Nonsystolic Heart Failure Research Articles

Correlation between the insertion-deletion variant of the angiotensin-converting enzyme gene and various classes of heart failure.

The angiotensin-converting enzyme (ACE) genetic variation for insertion/deletion (I/D) is located at the 16th intron of the ACE gene. A number of studies investigated the homozygous deletion genotype of ACE and its association with cardiovascular diseases. However, ACE's genetic variation and its association with heart failure (HF) is yet to be confirmed. We examined the possibility of the association between the ACE I/D gene variant with the severity of HF. The ACE genotypes were determined by polymerase chain reactions using samples derived from 150 patients with HF and 90 healthy subjects which were age and gender-matched. These patients included those of all four of the New York Heart Association (NYHA) classes. Echocardiography was performed on all HF patients and ejection fraction (EF), left ventricular systolic and diastolic diameters were measured. The HF patients were redistributed to systolic where EF is equal and less than 45% and non-systolic HF where EF is more than 45%. We demonstrate a statistically significant difference in DD genotype in NYHA class IV in comparison to the control group. The values of odds ratio (OR) (95%CI) of the DD genotype (DD vs ID and II) were 3.37 (1.01-11.19) (p value = 0.039) and the OR (95%CI) of the D allele (D vs I) was 2.55 (0.98-6.65) (p value = 0.049). Higher frequencies of D allele compared to I allele is linked to severity of HF. DD variant of the ACE gene is associated with NYHA class IV heart failure. This could have a profound impact on risk stratification and prognosis of HF in the management of this condition.

Utilization of galectin-3 in case management across the spectrum of heart failure.

In patients with heart failure as a result of mechanical and neurohormonal derangements, macrophages secrete galectin-3, which is a paracrine and endocrine factor that stimulates additional macrophages, pericytes, myofibroblasts, and fibroblasts to proliferate and secrete procollagen I, which is irreversibly crosslinked to form fibrotic collagen. Normal plasma concentrations of galectin-3 are < 11.0 ng/mL. Galectin-3 measured in blood has been shown to predict the development of all-cause mortality and heart failure in the general population, identify increased risk for de novo heart failure and progressive loss of renal filtration function in healthy middle-aged adults, predict cardiac failure in patients after acute coronary syndromes, help establish the diagnosis of heart failure with preserved ejection fraction in patients presenting with effort intolerance, and aid in the prognosis of both systolic and nonsystolic heart failure for the outcomes of hospitalization and death. This article presents case discussions of these applications to highlight the importance of galectin-3 measurement across the spectrum of patients at risk for cardiorenal disease.

Future of Implantable Devices for Cardiac Rhythm Management

The first cardiac implantable electronic device (CIED), the electronic pacemaker, maintains cardiac contraction during bradycardia. The implantable cardioverter-defibrillator (ICD) manages ventricular tachycardia (VT) or fibrillation (VF) and saves lives primarily through the use of high-energy shocks. The cardiac resynchronization therapy (CRT) device restores interventricular and intraventricular dyssynchrony in patients with heart failure (HF). Despite >50 years of pacing and 40 years of ICD therapy, the lead remains the weakest link between the device and the patient. Although CRT reduces mortality and morbidity in HF, it is applicable only to those patients with systolic left ventricular (LV) dysfunction and wide QRS complex, especially left bundle-branch block. At best, only 70% of such patients respond, and the majority of patients without left bundle-branch block or with nonsystolic HF derive no benefit from CRT. Early detection of worsening HF with implantable sensors enables corrective therapy to avert acute decompensated HF. Implantable cardiac monitors (ICMs) allow monitoring of arrhythmias such as atrial fibrillation (AF). Despite their efficacy at eliminating the risk of sudden cardiac death (SCD) in the highest-risk patient, ICDs currently have a limited role in reducing the overall burden of SCD, and ICM has the potential for early identification of asymptomatic subjects at risk of SCD to derive benefit from ICD. An increasing cause of SCD is pulseless electric activity (PEA), and alternative management other than defibrillation will be required. This review addresses the recent exciting development of CIEDs in response to these unmet clinical needs such as leadless and endocardial pacing, subcutaneous ICD (S-ICD), low-energy multistage electrotherapy for VT and AF, intermediate-strength stimulation for PEA, early detection of VT, sensors for HF monitoring, and novel therapies for arrhythmias and HF. ### Limitations of Cardiac Pacing With Current Pacemakers and CRT Despite the significant improvements in device longevity, reliability, size/profile, and ease of implantation over the last 50 years, implanting a pacemaker …

