High-dose Beta-blocker Research Articles

Maternal beta‐blocker dose and risk of small‐for gestational‐age in women with heart disease

Beta-blockers are prescribed for many pregnant women with heart disease, but whether there is a dose-dependent effect on fetal growth remains to be examined. We aimed to investigate if antenatal beta-blocker use and dose were associated with delivering a small-for-gestational-age infant among women with heart disease. Our cohort included women with heart disease who delivered at Oslo University Hospital between 2006 and 2015. Maternal heart disease was classified into modified WHO risk scores. Women with beta-blocker treatment were dichotomized into whether they had been treated with a low or high dose based on clinical factors. We compared the risk of delivering a small-for-gestational-age infant in women exposed to high doses, low doses, or with no exposure to antenatal beta-blockers while adjusting for severity of maternal heart disease in logistic regression models. Of a total of 540 pregnancies among women with heart disease, 163 (30.2%) were exposed to beta-blocker treatment. The majority were treated with metoprolol (86.5%). Almost twice as many babies in the beta-blocker group were small-for-gestational-age, compared with the non-exposed group (19.8 vs 9.5%, P < 0.001). Women using a high-dose beta-blocker had a five-fold increased risk of delivering a small-for-gestational-age infant compared with non-exposure (adjusted odds ratio [aOR] 4.89, 95% confidence interval [CI] 2.22-10.78, P < 0.001). Women using a low dose of beta-blocker had a two-fold increased risk of delivering a small-for-gestational-age infant; however, the confidence interval included the null (aOR 1.75, 95% CI 0.83-3.72, P=0.143). Results when restricting the analyses to metoprolol showed the same pattern, but with attenuation of risks. We found a five-fold increased risk of delivering a small-for-gestational-age infant in women with heart disease treated with a high dose of beta-blocker, and a two-fold increased risk among those treated with a low dose, showing an apparent dose-response relation. Close monitoring of fetal growth is warranted among women with heart disease treated with beta-blockers. As drug therapy in pregnancy concerns both mother and fetus, an optimum balance for both should be the goal.

The Dark Purple Side of Ceftriaxone: A Case Report on Leucocytoclastic Vasculitis.

We present a case of an 85-year-old woman diagnosed with uncomplicated pyelonephritis, who was treated with intravenous ceftriaxone. Her chronic medications were phenprocoumon, diltiazem and bisoprolol. During the infectious phase, the patient presented tachycardia – despite high-dose beta-blocker treatment – and developed left acute heart failure, with acute renal failure (pre-renal origin). After introduction of furosemide diuretic therapy, clinical conditions improved and better control of the volemic status and heart rate was achieved. Several days after ceftriaxone and digoxin therapy initiation, worsening multiple non-blanching palpable purpuric lesions with bullae and papules, limited to the lower extremities, were noted. Skin biopsy was performed and a diagnosis of leucocytoclastic vasculitis, with associated panniculitis, was made. Ceftriaxone was discontinued and systemic corticosteroids were introduced, with a clear improvement in the cutaneous condition.LEARNING POINTSLeucocytoclastic vasculitis is a rare but significant side effect related to the administration of ceftriaxone.The importance of skin biopsy in the differential diagnosis of skin eruptions.

Beta-Blocker Dose Stratifies Mortality Risk in a Racially Diverse Heart Failure Population.

Heart failure (HF) is highly prevalent and a major cause of death in the United States. The effect of HF medications on survival has been predicted by validated models studied in populations predominantly of European descent. This study aimed to identify medications associated with survival in a racially diverse HF population. Patients with HF were recruited and followed from 2001 to 2015. Data were collected from electronic health records and the Social Security Death Index. The primary analysis tested the association between medication dose and all-cause mortality, with a secondary analysis assessing the composite outcome of death or cardiac-related hospitalization. Circulating concentration of the fibrotic marker procollagen type III N-terminal peptide (PIIINP) was also compared with medication doses in patients with concentrations available. The study population consisted of 337 patients, of which 25.2% died and 46% were hospitalized. Increased beta-blocker (BB) dose was significantly associated with survival in the base model [hazard ratio (HR) = 0.71, P = 0.017] and marginally associated in the comprehensive model (HR = 0.75, P = 0.068). BB dose was also associated with decreased risk of the composite end point in the base model (HR = 0.80, P = 0.029) and to a lesser extent in the comprehensive model (HR = 0.83, P = 0.085). Furthermore, increased BB dose was inversely associated with circulating PIIINP concentration (P = 0.041). In conclusion, our study highlights the importance of BB dose escalation for survival and decreased hospitalization in patients with HF, regardless of race or HF type. It also suggests that benefits observed with high-dose BBs could be mediated, at least in part, by decreased cardiac fibrosis.

