjects of African origin.

OBJECTIVE: To determine whether the response to angiotensin-converting enzyme inhibitor (ACEI) monotherapy in subjects of African origin is determined by genetic variants within the angiotensinogen (AGT) gene. METHODS: A total of 194 hypertensive patients of African ancestry were recruited from district clinics in Johannesburg, South Africa. Eighty patients received open-label ACEI (enalapril or lisinopril) monotherapy, and 114 open-label calcium antagonist (nifedipine) as a drug class comparator. Twenty-four hour ambulatory blood pressure (ABP) monitoring was performed at baseline (off medication) and after 2 months of therapy. DNA was analysed for functional variants (-217G-->A and -20A-->C) of the AGT gene. The impact of genotype on ABP responses to ACEI monotherapy or calcium antagonists; and on plasma aldosterone and renin levels after ACEI monotherapy was assessed. RESULTS: Adjusting for baseline ABP and type of ACEI in the ACEI-treated group, the -217G-->A variant predicted ABP responses to ACEI (n = 77; P < 0.01), but not to nifedipine (n = 108). ACEI in patients with the AA genotype of the -217G-->A variant failed to elicit an antihypertensive response [change in ABP, mmHg: systolic blood pressure (SBP) +0.84 +/- 2.89, P = 0.78; diastolic blood pressure (DBP) -0.47 +/- 1.74, P = 0.79]. In contrast, those patients with at least one copy of the -217G allele developed a 7.23 +/- 1.55 and 5.38 +/- 1.12 mmHg decrease (P < 0.0001) in SBP and DBP, respectively, after ACEI administration. Similarly, the -20A-->C variant predicted ABP responses to ACEI monotherapy (P < 0.01) but not to nifedipine. Moreover, patients who were AA genotype for both variants failed to develop an antihypertensive response to ACEI (change in ABP, mmHg: SBP +1.06 +/- 3.05, P = 0.73; DBP -0.39 +/- 1.83, P = 0.83); whereas patients with at least one copy of both the -217G and the -20C allele developed substantial decreases in ABP (change in ABP, mmHg: SBP -14.08 +/- 3.72, P < 0.0001; DBP -9.62 +/- 2.74, P < 0.0001). Patients with at least one copy of the -217G allele demonstrated a significant reduction in the aldosterone-to-renin ratio (-0.098 +/- 0.035, P < 0.01), whereas in those patients who were -217AA genotype the ratio was unchanged (-0.03 +/- 0.16, P = 0.85). CONCLUSION: Functional variants of the AGT gene contribute to the variability of antihypertensive responses to ACEI monotherapy in individuals of African ancestry, with genotype determining whether or not responses occur.

Phosphodiesterase inhibition promotes the transition from compensated hypertrophy to cardiac dilatation in rats.

The cellular signaling pathways responsible for the transition from compensated left ventricular hypertrophy (LVH) to LV dilatation (remodeling) and heart failure are unclear. As chronic administration of a beta-adrenoreceptor (beta-AR) agonist mediates the premature onset of cardiac remodeling without myocyte necrosis or myocardial dysfunction in LVH, we suggest that beta-AR activation is critical in promoting the transition from compensated LVH to cardiac dilatation. However, beta-AR mediated effects in the heart can occur via either the cyclic adenosine monophosphate (cAMP) system or via cAMP independent signaling pathways. To determine the role of cAMP in promoting adverse cardiac chamber remodeling, we evaluated whether phosphodiesterase inhibition (PDEI) promotes LV dilatation in rats with compensated LVH. The impact of chronic administration of the PDEI, pentoxifylline, on LV remodeling and function was assessed in spontaneously hypertensive rats (SHR) with compensated LVH. The PDEI mediated inotropic effects and increased cAMP concentrations in SHR. This dose of the PDEI administered for 4 months to SHR did not modify LV weight or influence intrinsic myocardial systolic function (as assessed in the absence of the PDEI) in SHR. However, the PDEI mediated the development of a right shift in LV end diastolic (LVED) pressure-internal dimension and LVED pressure-volume relations, LV wall thinning, and increments in myocardial soluble (non-cross-linked) collagen concentrations. In conclusion, chronic PDEI administration induces adverse geometric and interstitial cardiac remodeling in SHR, a finding that supports the notion that the beta-AR-cAMP system is important in mediating the progression to heart failure by promoting interstitial remodeling and LV dilatation in LVH.

Endotoxin-independent white cell cytokine production in haemodynamically stable patients with idiopathic dilated cardiomyopathy.

