Primary care-based integrated disease management for heart failure: a study protocol for a cluster randomised controlled trial.

INTRODUCTION: Heart failure (HF) is a common chronic disease that increases in prevalence with age. It is associated with high hospitalisation rates, poor quality of life and high mortality. Management is complex with most interactions occurring in primary care. Disease management programmes implemented during or after an HF hospitalisation have been shown to reduce hospitalisation and mortality rates. Evidence for integrated disease management (IDM) serving the primary care HF population has been investigated but is less conclusive. The aim of this study is to evaluate the efficacy of IDM, focused on, optimising medication, self-management and structured follow-up, in a high-risk primary care HF population. METHODS AND ANALYSIS: 100 family physician clusters will be recruited in this Canadian primary care multicentre cluster randomised controlled trial. Physicians will be randomised to IDM or to care as usual. The IDM programme under evaluation will include case management, medication management, education, and skills training delivered collaboratively by the family physician and a trained HF educator. The primary outcome will measure the combined rate (events/patient-years) of all-cause hospitalisations, emergency department visits and mortality over a 12-month follow-up. Secondary outcomes include other health service utilisation, quality of life, knowledge assessments and acute HF episodes. Two to three HF patients will be recruited per physician cluster to give a total sample size of 280. The study has 90% power to detect a 35% reduction in the primary outcome. The difference in primary outcome between IDM and usual care will be modelled using a negative binomial regression model adjusted for baseline, clustering and for individuals experiencing multiple events. ETHICS AND DISSEMINATION: The study has obtained approval from the Research Ethics Board at the University of Western Ontario, London, Canada (ID 114089). Findings will be disseminated through local reports, presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT04066907.

Advances in the understanding and management of heart transplantation.

Cardiac transplantation represents one of the great triumphs in modern medicine and remains the cornerstone in the treatment of advanced heart failure. In this review, we contextualize pivotal developments in our understanding and management of cardiac transplant immunology, histopathology, rejection surveillance, drug development and surgery. We also discuss current limitations in their application and the impact of the left ventricular assist devices in bridging this gap.

Utilizing cardiac biomarkers to detect and prevent chemotherapy-induced cardiomyopathy.

The success achieved in advances in cancer therapy has been marred by development of cardiotoxicity, which causes significant morbidity and mortality. This has led to the development of surveillance protocols for cardiotoxicity utilizing multimodality imaging techniques and investigation of various drugs to treat and prevent cardiotoxicity in this subset of patients. Cardiac biomarkers hold important diagnostic and prognostic value in various cardiac diseases. In this review, we discuss the use of biomarkers in patients receiving chemotherapy, highlighting data behind the use of troponin, B-type natriuretic peptide, and myeloperoxidase. We also discuss the use of dexrazoxane, angiotensin-converting enzyme inhibitors, and beta blockers in the treatment and prevention of chemotherapy-induced cardiotoxicity. Cardiac biomarkers may serve an important role in selecting patients that are at high risk of cardiotoxicity and can potentially be used to guide the administration of drugs to treat and prevent cardiotoxicity.

Insufficient natriuretic response to continuous intravenous furosemide is associated with poor long-term outcomes in acute decompensated heart failure.

BACKGROUND: Treatment of acute decompensated heart failure (ADHF) with loop diuretics, such as furosemide, is frequently complicated by insufficient urine sodium excretion. We hypothesize that insufficient natriuretic response to diuretic therapy, characterized by lower urine sodium (UNa) and urine furosemide, is associated with subsequent inadequate decongestion, worsening renal function, and adverse long term events. METHODS AND RESULTS: We enrolled 52 consecutive patients with ADHF and measured serum and urine sodium (UNa), urine creatinine (UCr), and urine furosemide (UFurosemide) levels on a spot sample taken after treatment with continuous intravenous furosemide, and followed clinical and renal variables as well as adverse long-term clinical outcomes (death, rehospitalizations, and cardiac transplantation). We observed similar correlations between UNa:UFurosemide ratio and UNa and fractional excretion of sodium (FENa) with 24-hour net urine output (r = 0.52-0.64, all P < .01) and 24-hour weight loss (r = 0.44-0.56; all P < .01). Interestingly, FENa (but not UNa or UNa:UFurosemide) were influenced by estimated glomerular filtration rate (eGFR). We observed an association between lower UNa:UFurosemide with greater likelihood of worsening renal function (hazard ratio [HR] 3.01; P = .02) and poorer adverse clinical outcomes (HR 1.63, P = .008) after adjusting for age and eGFR. Meanwhile, both diminished weight loss and net fluid output over 24 hours of continuous intravenous furosemide were observed when UNa:UFurosemide ratios were <2 mmol/mg or when UNa <50 mmol. CONCLUSION: In patients with ADHF receiving continuous furosemide infusion, impaired natriuretic response to furosemide is associated with greater likelihood of worsening renal function and future adverse long-term outcomes, independently from and incrementally with decreasing intrinsic glomerular filtration.