Impact of new-onset diabetes mellitus and glycemic control on the prognosis of heart failure patients: A propensity-matched study in the community

ObjectivesTo assess the incidence of type 2 diabetes mellitus (DM) in patients with heart failure (HF), and to evaluate the effect of new-onset DM and glycemic control on the prognosis of HF patients treated with a contemporary medical regimen. MethodsProspective study of 5314 HF patients and previously unknown DM during 9years. Their mean age was 71.8±7.9years, 53.0% were women, and 50.2% had non-systolic HF. During a median follow-up of 56.9±18.2months, 68.9% of the patients died, 88.6% were hospitalized for HF, and 1519 (27.3%) developed new-onset DM. We propensity-matched those 1519 HF patients with DM, with 1519 HF patients non-diagnosed with DM. ResultsThe age- and sex-adjusted incidence (per 100HFpatients/years) of DM in HF patients was 3.20, higher in women and in patients with non-systolic HF (p<0.01). Patients with HF and DM and those with a mean HbA1c>7.0% presented an increased mortality (HR of death [CI 95%]: 2.44 [1.68–3.19] and, HR: 2.56 [1.77–3.35], respectively), mainly due to an increased cardiovascular mortality (HR≥2.40 [1.46–3.34]) (P<0.001). The rate of hospitalization, of 30-day readmissions, and the number of visits were higher among HF patients with DM or with HbA1c>7.0% (p<0.001). These relationships of DM and its poor metabolic control with prognosis were maintained, independently of the gender, the type of HF (systolic or, non-systolic), the comorbidities, and the medication used (P<0.01). ConclusionNew-onset diabetes mellitus and its poor metabolic control (HbA1c>7.0%) are associated with a increased mortality and morbidity of patients with heart failure.

Galectin-3: A Novel Blood Test for the Evaluation and Management of Patients With Heart Failure

Replacement of functional myocytes with crosslinked collagen as a result of tissue fibrosis is a final common pathway that is central to the progression of heart failure (HF), irrespective of etiology. In response to a variety of mechanical and neurohormonal stimuli, macrophages secrete galectin-3, which works as a paracrine and endocrine factor to stimulate additional macrophages, pericytes, myofibroblasts, and fibroblasts. The response to this signal is cellular proliferation and secretion of procollagen I. This protein is then irreversibly crosslinked to form collagen and result in cardiac fibrosis. With a commercially available assay, galectin-3 can now be measured in blood and has been found to aid in the prognosis of both systolic and nonsystolic HF. Measurement of galectin-3 before hospital discharge, on outpatient evaluation for suspected HF, and approximately twice per year for those with stable symptoms is supported by the evidence available at this time. Levels > 25.9 ng/mL, independent of symptoms, clinical findings, and other laboratory measures, predict a patient who is likely to have rapid progression of HF, resulting in hospitalization and death. In addition, a doubling in galectin-3 level over the course of 6 months, irrespective of baseline value, identifies a high-risk patient in whom additional care management efforts and advanced therapies could be warranted.