INTRODUCTION: In heart failure, increased circulating white cell tumour necrosis factor-alpha production could be attributed to elevated plasma endotoxin concentrations or an increase in white cell sensitivity to endotoxin. AIMS: To ascertain whether, in patients with IDC, circulating white cell TNF-alpha production is also mediated through endotoxin-independent mechanisms. METHODS: Whole blood production of TNF-alpha, both with and without the presence of an endotoxin stimulus, was evaluated in 89 controls and in 60 patients with IDC in New York Heart Association functional class I, II or III heart failure and without evidence of oedema, reduced peripheral perfusion or elevated plasma endotoxin concentrations. Circulating concentrations of selected pro and anti-inflammatory factors were also measured. RESULTS: In patients compared to controls, IgG (p < 0.01) (IgG1 and IgG3), but not IgM concentrations were elevated, and plasma TNF-alpha and TGF-beta concentrations were raised (p < 0.001, p < 0.02 respectively). In addition, endotoxin-free cultured whole blood TNF-alpha production (p < 0.0005) was increased. Against a role for endotoxin-mediated pre-activation of white cells in patients, the sensitivity of white cells to endotoxin, as determined from the excitatory endotoxin concentration producing 50% maximal TNF-alpha production was unchanged. Moreover, in favour of non-endotoxin-mediated white cell activation, the calcineurin inhibitor, cyclosporin-A, which did not alter endotoxin-induced TNF-alpha production, decreased TNF-alpha produced by unstimulated cultured cells in patients to values not significantly greater than those in controls. CONCLUSIONS: We concluded that circulating white cell cytokine over-production can occur through both endotoxin- dependent and -independent mechanisms in IDC.

Impact and mechanisms of action of neurotensin on cardiac contractility in the rat left ventricle.

Using immunoassay measurements, neurotensin was identified in rat ventricular tissue and in coronary effluent samples. Exogenous neurotensin evoked contractile responses in isolated ventricular preparations, which were equivalent in magnitude to those of norepinephrine and histamine, but greater than those for serotonin and angiotensin II. EC(50) values revealed neurotensin to be as potent as serotonin, but more potent than norepinephrine, histamine and angiotensin II. Structure-activity studies indicated that the contractile effects are attributed to the C-terminal portion of neurotensin. Neurotensin-induced responses were decreased by SR 48692, a specific neurotensin receptor antagonist. Neurotensin elicited an increase in coronary effluent norepinephrine concentrations, and a strong relationship between the magnitude of neurotensin-induced contractile effects and increments in myocardial norepinephrine release were noted. Neurotensin-induced contractile responses were abolished by beta-adrenoceptor antagonists, but not by histamine, serotonin or angiotensin II receptor antagonists. In conclusion, neurotensin increases ventricular contractility through stimulation of myocardial norepinephrine release.

Chronic beta-adrenoreceptor activation increases cardiac cavity size through chamber remodeling and not via modifications in myocardial material properties.

Chronic beta-adrenoreceptor (beta-AR) activation increases left ventricular (LV) cavity size by promoting a rightward shift in LV diastolic pressure-volume (P-V) relations in association with increases in low-tensile strength myocardial (non-cross-linked) collagen concentrations. Because diastolic P-V relations are determined by chamber remodeling as well as by myocardial material properties (indexed by myocardial stiffness), both of which are associated with modifications in myocardial collagen cross-linking, we evaluated whether chamber remodeling or alterations in myocardial material properties govern beta-AR-mediated modifications in diastolic P-V relations. The effects of chronic administration of isoproterenol (Iso; 0.04 mg.kg(-1).day(-1) from 12 to 19 mo of age) to spontaneously hypertensive rats (SHRs) on LV cavity dimensions, LV diastolic P-V relations, myocardial collagen characteristics, myocardial stiffness constants [e.g., the slope of the LV diastolic stress-strain relation (k)], and LV chamber and myocardial systolic function were assessed. SHRs at 19 mo of age had normal LV diastolic P-V relations, marked myocardial fibrosis (using a pathological score), increased myocardial cross-linked (insoluble to cyanogen bromide digestion) type I and type III collagen concentrations, and enhanced myocardial k values. Iso administration to SHRs resulted in enlarged LV cavity dimensions mediated by a rightward shift in LV diastolic P-V relations, increased volume intercept of the LV diastolic P-V relation, decreased LV relative wall thickness despite a tendency to augment LV hypertrophy, and increased non-cross-linked type I and type III myocardial collagen concentrations. Iso administration resulted in reduced pump function without modification of intrinsic myocardial systolic function. However, despite increasing myocardial non-cross-linked concentrations, Iso failed to alter myocardial k in SHRs. These results suggest that beta-AR-mediated rightward shifts in LV diastolic P-V relations, which induce decreased pump function, are mediated by chamber remodeling but not by modifications in myocardial material properties.