Anticoagulation and antiplatelet therapy in acute coronary syndromes.

Antiplatelet and anticoagulant drugs are the mainstay of treatment of acute coronary syndrome (ACS). The last 30 years have seen the development of various agents, a deeper understanding of the pathobiology of this disease, and an evolution in its treatment. We review the role of contemporary agents in ACS and highlight key clinical trials of these agents.

Significance of aortic valve calcification in patients with low-gradient low-flow aortic stenosis.

BACKGROUND: Assessment of patients with aortic stenosis (AS) and impaired left ventricular function remains challenging. Aortic valve calcium (AVC) scoring with computed tomography (CT) and fluoroscopy has been proposed as means of diagnosing and predicting outcomes in patients with severe AS. HYPOTHESIS: Severity of aortic valve calcification correlates with the diagnosis of true severe AS and outcomes in patients with low-gradient low-flow AS. METHODS: Echocardiography and CT database records from January 1, 2000 to September 26, 2009 were reviewed. Patients with aortic valve area (AVA)<1.0 cm2 who had ejection fraction (EF)≤25% and mean valvular gradient≤25 mmHg with concurrent noncontrast CT scans were included. AVC was evaluated using CT and fluoroscopy. Mortality and aortic valve replacement (AVR) were established using the Social Security Death Index and medical records. The role of surgery in outcomes was evaluated. RESULTS: Fifty-one patients who met the above criteria were included. Mean age was 75.1±9.6 years, and 15 patients were female. Mean EF was 21%±4.6% with AVA of 0.7±0.1 cm2. The peak and mean gradients were 35.5±10.6 and 19.0±5.1 mmHg, respectively. Median aortic valve calcium score was 2027 Agatston units. Mean follow-up was 908 days. Patients with calcium scores above the median value were found to have increased mortality (P=0.02). The benefit of surgery on survival was more pronounced in patients with higher valvular scores (P=0.001). Fluoroscopy scoring led to similar findings, where increased AVC predicted worse outcomes (P=0.04). CONCLUSIONS: In patients with low-gradient low-flow AS, higher valvular calcium score predicts worse long-term mortality. AVR is associated with improved survival in patients with higher valve scores.

Novel urinary biomarkers in detecting acute kidney injury, persistent renal impairment, and all-cause mortality following decongestive therapy in acute decompensated heart failure.

BACKGROUND: New urinary biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and interleukin-18 (IL-18), are proposed to allow a more reliable early diagnosis and prognosis of acute kidney injury (AKI) in acute decompensated heart failure (ADHF). Our aim was to compare the predictive value of urinary NGAL, KIM-1, and IL-18 for the occurrence of AKI, persistent renal impairment, and mortality in ADHF. METHODS AND RESULTS: Eighty-three patients admitted for ADHF were analyzed. Urinary creatinine (Cr), NGAL, KIM-1, and IL-18 were measured at baseline. Serum Cr was measured daily during the next 4 days and again at outpatient follow-up after 6 months. Mortality data were prospectively collected. Urinary NGAL, KIM-1, and IL-18 were modestly correlated with each other (Spearman ρ ≤0.61) and poorly correlated with estimated glomerular filtration rate (eGFR; Spearman ρ ≤0.28). None predicted AKI, defined as a 25% decrease in eGFR, during the index hospitalization, but urinary IL-18/Cr was the strongest predictor of persistently elevated serum Cr ≥0.3 mg/dL after 6 months compared with baseline (area under the receiver operating characteristic curve 0.674; P = .013). Urinary IL-18 was also significantly associated with all-cause mortality (hazard ratio 1.48, 95% confidence interval 1.16-1.87; P = .001). CONCLUSIONS: Like urinary NGAL, urinary KIM-1 and IL-18 are relatively modest predictors of AKI in ADHF. Among these novel renal biomarkers examined, further investigations regarding the prognostic value of urinary IL-18 are warranted.