INFLUENCE OF MYOCARDIAL ISCHEMIA ON OUTCOMES IN PATIENTS WITH SYSTOLIC VERSUS NON-SYSTOLIC HEART FAILURE

Heart failure (HF) is a leading cause of adult hospitalization, morbidity, and mortality. We evaluated the influence of myocardial ischemia and left ventricular ejection fraction (LVEF) on outcomes in patients who were hospitalized with new onset HF.We prospectively recruited 201 consecutive patients hospitalized for a first episode of HF from 17 medical centers across Europe and North America. All patients received gated single-photon emission computed tomographic testing with standardized study interpretations by trained core laboratory investigators. Predefined data from routine care were collected and aggregated. Computerized scoring was performed at the core laboratory and participants with a summed difference score ≥4 were defined as having myocardial ischemia. Participants were categorized as having systolic heart failure (SHF) (LVEF<40%) or nonsystolic heart failure (NS-HF) (LVEF≥40%). A proportional hazards model was used to assess the impact of clinical predictors on the outcomes of mortality, cardiac rehospitalization and a combined outcome within 2 years of study enrollment.180 patients (mean age was 65.5 ± 14.6 years and 57.2% male) fulfilled study criteria and were included. Myocardial ischemia was present in 45 (41.2%) patients with SHF and 19 (27.5%) patients with NS-HF (p <0.01). During the follow-up period, 11.1% (n=20) died and 42.2% (n=76) experienced a recurrent hospitalization. Patients with NS-HF and ischemia had the highest (73.7%) event rate compared with the other cohorts (multivariate OR=3.29, 95% CI 1.69-6.42, p=0.001).In new-onset HF, those with NS-HF and myocardial ischemia are at the highest risk for poor outcomes.

Relation of Baseline Systolic Blood Pressure and Long-Term Outcomes in Ambulatory Patients With Chronic Mild to Moderate Heart Failure

We studied the impact of baseline systolic blood pressure (SBP) on outcomes in patients with mild to moderate chronic systolic and diastolic heart failure (HF) in the Digitalis Investigation Group trial using a propensity-matched design. Of 7,788 patients, 7,785 had baseline SBP data and 3,538 had SBP ≤ 120 mm Hg. Propensity scores for SBP ≤ 120 mm Hg, calculated for each of the 7,785 patients, were used to assemble a matched cohort of 3,738 patients with SBP ≤ 120 and >120 mm Hg who were well-balanced in 32 baseline characteristics. All-cause mortality occurred in 35% and 32% of matched patients with SBPs ≤ 120 and >120 mm Hg respectively, during 5 years of follow-up (hazard ratio [HR] when SBP ≤ 120 was compared to >120 mm Hg 1.10, 95% confidence interval [CI] 0.99 to 1.23, p = 0.088). HRs for cardiovascular and HF mortalities associated with SBP ≤ 120 mm Hg were 1.15 (95% CI 1.01 to 1.30, p = 0.031) and 1.30 (95% CI 1.08 to 1.57, p = 0.006). Cardiovascular hospitalization occurred in 53% and 49% of matched patients with SBPs ≤ 120 and > 120 mm Hg, respectively (HR 1.13, 95% CI 1.03 to 1.24, p = 0.008). HRs for all-cause and HF hospitalizations associated with SBP ≤ 120 mm Hg were 1.10 (95% CI 1.02 to 1.194, p = 0.017) and 1.21 (95% CI 1.07 to 1.36, p = 0.002). In conclusion, in patients with mild to moderate long-term systolic and diastolic HF, baseline SBP ≤ 120 mm Hg was associated with increased cardiovascular and HF mortalities and all-cause, cardiovascular, and HF hospitalizations that was independent of other baseline characteristics.

Mortality of newly diagnosed heart failure treated with amiodarone: A propensity-matched study

BackgroundStudies on the safety of amiodarone therapy in heart failure (HF) presented conflicting results. We evaluated the relationship of commencing treatment with amiodarone (CTA) with the mortality and the morbidity of patients newly diagnosed with HF. MethodsProspective cohort study over 7years on 3734 patients with HF. Main outcomes were all-cause and cardiovascular mortality, hospitalizations and visits. 739 patients who commenced treatment with amiodarone were propensity-matched with another 739 patients. Non-commencing treatment with amiodarone. We analyze the independent relationship of commencing treatment with amiodarone, with the mortality and the morbidity, stratifying patients for cardiovascular co-morbidity, after propensity score-matching. ResultsDuring a median follow-up of 46.1months, 644 (43.6%) died, and 1086 (73.5%) were hospitalized. Commencing treatment with amiodarone was associated with a higher all-cause mortality (HR 1.70 [CI 95%, 1.50 to 1.91]), particularly among women (HR: 1.77 [1.55 to 2.00]), and among patients with non-systolic HF (HR: 1.87 [1.66 to 2.09], P<0.001 in all the cases), even after adjustment for the propensity to take amiodarone, or other medications, and other potential confounders. Commencing treatment with amiodarone was not associated with cardiovascular mortality, hospitalizations, or visits. ConclusionThe commencement of treatment with amiodarone is associated with an increased mortality of patients with heart failure, mainly in women and in patients with non-systolic heart failure.