Therapy of ischemic cardiomyopathy with the immunomodulating agent pentoxifylline: results of a randomized study.

BACKGROUND: Inflammatory immune activation commonly occurs in heart failure and may perpetuate this syndrome. We sought to determine whether the immunomodulating agent pentoxifylline enhances left ventricular function in patients with ischemic cardiomyopathy. We also investigated the effect of therapy on levels of brain natriuretic peptide (NT-pro BNP), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), and the marker of apoptosis, Fas/Apo-1. METHODS AND RESULTS: In a single-center, prospective, randomized, double-blind, placebo-controlled study, 38 patients with ischemic cardiomyopathy received pentoxifylline 400 mg TID or placebo in addition to standard therapy. Clinical assessment, radionuclide ventriculography, echocardiography, and blood analyses were performed at baseline and after 6 months. There were no differences in baseline characteristics between the groups. Five patients died (4 in the placebo group). Pentoxifylline treatment resulted in an improvement in functional class (P<0.005) and an increase in systolic blood pressure (P<0.05) and left ventricular radionuclide ejection fraction (P<0.05) compared with the placebo-treated group. There were reductions in plasma concentrations of CRP, NT-pro BNP, TNF-alpha, and Fas/Apo-1 in the pentoxifylline compared with the placebo-treated group. CONCLUSIONS: In patients with heart failure due to ischemic left ventricular dysfunction, the addition of pentoxifylline to standard therapy results in improvements in clinical status and radionuclide ejection fraction, which are accompanied by reductions in plasma markers of inflammation, prognosis, and apoptosis.

Impact of renin-angiotensin-aldosterone system gene variants on the severity of hypertension in patients with newly diagnosed hypertension.

BACKGROUND: The severity of hypertension has prognostic significance. Previous studies have assessed the relationship between renin-angiotensin-aldosterone system (RAAS) genotype and the severity of hypertension in either treated patients or those who have only recently discontinued treatment. METHODS: We assessed the impact of RAAS genotype on ambulatory and office blood pressure (BP) in 231 newly diagnosed hypertensive patients of African ancestry who had never received therapy. Subjects were genotyped for variants of the angiotensin-converting enzyme (insertion/deletion), angiotensinogen (M235T, -20A-->C), and aldosterone synthase (CYP11B2)(-344C-->T) genes. RESULTS: The CYP11B2 gene polymorphism was associated with systolic BP (SBP). In comparison to subjects with at least one copy of the -344C allele (n = 75), patients who were homozygous for the -344T allele (n = 156) had both higher ambulatory SBP (150 +/- 1 v 144 +/- 1 mm Hg, P =.002 before and P =.01 after adjusting for multiple genotyping) and office SBP (163 +/- 2 v 156 +/- 2 mm Hg, P =.01 before and P =.05 after adjusting for multiple genotyping). Neither the angiotensin-converting enzyme insertion/deletion nor the angiotensinogen gene polymorphisms were associated with ambulatory or office SBP or diastolic BP (DBP). The CYP11B2 gene variant also did not affect DBP. CONCLUSION: A variant within the CYP11B2 locus has a clinically important impact on the severity of SBP changes in individuals with newly diagnosed hypertension who are of African ethnicity.

T594M variant of the epithelial sodium channel beta-subunit gene and hypertension in individuals of African ancestry in South Africa.

BACKGROUND: The T594M variant of the beta-subunit of the sodium epithelial channel (ENaC) gene may contribute to hypertension in individuals of African origin. METHODS: A case-control study was performed to assess the role of the ENaC gene variant as an independent risk factor for hypertension in subjects of African ancestry. The effects of the ENaC gene variant on ambulatory blood pressure (BP) in hypertensive individuals and on office BP in hypertensive individuals and control subjects were also assessed. A total of 519 hypertensive patients with 24-h ambulatory BP (ABP) values determined while off medication, and 514 normotensive South African individuals of African ancestry were genotyped for the T594M polymorphism of the ENaC gene. RESULTS: A total of 22 (4.2%) hypertensive participants compared with 23 (4.5%) normotensive participants possessed the T594M variant (odds ratio = 1.06, confidence interval = 0.58 to 1.92, not significant). A similar genotype frequency distribution was noted in subjects representing the two predominant chiefdoms (Nguni and Sotho) in both case and control groups. No differences in frequency distribution of the T594M variant were noted with respect to either body mass index or gender. There were no differences in clinic or ambulatory mean, day, or night BP between hypertensive patients with or without the variant. Similarly, no differences were noted in clinic BP between control subjects with or without the variant. Other phenotypic parameters (including age and hypertension duration and severity) were also similar among hypertensive patients with or without the variant. CONCLUSION: These results do not support an important role for the T594M variant of the ENaC gene contributing to either the development or severity of hypertension in subjects of African ancestry.