Role of High-Dose Beta-Blockers in Patients with Heart Failure with Preserved Ejection Fraction and Elevated Heart Rate

BackgroundBeta-blockers in high target doses are recommended for heart failure with reduced ejection fraction (HFrEF) but not for preserved ejection fraction (HFpEF). Treatment benefits are often more pronounced in high-risk subgroups, and patients with HFpEF with heart rate ≥70 beats per minute have emerged as such a high-risk subgroup. We examined the associations of high-dose beta-blocker use with outcomes in these patients. MethodsOf the 8462 hospitalized patients with heart failure with ejection fraction ≥50% in the Medicare-linked Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF) registry, 5422 had a discharge heart rate ≥70 beats per minute. Of these, 4537 had no contraindications to beta-blocker use, of which 2797 (2592 with dose data) received prescriptions for beta-blockers. Of the 2592, 730 received high-dose beta-blockers, defined as atenolol ≥100 mg/day, carvedilol ≥50 mg/day, metoprolol tartrate or succinate ≥200 mg/day, or bisoprolol ≥10 mg/day, and 1740 received no beta-blockers. Using propensity scores for the receipt of high-dose beta-blockers, we assembled a matched cohort of 1280 patients, balanced on 58 characteristics. ResultsAll-cause mortality occurred in 63% and 68% of matched patients receiving high-dose beta-blocker vs no beta-blocker, respectively, during 6 years (median, 2.8) of follow-up (hazard ratio, 0.86; 95% confidence interval, 0.75-0.98; P = .027). The hazard ratios (95% confidence intervals) for all-cause readmission and the combined endpoint of all-cause readmission or all-cause mortality associated with high-dose beta-blocker use were 0.90 (0.81-1.02) and 0.89 (0.80-1.00), respectively. ConclusionsIn patients with HFpEF and heart rate ≥70 beats per minute, high-dose beta-blocker use was associated with a significantly lower risk of death. Future randomized controlled trials are needed to examine this association.

Importance of beta-blocker dose in prevention of ventricular tachyarrhythmias, heart failure hospitalizations, and death in primary prevention implantable cardioverter-defibrillator recipients: a Danish nationwide cohort study

There is a paucity of studies investigating a dose-dependent association between beta-blocker therapy and risk of outcome. In a nationwide cohort of primary prevention implantable cardioverter-defibrillator (ICD) patients, we aimed to investigate the dose-dependent association between beta-blocker therapy and risk of ventricular tachyarrhythmias (VT/VF), heart failure (HF) hospitalizations, and death. Information on ICD implantation, endpoints, comorbidities, beta-blocker usage, type, and dose were obtained through Danish nationwide registers. The two major beta-blockers carvedilol and metoprolol were examined in three dose levels; low (metoprolol ≤ 25 mg; carvedilol ≤ 12.5 mg), intermediate (metoprolol 26-199 mg; carvedilol 12.6-49.9 mg), and high (metoprolol ≥ 200 mg; carvedilol ≥ 50 mg). Time to events was investigated utilizing multivariate Cox models with beta-blocker as a time-dependent variable. From 2007 to 2012, 2935 first-time ICD devices were implanted. During follow-up, 399 patients experienced VT/VF, 728 HF hospitalizations and 361 died. As compared with patients not on beta-blockers, low, intermediate, and high dose had significantly reduced risk of HF hospitalizations {hazard ratio (HR) = 0.68 [0.54-0.87], P = 0.002; HR = 0.53 [0.42-0.66], P < 0.001; HR = 0.43 [0.34-0.54], P < 0.001} and death (HR = 0.47 [0.35-0.64], P < 0.001; HR = 0.29 [0.22-0.39], P = 0.001; HR = 0.24 [0.18-0.33], P < 0.001). For the endpoint of VT/VF, only intermediate and high dose beta-blocker was associated with significantly reduced risk (HR = 0.58 [0.43-0.79], P < 0.001; HR = 0.53 [0.39-0.72], P < 0.001). No significant difference was found between comparable doses of carvedilol and metoprolol on any endpoint (P = 0.06-0.94). In primary prevention ICD patients, beta-blocker therapy was associated with significantly reduced risk of all endpoints, as compared with patients not on beta-blocker, with the suggestion of a dose-dependent effect. No detectable difference was found between comparable doses of carvedilol and metoprolol.

