Abstract Background Patients with chronic heart failure (CHF) secondary to left ventricular (LV) systolic dysfunction (LVSD) are frequently deficient in vitamin D. Low vitamin D levels are associated ...with a worse prognosis. It is unclear whether vitamin D deficiency is a marker of disease severity or plays a pathophysiological role. Objectives The VitamIN D treatIng patients with Chronic heArT failurE (VINDICATE) study was designed to establish the safety and efficacy of high-dose vitamin D supplementation in patients with CHF due to LVSD. Methods We enrolled 229 patients (179 men) with CHF due to LVSD and vitamin D deficiency ((25(OH) vitamin D3 <50nmol/L (<20ng/mL)) into a randomised, placebo-controlled double-blind trial of vitamin D supplementation. Participants were either allocated to one year of vitamin D3 supplementation (4000IU (100μg) 25(OH)D3 daily) or matching non-calcium-based placebo. The primary endpoint was change in six-minute walk distance from baseline to 12 months. Pre-specified secondary endpoints included change in left ventricular ejection fraction at one year, and safety measures of renal function and serum calcium concentration assessed every three months. Results One year of high-dose vitamin D supplementation did not improve 6-minute walk distance at one year, but was associated with a significant improvement in cardiac function on echocardiography (left ventricular ejection fraction +6.07% (95% CI 3.20, 8.95; p<0.0001); and a reversal of left ventricular remodeling (left ventricular end diastolic diameter -2.49mm (95% CI -4.09, -0.90; p=0.002) and left ventricular end systolic diameter -2.09mm (95% CI -4.11; -0.06 p=0.043). There were no clinically significant effects on calcium levels or renal function. Conclusions One year of 100μg daily 25-OH vitamin D3 supplementation does not improve 6-minute walk distance but has beneficial effects on LV structure and function in patients on contemporary optimal medical therapy. Further studies are necessary to determine whether these translate to improvements in outcomes.
To characterise the association between socioeconomic deprivation and adverse outcomes in patients with chronic heart failure (CHF).
We prospectively observed 1802 patients with CHF and left ...ventricular ejection fraction (LVEF) ≤45%, recruited in four UK hospitals between 2006 and 2014. We assessed the association between deprivation defined by the UK Index of Multiple Deprivation (IMD) and: mode-specific mortality (mean follow-up 4 years); mode-specific hospitalisation; and the cumulative duration of hospitalisation (after 1 year).
A 45-point difference in mean IMD score was noted between patients residing in the least and most deprived quintiles of geographical regions. Deprivation was associated with age, sex and comorbidity, but not CHF symptoms, LVEF or prescribed drug therapy. IMD score was associated with the risk of age-sex adjusted all-cause mortality (6% higher risk per 10-unit increase in IMD score; 95% CI 2% to 10%; P=0.004), and non-cardiovascular mortality (9% higher risk per 10-unit increase in IMD score; 95% CI 3% to 16%; P=0.003), but not cardiovascular mortality. All-cause, but not heart failure-specific, hospitalisation was also more common in the most deprived patients. Overall, patients spent a cumulative 3.3 days in hospital during 1 year of follow-up, with IMD score being associated with the age-sex adjusted cumulative duration of hospitalisations (4% increase in duration per 10-unit increase in IMD score; 95% CI 3% to 6%; P<0.0005).
Socioeconomic deprivation in people with CHF is linked to increased risk of death and hospitalisation due to an excess of non-cardiovascular events.
Purpose
Low 25-hydroxyvitamin D (25OHD) concentrations have been associated with adverse outcomes in selected populations with established chronic heart failure (CHF). However, it remains unclear ...whether 25OHD deficiency is associated with mortality and hospitalisation in unselected patients receiving contemporary medical and device therapy for CHF.
Methods
We prospectively examined the prevalence and correlates of 25OHD deficiency in 1802 ambulatory patients with CHF due to left ventricular systolic dysfunction (left ventricular ejection fraction ≤ 45%) attending heart failure clinics in the north of England.
Results
73% of patients were deficient in 25OHD (< 50 nmol/L). 25OHD deficiency was associated with male sex, diabetes, lower serum sodium, higher heart rate, and greater diuretic requirement. During a mean follow-up period of 4 years, each 2.72-fold increment in 25OHD concentration (for example from 32 to 87 nmol/L) is associated with 14% lower all-cause mortality (95% confidence interval (CI) 1, 26%;
p
= 0.04), after accounting for potential confounding factors.
Conclusions
Low 25-hydroxyvitamin D deficiency is associated with increased mortality in patients with chronic heart failure due to left ventricular systolic dysfunction. Whether vitamin D supplementation will improve outcomes is, as yet, unproven.