Incidence and mortality of heart failure: A community-based study

BackgroundData on the incidence and mortality of heart failure (HF) in community-based populations of developed countries are limited. We estimated the trends of the incidence and, the mortality of HF. MethodsProspective population-based study in a white, low-middle class Mediterranean community of 267,231 inhabitants in Spain. Participants were all the patients (=>14years), newly diagnosed with HF (4793), according to the Framingham criteria, from January 1, 2000 through December 31, 2007. Main outcome were incidence and mortality following an HF diagnosis. ResultsIncidence of HF increased among both men and women, and among persons with systolic and non-systolic HF. Incidence of HF increased from 296 per 100,000 person-years in 2000 to 390 per 100,000 person-years in 2007 (RR 1.32, CI 95% 1.27–13.7, P<.01). Although, risk-adjusted mortality declined from 2000 to 2007, the prognosis for patients with newly diagnosed HF remains poor. In 2007, risk-adjusted 30-day, 1-year, and 4-years mortality was 12.1%, 28.8%, and 61.4%, respectively. Incidence and mortality of systolic HF were higher than those of non-systolic HF (P<0.05). ConclusionsDuring the last 8years, in a white, middle class population of the south of Europe, the increased incidence and the decreased mortality of heart failure have resulted in an increased prevalence of heart failure. Incidence and mortality of systolic heart failure were higher than those of non-systolic heart failure.

Mortality and morbidity of non-systolic heart failure treated with angiotensin-converting enzyme inhibitors: A propensity-adjusted case–control study

BackgroundThe effect of treatment with angiotensin-converting enzyme inhibitors (ACEIs) on the prognosis of patients newly diagnosed with heart failure with preserved systolic function (HF-PSF) is unclear. We evaluate the relationship of commencing ACEI therapy (C-ACEI-T) with the morbidity and mortality of patients with HF-PSF. MethodsProspective propensity-adjusted cohort study over 5 years on 1120 adults diagnosed with HF-PSF for the first time, within an integrated health organization in Spain. We analyzed the independent relationship between C-ACEI-T and mortality, and morbidity, stratifying patients according to comorbidity, after a multivariable adjustment for potential confounders. ResultsThe 865 patients (77.2%) who C-ACEI-T were younger, with more cardiovascular comorbidity. During the median follow-up of 908.3 days (interquartile range 558.6–1302.0) 580 patients (51.8%) died, and 727 (64.9%) were hospitalized. Using an intention-to-treat analysis, C-ACEI-T was associated with a lower risk of all-cause (RR [CI 95%] 0.34 [0.23 to 0.46]), and cardiovascular (RR 0.28 [0.20 to 0.36]) mortality, and a lower age- and sex-adjusted rate of hospitalization (per 100 persons-year), 12.3 vs. 19.4, (P<0.001 in all cases), even after adjustment for the propensity to take ACEIs, or other medications, comorbidities, and other potential confounders. ConclusionIn this prospective observational study the establishment of ACEI therapy is associated with a reduced mortality and morbidity of patients with newly diagnosed non-systolic heart failure.