Biventricular Hypertrophic Cardiomyopathy in a Child with LEOPARD Syndrome: a Case Report

Abstract Background: LEOPARD syndrome is a complex dysmorphogenetic disorder of inconstant penetrance and various morphologic expressions. The syndrome is an autosomal dominant disease that features multiple lentigines, electrocardiographic changes, eye hypertelorism, pulmonary valve stenosis or hypertrophic cardiomyopathy, genital malformations, and a delayed constitutional growth hearing loss, which can be associated with rapidly progressive severe biventricular obstructive hypertrophic cardiomyopathy. No epidemiologic data are available on the real incidence of LEOPARD syndrome; however, this seems to be a rare disease, being often underdiagnosed, as many of its features are mild. Case presentation: We report the case of a 10-year-old female pediatric patient, diagnosed with obstructive hypertrophic cardiomyopathy at the age of 3 months, and recently diagnosed with LEOPARD syndrome. The patient first presented for a cardiologic examination at the age of 3 months, due to a murmur. She presented failure to thrive and psychomotor retardation, and was diagnosed with biventricular obstructive hypertrophic cardiomyopathy for which she had received high-dose beta-blocker therapy. At the age of 7 years she underwent a biventricular myectomy for relief of outflow tract obstruction, completed with another myectomy after 2 years due to progressive increase of pressure gradient in the left ventricular outflow tract. Prior to the second surgical intervention, multiple lentigines appeared on her skin, and genetic testing revealed the presence of LEOPARD syndrome. Conclusion: LEOPARD syndrome is a rare disease, which can be very difficult to diagnose, especially based on features other than lentigines. Cardiac involvement in LEOPARD syndrome can be progressive and requires multiple medical and surgical interventions.

O54-2 - Super High Dose Beta-blocker Administration for the Patients with Dilated Cardiomyopathy

First case is a 25-year-old female with dilated cardiomyopathy. Left ventricular end-diastolic diameter (LVEDD) was 74 mm and ejection fraction (EF) was 29%. Carvedilol was already uptitrated to 20 mg twice daily. Right heart catheterization (RHC) revealed very low cardiac output (C.O. 2.82 l/min), cardiac index (C.I. 1.47 l/min/m2), stroke volume (SV 29 ml) and rapid heart rate (HR 96/min) despite maximum dosage of carvedilol in Japan. Carvedilol was uptitrated to 50 mg twice daily and additional 10 mg bisoprolol twice daily was started under administration of low-dose dobutamine. After complete uptitration of beta blockers and termination of dobutamine, RHC showed elevated C.O. (4.25 l/min), C.I. (2.25 l/min/m2), SV (52 ml) and decreased HR (82/min). After the initiation of super high dose beta-blocker therapy, she has no heart failure rehospitalization. Second case was 35-year-old male. He has a history of myocarditis following influenza viral infection 7 years before. LVEDD was 79 mm and EF was 21%. Carvedilol was 5 mg twice daily. To reduce HR (93/min at rest), carvedilol was uptitrated to 50 mg twice daily and additional bisoprolol 10 mg twice daily was introduced. LVEDD improved to 69 mm and EF increased to 27% after six months. Beta-blocker is a key drug for heart failure therapy. We should make every effort to maximize the dose of beta blocker as much as possible.