Therapies for patients with chronic heart failure caused by left ventricular systolic dysfunction have advanced substantially over recent decades. The cumulative effect of these therapies on ...mortality, mode of death, symptoms, and clinical characteristics has yet to be defined.
This study was a comparison of 2 prospective cohort studies of outpatients with chronic heart failure caused by left ventricular systolic dysfunction performed between 1993 and 1995 (historic cohort: n=281) and 2006 and 2009 (contemporary cohort: n=357). In the historic cohort, 83% were prescribed angiotensin-converting enzyme inhibitors and 8.5% were prescribed β-adrenoceptor antagonists, compared with 89% and 80%, respectively, in the contemporary cohort. Mortality rates over the first year of follow-up declined from 12.5% to 7.8% between eras (P=0.04), and sudden death contributed less to contemporary mortality (33.6% versus 12.7%; P<0.001). New York Heart Association class declined between eras (P<0.001). QTc dispersion across the chest leads declined from 85 ms (SD, 2) to 34 ms (SD, 1) and left ventricular end-diastolic dimensions declined from 65 mm (SD, 0.6) to 59 mm (SD, 0.5) (both P<0.001).
Survival has significantly improved in patients with chronic heart failure caused by left ventricular systolic dysfunction over the past 15 years; furthermore, sudden death makes a much smaller contribution to mortality, and noncardiac mortality is a correspondingly greater contribution. This has been accompanied by an improvement in symptoms and some markers of adverse electric and structural left ventricular remodeling.
Define the real-world performance of recently updated National Institute for Health and Care Excellence guidelines (TA314) on implantable cardioverter-defibrillator (ICD) use in people with chronic ...heart failure.
Multicentre prospective cohort study of 1026 patients with stable chronic heart failure, associated with left ventricular ejection fraction (LVEF) ≤45% recruited in cardiology outpatient departments of four UK hospitals. We assessed the capacity of TA314 to identify patients at increased risk of sudden cardiac death (SCD) or appropriate ICD shock.
The overall risk of SCD or appropriate ICD shock was 2.1 events per 100 patient-years (95% CI 1.7 to 2.6). Patients meeting TA314 ICD criteria (31.1%) were 2.5-fold (95% CI 1.6 to 3.9) more likely to suffer SCD or appropriate ICD shock; they were also 1.5-fold (95% CI 1.1 to 2.2) more likely to die from non-cardiovascular causes and 1.6-fold (95% CI 1.1 to 2.3) more likely to die from progressive heart failure. Patients with diabetes not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients without diabetes who met TA314 criteria. Patients with ischaemic cardiomyopathy not meeting TA314 criteria experienced comparable absolute risk of SCD or appropriate ICD shock to patients with non-ischaemic cardiomyopathy who met TA314 criteria.
TA314 can identify patients with reduced LVEF who are at increased relative risk of sudden death. Clinicians should also consider clinical context and the absolute risk of SCD when advising patients about the potential risks and benefits of ICD therapy.
Abstract
Aims
The UK National Institute for Health and Care Excellence (UK-NICE) and European Society of Cardiology (ESC) guidelines advise natriuretic peptide (NP) assessment in patients presenting ...to primary care with symptoms possibly due to chronic heart failure (HF), to determine need for specialist involvement. This prospective service evaluation aimed to describe the diagnostic and prognostic utility of these guidelines.
Methods and results
We prospectively collected clinical, echocardiography and outcomes data (minimum 5 years) from all patients referred to the Leeds HF Service for 12 months of following the initiation of the NP-guideline-directed pathway. Between 1 May 2012 and 1 August 2013, 1020 people with symptoms possibly due to HF attended either with a raised NT-pro-BNP or a previous myocardial infarction (MI) with an overall rate of left ventricular systolic dysfunction (LVSD) of 33%. Of these, 991 satisfied the ESC criteria (NT-pro-BNP ≥125 pg/mL) in whom the rate of LVSD was 32%, and 821 the UK-NICE criteria in whom the rate of LVSD was 49% in those with a previous MI, 25% in those with NT-pro-BNP concentration 400–2000 pg/mL, and 54% in those with NT-pro-BNP concentration of >2000 pg/mL. An NT-pro-BNP concentration 125–400 pg/mL had a 12% risk of LVSD. Specificity was poor in women >70 years, who made up the largest proportion of attendees. Elevated NT-pro-BNP levels were associated with lower survival even in the absence of LVSD.
Conclusion
In people referred through the ESC and UK-NICE guidelines, elevated NT-pro-BNP is a marker of increased mortality risk, but there is wide variation in specificity for LVSD. Age- and sex-adjusted criteria might improve performance.
Patients with chronic heart failure (HF) secondary to left ventricular systolic dysfunction (LVSD) are frequently deficient in vitamin D. Low vitamin D levels are associated with a worse prognosis.