Chronic obstructive pulmonary disease in patients admitted with heart failure

Chronic obstructive pulmonary disease (COPD) is an important differential diagnosis in patients with heart failure (HF). The primary aims were to determine the prevalence of COPD and to test the accuracy of self-reported COPD in patients admitted with HF. Secondary aims were to study a possible relationship between right and left ventricular function and pulmonary function. Prospective substudy. Systematic screening at 11 centres. Consecutive patients (n = 532) admitted with HF requiring medical treatment with diuretics and an episode with symptoms corresponding to New York Heart Association class III-IV within a month prior to admission. Forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC) were measured by spirometry and ventricular function by echocardiography. The diagnosis of COPD and HF were made according to established criteria. The prevalence of COPD was 35%. Only 43% of the patients with COPD had self-reported COPD and one-third of patients with self-reported COPD did not have COPD based on spirometry. The prevalence of COPD in patients with preserved left ventricular ejection fraction (i.e. LVEF >or=45%) was significantly higher than in patients with impaired LVEF (41% vs. 31%, P = 0.03). FEV(1) and FVC were negatively correlated with right ventricular end-diastolic diameter and tricuspid annular plane systolic excursion and FVC positively correlated with systolic gradient across the tricuspid valve. Chronic obstructive pulmonary disease is frequent in patients admitted with HF and self-reported COPD only identifies a minority. The prevalence of COPD was high in both patients with systolic and nonsystolic HF.

Altered Creatine Kinase Adenosine Triphosphate Kinetics in Failing Hypertrophied Human Myocardium

The progression of pressure-overload left ventricular hypertrophy (LVH) to chronic heart failure (CHF) may involve a relative deficit in energy supply and/or delivery. We measured myocardial creatine kinase (CK) metabolite concentrations and adenosine triphosphate (ATP) synthesis through CK, the primary energy reserve of the heart, to test the hypothesis that ATP flux through CK is impaired in patients with LVH and CHF. Myocardial ATP levels were normal, but creatine phosphate levels were 35% lower in LVH patients (n = 10) than in normal subjects (n = 14, P < 0.006). Left ventricular mass and CK metabolite levels in LVH were not different from those in patients with LVH and heart failure (LVH+CHF, n = 10); however, the myocardial CK pseudo first-order rate constant was normal in LVH (0.36 +/- 0.04 s(-1) in LVH versus 0.32 +/- 0.06 s(-1) in normal subjects) but halved in LVH+CHF (0.17 +/- 0.06 s(-1), P < 0.001). The net ATP flux through CK was significantly reduced by 30% in LVH (2.2 +/- 0.7 micromol x g(-1) x s(-1), P = 0.011) and by a dramatic 65% in LVH+CHF (1.1 +/- 0.4 micromol x g(-1) x s(-1), P < 0.001) compared with normal subjects (3.1 +/- 0.8 micromol x g(-1) x s(-1)). These first observations in human LVH demonstrate that it is not the relative or absolute CK metabolite pool sizes but rather the kinetics of ATP turnover through CK that distinguish failing from nonfailing hypertrophic hearts. Moreover, the deficit in ATP kinetics is similar in systolic and nonsystolic heart failure and is not related to the severity of hypertrophy but to the presence of CHF. Because CK temporally buffers ATP, these observations support the hypothesis that a deficit in myofibrillar energy delivery contributes to CHF pathophysiology in human LVH.

Effect of obesity and being overweight on long-term mortality in congestive heart failure: influence of left ventricular systolic function

Previous studies have suggested that a high body mass index (BMI) is associated with an improved outcome in congestive heart failure (CHF). However, the studies addressing this problem have not included enough patients with non-systolic heart failure to evaluate how left ventricular systolic function interacts with obesity on prognosis in CHF. The aim of this study was to evaluate how BMI influences mortality in patients hospitalized with CHF, and to address in particular whether the effect of BMI is influenced by left ventricular (LV) systolic function. Retrospective analysis of baseline and survival data for 4700 hospitalized CHF patients for whom BMI was available. LV systolic function, as assessed by wall motion index was available for 95% of the patients. Follow-up time ranged from 5 to 8 years. In the total population, the risk of death decreased steadily with increasing BMI from the underweight to the obese. Compared with normal weight, and adjusted for sex and age, risk ratios (RR) and 95% confidence limits were: underweight 1.56 (1.33-1.84), overweight 0.90 (0.83-0.97), obese 0.77 (0.70-0.86). Being underweight conferred a greater risk in CHF patients with normal systolic function [RR 1.66 (1.29-2.14), compared with normal weight] than in patients with reduced systolic function [RR 1.11 (0.87-1.42), P for interaction 0.03]. In patients with systolic dysfunction, obesity was associated with increased risk compared with normal weight [RR 1.21 (1.01-1.45)]. Increasing BMI in CHF is associated with a lower mortality, but the influence is complex and depends on left ventricular systolic function. Hence, in patients with systolic dysfunction obesity may indicate an increased risk.

Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction: Results from the Breathing Not Properly Multinational Study

ObjectivesThis study examines B-type natriuretic peptide (BNP) levels in patients with systolic versus non-systolic dysfunction presenting with shortness of breath. BackgroundPreserved systolic function is increasingly common in patients presenting with symptoms of congestive heart failure (CHF) but is still difficult to diagnose. MethodsThe Breathing Not Properly Multinational Study was a seven-center, prospective study of 1,586 patients who presented with acute dyspnea and had BNP measured upon arrival. A subset of 452 patients with a final adjudicated diagnosis of CHF who underwent echocardiography within 30 days of their visit to the emergency department (ED) were evaluated. An ejection fraction of greater than 45% was defined as non-systolic CHF. ResultsOf the 452 patients with a final diagnosis of CHF, 165 (36.5%) had preserved left ventricular function on echocardiography, whereas 287 (63.5%) had systolic dysfunction. Patients with non-systolic heart failure (NS-CHF) had significantly lower BNP levels than those with systolic heart failure (S-CHF) (413 pg/ml vs. 821 pg/ml, p < 0.001). As the severity of heart failure worsened by New York Heart Association class, the percentage of S-CHF increased, whereas the percentage of NS-CHF decreased. When patients with NS-CHF were compared with patients without CHF (n = 770), a BNP value of 100 pg/ml had a sensitivity of 86%, a negative predictive value of 96%, and an accuracy of 75% for detecting abnormal diastolic dysfunction. Using Logistic regression to differentiate S-CHF from NS-CHF, BNP entered first as the strongest predictor followed by oxygen saturation, history of myocardial infarction, and heart rate. ConclusionsWe conclude that NS-CHF is common in the setting of the ED and that differentiating NS-CHF from S-CHF is difficult in this setting using traditional parameters. Whereas BNP add modest discriminatory value in differentiating NS-CHF from S-CHF, its major role is still the separation of patients with CHF from those without CHF.

Beside B-type natriuretic peptide in the emergency diagnosis of systolic and nonsystolic heart failure: Results from the breathing not properly (BNP) multinational study

Background: The impact of creatinine levels on plasma concentrations as well as the prognostic value of N-terminal proENP (pmBNP) was evaluated in patients with symp- toms of congestive heart failure (CHF) at rest or on minimal exertion. Methods: Plasma concentrations of proBNP, were measured using a newly developed sandwich ELISA in a subgroup of 1048 patrents of the European part of the COPERNI- CUS study. Results: ProBNP baseline values, mean*SD. were 74lilO16 pmol/L in patients with ele- vated (a=125 U/L) creatinine, compared to 403~461 pmollL in patients with normal (cl25UiL) creatinine (p=O.OOOl, Wilcoxon P-sample test). A significant positive correla- tion (r= 0.35, p=O.OOOl, Pearson Correlation Coefficient) was detected between proBNP and creatinine. By multivariate Cox regression, NT-proBNP but not creatinine was a pow- erful independent indicator of subsequent cardiac events. A statistical significant creati- nine-proBNP interaction could be detected (p=O.O2 for the primary endpoint), indicating that the prognostic value of proBNP for survival is not constant Over the range of creati- nine. Risk ratios for proBNP levels below vs. above median are indicated in the table according to quartiles of baseline creatinine. Conclusions: In patients wtth advanced CHF treated wrthin the COPERNICUS study, proBNP plasma concentrations are related to creatinine both at baseline and during treatment. In addihon, baseline creatinine levels seam to influence the prognostic value of proBNP concentrations.