How to Select Adequate Candidates for Each Therapeutic Tool in Patients with Advanced Heart Failure?

Thus far, several potent therapeutic tools can be used in patients with advanced heart failure, e.g. high dose beta-blocker, tolvaptan, adaptive servo-ventilation, cardiac resynchronization therapy, and ventricular assist device. However, there are a certain number of “non-responders” for each therapy. Inadequate therapies often result in fatal in patients with advanced heart failure. We here try to find predictors of responsiveness to each therapy, and construct therapeutic strategy in patients with advanced heart failure.

Beta-Blockers in Pediatric Hypertrophic Cardiomyopathies.

Congestive cardiac failure accounts for 36% of childhood deaths in hypertrophic cardiomyopathy, and in infants with heart failure symptoms before two years of age, the mortality is extremely high unless treatment with beta-receptor antagonists is instituted. The mechanism of heart failure is not systolic dysfunction, but rather extreme diastolic dysfunction leading to high filling pressures.Risk factors for development of heart failure are a generalized pattern of hypertrophy with a left ventricular posterior wall-to-cavity ratio >0.30, the presence of left ventricular outflow tract obstruction at rest, and the co-existence of syndromes in the Noonan/Leopard/Costello spectrum. The 5-year survival of high-risk patients is improved from 54% to 93% by high-dose beta-blocker therapy (>4.5 mg/kg/day propranolol). The mechanism of the beneficial effect of beta-blockers is to improve diastolic function by lengthening of diastole, reducing outflow-obstruction, and inducing a beneficial remodelling resulting in a larger left ventricular cavity, and improved stroke volume. Hypertrophic cardiomyopathy is associated with increased activity of cardiac sympathetic nerves, and infants in heart failure with hypertrophic cardiomyopathy show signs of extreme sympathetic over-activity, and require exceptionally high doses of beta-blockers to achieve effective beta-blockade as judged by 24 h Holter recordings, often 8-24 mg/kg/day of propranolol or equivalent. Conclusion: Beta-blocker therapy is without doubt the treatment of choice for patients with heart failure caused by hypertrophic cardiomyopathy, but the dose needs to carefully titrated on an individual basis for maximum benefit, and the dose required is surprisingly large in infants with heart failure due to hypertrophic cardiomyopathy.

Jervell and Lange–Nielsen Syndrome: Homozygous Missense Mutation of KCNQ1 in a Turkish Family

Long QT syndrome is one of the most common cardiac ion channel diseases, but its morbidity and mortality rate can be lessened with an early diagnosis and proper treatment. This cardiac ventricular repolarization abnormality is characterized by a prolonged QT interval and a propensity for ventricular tachycardia (VT) of the torsades de pointes type. The long QT syndrome represents a high risk for presyncope, syncope, cardiac arrest, and sudden death. Jervell and Lange-Nielsen syndrome (JLNS) is a recessively inherited form of long QT syndrome characterized by profound sensorineural deafness and prolongation of the QT interval. Findings have shown that JLNS occurs due to homozygous and compound heterozygous pathogenic variants in KCNQ1 or KCNE1. A 3.5-year-old girl presented to the hospital with recurrent syncope, seizures, and congenital sensorineural deafness. Her electrocardiogram showed a markedly prolonged QT interval, and she had a diagnosis of JLNS. The sequence analysis of the proband showed the presence of a pathogenic homozygous missense variant (c.728G>A, p.Arg243His). Heterozygous mutations of KCNQ1 were identified in her mother, father, and sister, demonstrating true homozygosity. Even with high-dose beta-blocker therapy, the patient had two VT attacks, so an implantable cardioverter defibrillator was fitted. The authors suggest early genetic diagnosis for proper management of the disease in the proband and genetic counseling for both the proband and the girl's extended family.