Cross-linking influences the impact of quantitative changes in myocardial collagen on cardiac stiffness and remodelling in hypertension in rats.

OBJECTIVE: To assess whether the variable impact of quantitative changes in myocardial collagen on left ventricular (LV) diastolic myocardial stiffness (myocardial k) and remodelling (increased volume intercept of diastolic pressure-volume relations) in LV hypertrophy (LVH) is associated with alterations in myocardial collagen cross-linking. METHODS: We evaluated myocardial collagen content (hydroxyproline concentrations [HPRO]) and the degree of myocardial collagen cross-linking (solubility to cyanogen bromide digestion) in 14-15- and 21-22-month-old spontaneously hypertensive rats (SHRs), and in aortic-banded rats with pressure overload hypertrophy (POH). RESULTS: In rats with POH and in SHRs irrespective of age, increases in myocardial [HPRO] were noted. However, hypertensive rats differed in the material and geometric properties of the myocardium, and in qualitative aspects of fibrosis. In 14-15-month-old SHRs myocardial k (determined from diastolic stress-strain relations) and insoluble (cross-linked) [HPRO] were increased, but no LV remodelling or increases in myocardial soluble (non-cross-linked) [HPRO] were noted. In rats with POH, LV remodelling and increases in soluble myocardial [HPRO] occurred, but no increase in k or insoluble myocardial [HPRO] were observed. In 21-22-month-old SHRs, increases in k, soluble and insoluble myocardial [HPRO], as well as LV remodelling occurred. CONCLUSIONS: Collagen cross-linking may determine the diverse relation that exists between increases in myocardial collagen concentrations and either myocardial stiffness or chamber remodelling in hypertension. These findings support the notion that fibrosis contributes to myocardial stiffness as well as LV dilatation in LVH, albeit an effect that is modulated by collagen quality.

Beta-adrenergic activation initiates chamber dilatation in concentric hypertrophy.

It is uncertain whether chronic beta-adrenoreceptor (beta-AR)-activation in hypertension could initiate the progression from compensated left ventricular (LV) hypertrophy to pump dysfunction. It is also uncertain if this effect is through adverse LV remodeling (chamber dilatation with wall thinning and pump dysfunction) or intrinsic myocardial contractile dysfunction. We evaluated the effect of 5 months of isoprenaline (0.02 mg x kg(-1) x d(-1)) on hemodynamics, LV wall thickness, cavity size, and interstitial characteristics in spontaneously hypertensive rats (SHR) with compensated LV hypertrophy. In the absence of myocyte necrosis, changes in volume preload, pressure afterload, and heart rate or decreases in baseline systolic myocardial elastance (load independent measure of intrinsic myocardial contractility), ISO produced a right shift in LV diastolic pressure-volume (P-V) relations (chamber dilatation), a decrease in LV wall thickness despite a further increase in LV weight in SHR, LV pump dysfunction (right shift in LV systolic P-V relations), and deleterious interstitial remodeling (increments in total and noncrosslinked myocardial collagen concentrations). The isoprenaline-induced LV geometric, chamber performance, and interstitial changes were similar to alterations noted during decompensation in older SHR. In summary, in the absence of tissue necrosis and baseline intrinsic myocardial contractile dysfunction, chronic beta-AR activation induces interstitial and chamber remodeling and, hence, pump dysfunction. These data suggest that chronic sympathetic activation initiates the progression from compensated concentric LV hypertrophy in hypertension to cardiac dysfunction primarily through deleterious cardiac remodeling rather than intrinsic myocardial contractile dysfunction.

Effects of pentoxifylline on cytokine profiles and left ventricular performance in patients with decompensated congestive heart failure secondary to idiopathic dilated cardiomyopathy.