...The VINDICATE (VitamIN D treatIng patients with Chronic heArT failurE) study was undertaken to establish safety and efficacy of high-dose 25 (OH) vitamin D3 (cholecalciferol) supplementation in patients with chronic HF due to LVSD.
We enrolled 229 patients (179 men) with chronic HF due to LVSD and vitamin D deficiency (cholecalciferol <50 nmol/l <20 ng/ml). Participants were allocated to 1 year of vitamin D3 supplementation (4,000 IU 100 μg daily) or matching non−calcium-based placebo. The primary endpoint was change in 6-minute walk distance between baseline and 12 months. Secondary endpoints included change in LV ejection fraction at 1 year, and safety measures of renal function and serum calcium concentration assessed every 3 months.
One year of high-dose vitamin D3 supplementation did not improve 6-min walk distance at 1 year, but was associated with a significant improvement in cardiac function (LV ejection fraction +6.07% 95% confidence interval (CI): 3.20 to 8.95; p < 0.0001); and a reversal of LV remodeling (LV end diastolic diameter -2.49 mm 95% CI: -4.09 to -0.90; p = 0.002 and LV end systolic diameter -2.09 mm 95% CI: -4.11 to -0.06 p = 0.043).
One year of 100 μg daily vitamin D3 supplementation does not improve 6-min walk distance but has beneficial effects on LV structure and function in patients on contemporary optimal medical therapy. Further studies are necessary to determine whether these translate to improvements in outcomes. (VitamIN D Treating patIents With Chronic heArT failurE VINDICATE; NCT01619891)
Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder in which nail, patella and elbow dysplasia is associated ...with other skeletal abnormalities and variably nephropathy and glaucoma. It is thought to be a haploinsufficient disorder. Studies in the mouse have shown that during development Lmxlb controls limb dorsal-ventral patterning and is also required for kidney and eye development, midbrain-hindbrain boundary establishment and the specification of specific neuronal subtypes. Mice completely deficient for Lmxlb die at birth. In contrast to the situation in humans, heterozygous null mice do not have a mutant phenotype. Here we report a novel mouse mutant Icst, an N-ethyl-N-nitrosourea-induced missense substitution, V265D, in the homeodomain of LMX1B that abolishes DNA binding and thereby the ability to transactivate other genes. Although the homozygous phenotypic consequences of Icst and the null allele of Lmxlb are the same, heterozygous Icst elicits a phenotype whilst the null allele does not. Heterozygous Icst causes glaucomatous eye defects and is semi-lethal, probably due to kidney failure. We show that the null phenotype is rescued more effectively by an Lmxlb transgene than is Icst. Co-immunoprecipitation experiments show that both wild-type and Icst LMX1B are found in complexes with LIM domain binding protein 1 (LDB1), resulting in lower levels of functional LMX1B in Icst heterozygotes than null heterozygotes. We conclude that Icst is a dominant-negative allele of Lmxlb. These findings indicate a reassessment of whether nail-patella syndrome is always haploinsufficient. Furthermore, Icst is a rare example of a model of human glaucoma caused by mutation of the same gene in humans and mice.
Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder in which nail, patella and elbow dysplasia is associated ...with other skeletal abnormalities and variably nephropathy and glaucoma. It is thought to be a haploinsufficient disorder. Studies in the mouse have shown that during development Lmx1b controls limb dorsal-ventral patterning and is also required for kidney and eye development, midbrain-hindbrain boundary establishment and the specification of specific neuronal subtypes. Mice completely deficient for Lmx1b die at birth. In contrast to the situation in humans, heterozygous null mice do not have a mutant phenotype. Here we report a novel mouse mutant Icst, an N-ethyl-N-nitrosourea-induced missense substitution, V265D, in the homeodomain of LMX1B that abolishes DNA binding and thereby the ability to transactivate other genes. Although the homozygous phenotypic consequences of Icst and the null allele of Lmx1b are the same, heterozygous Icst elicits a phenotype whilst the null allele does not. Heterozygous Icst causes glaucomatous eye defects and is semi-lethal, probably due to kidney failure. We show that the null phenotype is rescued more effectively by an Lmx1b transgene than is Icst. Co-immunoprecipitation experiments show that both wild-type and Icst LMX1B are found in complexes with LIM domain binding protein 1 (LDB1), resulting in lower levels of functional LMX1B in Icst heterozygotes than null heterozygotes. We conclude that Icst is a dominant-negative allele of Lmx1b. These findings indicate a reassessment of whether nail-patella syndrome is always haploinsufficient. Furthermore, Icst is a rare example of a model of human glaucoma caused by mutation of the same gene in humans and mice.
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