Pharmacological and Non- Pharmacological Therapies of Catecholaminergic Polymorphic Ventricular Tachycardia

Pharmacological and Non- Pharmacological Therapies of Catecholaminergic Polymorphic Ventricular Tachycardia Polymorphic Ventricular Tachycardia (CPVT) is an inherited cardiac channelopathy characterized by exercise related ventricular tachycardia (VT) manifested as syncope and sudden death among young patients with structurally normal hearts. High dose Beta blocker is the mainstay therapy. Recently, flecainide was introduced to treat symptomatic CPVT patients despite beta blockers. Implantable cardioverter defibrillator is recommended for symptomatic patients if optimal medical treatment does not control ventricular arrhythmias. Left cardiac sympathetic denervation should be considered for intractable cases.

Catecholaminergic polymorphic ventricular tachycardia detected by an implantable loop recorder in a child

We present a six-year-old boy with a history of recurrent syncope whose physical examination and family history were inconclusive. Laboratory findings, 12-lead ECG, chest radiography, Holter monitoring, event recorder monitoring, echocardiography, coronary computed tomography (CT) angiography, Brugada challenge test (ajmaline), cranial magnetic resonance imaging, and awake/sleep electroencephalogram were all unremarkable. Since syncope was exercise-induced, an electrophysiology study was also performed, but revealed no inducible ventricular arrhythmias. Implantable loop recorder (ILR) was implanted. Three weeks later, bidirectional ventricular tachycardia was found in ILR record during presyncope that was related to exercise. The patient, with the diagnosis of catecholaminergic polymorphic ventricular tachycardia, was started on high-dose beta-blocker therapy. Due to the recurrence of syncopes despite the presence of beta-blockers, an implantable cardioverter defibrillator was implanted.

Löffler endocarditis: a rare cause of acute cardiac failure

We describe a patient with acute cardiogenic shock due to cardiac involvement in idiopathic hypereosinophilic syndrome (Löffler endocarditis). At the echocardiography, there was a huge mass in the left ventricular cavity, resulting in inflow- and outflow tract obstruction. The posterior leaflet of the mitral valve apparatus was completely embedded in a big (organized) thrombus mass. The patient was treated with high dose corticosteroids, however without effect. Partial remission was achieved after treatment with hydroxycarbamide. He was also treated with anticoagulants and high dose beta-blockers. The patient’s condition improved remarkably after correction of the mitral valve insufficiency by a mitral valve bioprosthesis.

569 Thoracoscopic Sympathectomy for Long-Qt Syndrome In a Sickle Cell Anemia Patient

Background and AimLong QT syndrome (LQTS) is a relatively common disease, however, it is rarely described in Black African patients. We would like to present a west African patient with...

Beta-blockers and cardiovascular outcomes in dialysis patients: a cohort study in Ontario, Canada

Beta-blockers may be cardioprotective in patients receiving chronic dialysis. We examined cardiovascular outcomes among incident dialysis patients receiving beta-blocker therapy. We conducted a retrospective cohort study employing linked healthcare databases in Ontario, Canada. We studied all consecutive chronic dialysis patients aged≥66 years who initiated dialysis between 1 July 1991 and 31 July 2007. Patients were divided into three groups according to new medication use after the initiation of chronic dialysis. The three groups were patients initiated on beta-blockers, calcium channel blockers and statins only. Patients in the beta-blocker and calcium channel blocker groups could also be concurrently receiving a statin. The primary outcome was time to a composite endpoint of death, myocardial infarction, stroke or coronary revascularization. There were a total of 1836 patients (504 beta-blocker, 570 calcium channel blocker and 762 statin-only users). Compared to statin-only use, beta-blocker use was not associated with improved cardiovascular outcomes [adjusted hazard ratio (aHR) 1.07, 95% confidence interval (CI) 0.92-1.23]. As expected, calcium channel blocker use was also not associated with improved cardiovascular outcomes (aHR 0.91, 95% CI 0.79-1.06). Among all subgroup analyses by beta-blocker attributes, only high-dose beta-blocker therapy was associated with better cardiovascular outcomes as compared to low-dose beta-blockers (aHR 0.50, 95% CI 0.29-0.88). We observed no beneficial effect of beta-blocker use among patients receiving chronic dialysis relative to our comparator groups. Given current uncertainty around the cardioprotective benefits of beta-blockers in patients receiving dialysis, a large randomized clinical trial is warranted.