Patients with severe heart failure have plasma cytokine concentrations that are more than twofold greater than those in patients with moderate heart failure. Although pentoxifylline, an immunomodulatory agent that inhibits tumour necrosis factor-alpha (TNF-alpha) production, improves pump function in mild-to-moderate heart failure, its effects on advanced heart failure have not been determined. In a prospective, randomized, double-blind, placebo-controlled study we compared the effects of 1-month therapy with pentoxifylline (400 mg 3 times daily) (n = 9) and placebo (n = 9) on left ventricular systolic function and dimensions as well as on plasma TNF-alpha (picograms per milliliter), interleukin-10 (IL-10), and the apoptosis-signaling receptor Fas/Apo-1 in patients with idiopathic dilated cardiomyopathy and advanced heart failure. All patients had New York Heart Association functional class IV heart failure, required intravenous inotropic agents for >72 hours at the beginning of the study, and received diuretics, digoxin, and an angiotensin-converting enzyme inhibitor for the duration of the study. Marked increases in TNF-alpha and Fas/Apo-1 concentrations were noted in the 18 patients compared with patients with functional class II to III heart failure and controls (p <0.001). Baseline characteristics were the same between the pentoxifylline and placebo groups. Pentoxifylline administration resulted in reduced TNF-alpha and Fas/Apo-1 concentrations, and an increase in ejection fraction at 1 month (p <0.05 compared with baseline and with placebo), effects that were not observed in the placebo-treated group. These data suggest that pentoxifylline may be a useful adjunct to conventional therapy in patients with severe heart failure.

Association between an atrial natriuretic peptide gene polymorphism and normal blood pressure in subjects of African ancestry.

AIM: The roles of the atrial natriuretic peptide (ANP) gene and the clearance receptor of the ANP (NPRC) gene in hypertensive groups of African ancestry are unclear. The aim of the present study was to assess the relationship between both ANP and NPRC gene polymorphisms and hypertension in Black South Africans. METHODS: 298 patients, diagnosed as having essential hypertension according to 24-hour ambulatory blood pressure (BP) measurements (mean daytime diastolic BP> 90 mm Hg) whilst off medication, and 278 normotensive control subjects of a similar African ancestry, were genotyped for polymorphic markers in intron 2 (which is in complete linkage disequilibrium with a potentially functional exon 1 variant) and exon 3 (which leads to the extension of ANP by two additional arginines) of the ANP gene. Moreover, 64 hypertensives and 63 control from the same groups were genotyped for the cis-acting promoter/enhancer element of the NPRC gene. RESULTS: No relationship between the exon 3 variant and either the presence (odds ratio = 1.075) or the severity (24-hour BP) of hypertension was noted. The intron 2 polymorphism occurred at a low frequency in the control group (frequency of subjects heterozygous for the variant = 6.1%), but was almost absent in the hypertensive group (frequency of heterozygotes = 1.7%). Consequently, a relationship between a normal BP and the intron 2 variant was noted (odds ratio = 0.28, confidence interval = 0.10-0.76, p < 0.01, <1% chance of false positive results). The NPRC gene variant occurred with an equally low frequency in both the hypertensive (4.7%) and the control (4.8%) groups. CONCLUSIONS: The results of the present study suggest that the ANP, but not the NPRC locus contributes to BP in subjects of African ancestry.

An aldosterone synthase gene variant is associated with improvement in left ventricular ejection fraction in dilated cardiomyopathy.

OBJECTIVE: To assess whether renin-angiotensin-aldosterone (RAA) system gene polymorphisms shown to be associated with alterations in the activity of the system, may predict cardiac function changes subsequent to initiating medical therapy in heart failure. METHODS: The impact of RAA system genotypes on left ventricular ejection fraction (LVEF) following therapy to patients with idiopathic dilated cardiomyopathy (IDC) and class II-III heart failure was assessed. In 107 patients LVEF and LV dimensions were determined using radionuclide ventriculography and echocardiography prior to and subsequent to receiving furosemide, digoxin and angiotensin-converting enzyme (ACE) inhibitor therapy. Patients and controls were genotyped for variants of the ACE (insertion-deletion polymorphism), angiotensinogen (AGT; M235T polymorphism) and the aldosterone synthase (CYP11B2, C-344T polymorphism) genes. RESULTS: RAA system genotypes were not significantly associated with LVEF prior to initiating medical therapy. However, the CYP11B2 gene variant (P=0.0064 on covariate analysis [adjusted for multiple genotyping] with a 1-2% chance of false positive data), but neither the ACE, nor the AGT variants, predicted improvement in LV ejection fraction in patients on medical therapy. CONCLUSION: A CYP11B2 gene variant predicts the variable improvement in LV ejection fraction that occurs subsequent to initiating medical therapy in IDC. These data suggest a role for the aldosterone synthase locus in regulating the progression of heart failure.