Management issues in hypertensive diabetics

Diabetes mellitus (DM) and hypertension are common clinical conditions that often co-exist. This combination has been called the deadly duet to emphasise the increased cardiovascular risk when the two conditions co-exist. Hypertension occurs more commonly in diabetics than in comparable non-diabetics, as the prevalence of hypertension in diabetics is about two times higher than that of hypertension as observed in the general population. In type 2 diabetes mellitus, hypertension is often present as part of a possible common underlying metabolic abnormality, such as insulin resistance. However, in type 1 diabetes mellitus, hypertension is often due to the onset of diabetic nephropathy. Hypertensive people are 2.5 times more likely to develop diabetes mellitus within five years. This may be due to the presence of an underlying metabolic syndrome, and made worse by the type of antihypertensive drug used, e.g. high-dose thiazides combined with high-dose beta blockers. The co-existence of hypertension and diabetes mellitus greatly increases the risk for macrovascular and microvascular diabetes complications. The presence of hypertension causes a 7.2-fold increase and a 37-fold increase in mortality in diabetic patients and in diabetic nephropathy respectively. Most patients with diabetes and hypertension will die from a cardiovascular cause. Hypertension exacerbates all the vascular complications of diabetes, including coronary artery disease, renal disease, stroke, peripheral artery disease, leg amputations and retinopathy. Diabetes increases the risk of coronary artery disease two fold in men and four fold in women, putting women in particular, at risk.

Meta-analysis: β-Blocker Dose, Heart Rate Reduction, and Death in Patients With Heart Failure

Guidelines recommend that patients with heart failure receive beta-blockers in doses used in the trials that have proven their efficacy. Although the adverse effects of beta-blockade are dose-related, it is unclear whether the benefits are. To determine whether the survival benefits of beta-blockade in heart failure are associated with the magnitude of heart rate reduction or the beta-blocker dose. MEDLINE, EMBASE, CINAHL, SIGLE, Web of Science, and the Cochrane Central Register of Controlled Trials, supplemented by hand-searches of bibliographies. Randomized, placebo-controlled heart failure trials that reported all-cause mortality. Two reviewers independently extracted data on study characteristics, beta-blocker dosing and heart rate reduction, and death. The mean left ventricular ejection fraction in the 23 beta-blocker trials ranged from 0.17 to 0.36, and more than 95% of the 19 209 patients had systolic dysfunction. The overall risk ratio for death was 0.76 (95% CI, 0.68 to 0.84); however, heterogeneity testing revealed moderate heterogeneity among trials (I (2) = 30%), which was associated with the magnitude of heart rate reduction achieved within each trial (P for meta-regression = 0.006). For every heart rate reduction of 5 beats/min with beta-blocker treatment, a commensurate 18% reduction (CI, 6% to 29%) in the risk for death occurred. No significant relationship between all-cause mortality and beta-blocker dosing was observed (risk ratio for death, 0.74 [CI, 0.64 to 0.86]) in high-dose beta-blocker trials vs. 0.78 [CI, 0.63 to 0.96] in low-dose beta-blocker trials; P for meta-regression = 0.69). The analysis is based on aggregate data and resting heart rates. Few patients in these trials had bradycardia or diastolic dysfunction at baseline. The magnitude of heart rate reduction is statistically significantly associated with the survival benefit of beta-blockers in heart failure, whereas the dose of beta-blocker is not.

Comprehension of Affective Prosody in Veterans With Chronic Posttraumatic Stress Disorder

Posttraumatic stress disorder (PTSD) is one of the few psychiatric conditions in which a subjective decrease in emotional range serves as a diagnostic criterion. In order to investigate whether veterans with chronic PTSD also experienced objective limitations in emotional perception, the authors administered the Aprosodia Battery to a group of 11 veterans with chronic PTSD, nine subjects with right hemisphere damage, seven subjects with left hemisphere damage, and 12 comparison subjects. The patients with PTSD displayed significant deficiencies in the comprehension and discriminative components of affective speech, similar in severity and performance profile on the Aprosodia Battery to the individuals with focal right hemisphere damage due to ischemic infarction.

Impact of β1-Adrenergic Receptor Polymorphisms on Susceptibility to Heart Failure, Arrhythmogenesis, Prognosis, and Response to Beta-Blocker Therapy

Beta1-adrenergic receptor polymorphisms have been implicated with inconsistent results in the pathogenesis, clinical presentation, and prognosis of patients with heart failure (HF). The impact of 2 functional polymorphisms (beta1-Arg389Gly and beta1-Ser49Gly) on HF susceptibility, arrhythmogenesis, and prognosis was evaluated in Brazilian outpatients. Genotyping at codons 389 and 49 was performed using polymerase chain reaction with restriction fragment length polymorphism analysis in 201 outpatients with systolic HF and 141 apparently healthy controls. Enrolled patients were followed up at the HF clinic, and vital status was evaluated using electronic hospital records, telephone contact, and a local death certificate database. Allele frequencies were similar between patients with HF and controls, with neither polymorphism related to HF susceptibility. The beta1-389Gly homozygotes had significantly less nonsustained ventricular tachycardia on Holter monitoring (17% vs 48% for Arg/Arg patients; p = 0.015) and improved HF-related survival, with no events after a median follow-up of 40 months (log-rank statistics = 0.025). The negative impact of beta1-389Arg allele on HF-related survival was substantially reduced using high-dose beta-blocker therapy (80% survival for high-dose vs 42% for low-dose beta blockers or nonusers; log-rank statistics = 0.0003). The beta1-Ser49Gly polymorphism was not associated with nonsustained ventricular tachycardia or HF prognosis. In conclusion, beta1-Arg389Gly and beta1-Ser49Gly polymorphisms had no influence on HF susceptibility. However, the Gly389 allele was associated with a lower prevalence of ventricular arrhythmias and better HF-related survival. A pharmacogenetic interaction is suggested because beta blockers were more effective in beta1-389Arg allele carriers.

Association of β‐Blocker Dose with Serum Procollagen Concentrations and Cardiac Response to Spironolactone in Patients with Heart Failure

To determine whether beta-blocker dose influences cardiac collagen turnover and the effects of spironolactone on cardiac collagen turnover in patients with heart failure. Prospective clinical study. Two heart failure centers. Eighty-eight spironolactone-naïve patients with heart failure who were taking beta-blockers. In a subset of 29 patients, spironolactone was started at 12.5 mg/day, with the dosage titrated to 25 mg/day if tolerated. Venous blood samples were collected from each patient. Serum procollagen type I and type III aminoterminal peptides (PINP and PIIINP) were determined by radioimmunoassay and compared between the 25 patients receiving low doses (< 50% of recommended target dose) and the 63 patients receiving high doses (> or = 50% of recommended target dose) of beta-blockers. Patients receiving low-dose beta-blockers had higher mean +/- SD PIIINP concentrations (6.6 +/- 3.5 vs 4.9 +/- 2.6 microg/L, p=0.03) and tended to have higher PINP concentrations (74.0 +/- 44.1 vs 57.1 +/- 28.6 microg/L, p=0.10) compared with those receiving high doses. A repeat blood sample was collected from the 29 patients who received spironolactone after 6 months of therapy. Changes in procollagen peptides also were compared in this subset between low-dose (9 patients) and high-dose (20 patients) beta-blocker groups. Low beta-blocker doses were associated with greater reductions in concentrations of PINP (median [intraquartile range] -14.3 microg/L [-9.8 to -19.3 microg/L] vs -2.5 microg/L [5.9 to -9.8 microg/L], p=0.02) and PIIINP (-1.4 microg/L [-0.9 to -2.4 microg/L] vs 0.1 microg/L [0.9 to -1.3 microg/L], p=0.045) with spironolactone therapy than high beta-blocker doses. In addition, 100% of the patients in this subset taking low-dose beta-blockers versus only 35% taking higher doses had reductions in both markers of cardiac fibrosis. Spironolactone may benefit patients with heart failure who cannot tolerate upward titration of beta-blocker dosages, at least in terms of its effects on cardiac remodeling.