Atrial fibrillation ablation in patients with gastroesophageal reflux disease or irritable bowel syndrome-the heart to gut connection!

PURPOSE: An association between atrial fibrillation (AF) and gastroesophageal reflux disease (GERD) and/or irritable bowel syndrome (IBS) is increasingly being identified; yet the role of radiofrequency catheter ablation (RFA) of AF has not been systematically evaluated in these patient populations. METHODS: We performed a prospective matched case-control study of AF patients with GERD and/or IBS who underwent RFA for AF in two centers in North America. AF patients with GERD and/or IBS (gastrointestinal [GI] group) were matched by age, gender, and type of AF at each of the centers with an equal number of AF patients without GERD or IBS (non-GI group). RESULTS: Sixty patients were included in the study with 30 in each group. Mean age of the population was 45 years with 14 (47 %) males and 21 (87 %) patients with paroxysmal AF in each group. More patients in the GI group had identifiable GI triggers for AF episodes. During RFA, more patients in the GI group had a "vagal response" compared to non-GI group (60 vs 13 %; p < 0.001). Left atrial scar as identified by electroanatomical mapping was more common in patients in the non-GI group compared to the GI group (57 vs 27 %; p = 0.018). At 1-year follow-up, 56 (93 %) of the patients were free from AF with no difference between both groups. CONCLUSIONS: Majority of AF patients with GERD and/or IBS have triggered AF and a positive vagal response during RFA. RFA is equally effective in this patient population when compared to those without GERD or IBS.

Lack of concordance in defining worsening renal function by rise in creatinine vs rise in cystatin C.

Worsening renal function (WRF) during treatment of acute decompensated heart failure (ADHF) is generally associated with adverse outcomes. An increase ≥0.3 mg/dL in creatinine level is widely used as the definition of WRF. The authors sought to determine the level of agreement between WRF based on changes in creatinine and changes in cystatin C (CysC) by analyzing data from 121 ADHF patients with available admission and day 3 creatinine and CysC levels. Admission creatinine and CysC levels were 1.39 (0.98-2.11) mg/dL and 1.95 (1.42-2.69) mg/L, respectively, and correlated well (r=0.81). On average, creatinine (-0.04±0.40 mg/dL) and CysC (0.001±0.34 mg/L) changed minimally from admission to day 3. Although the correlation between both markers on day 3 was still good (r=0.79), the correlation between changes therein was only modest (r=0.43). From the 14 and 15 patients who had WRF based on a ≥0.3 mg/dL increase in creatinine and ≥0.3 mg/L increase in CysC, respectively, only four (about 30%) met both definitions. These observations, together with recent insights in the inconsistencies of creatinine-defined concept of worsening renal function and outcomes, raises the need to research more reliable measures of renal function during treatment of ADHF.

Postprocedural neuropathy after atrial fibrillation ablation.

PURPOSE: Access-related neuropathy after atrial fibrillation (AF) ablation is underappreciated. We intend to describe the incidence, management, and prognosis of postprocedural neuropathy after AF ablation. METHODS: We performed a retrospective analysis of all consecutive patients with postprocedural neuropathy who underwent AF ablation in three high-volume tertiary care hospitals between January 2007 and April 2011. RESULTS: Of the 3,128 patients who underwent AF ablation during the study period, 25 (0.8 %) patients had postprocedural neuropathy and were included in the current study. Mean age was 58.5 ± 11.5 years with 18 (72 %) being males and 14 (56 %) having paroxysmal AF. Ulnar nerve, lateral femoral cutaneous nerve manifesting as meralgia paresthetica, and femoral nerve were involved in 5 (20 %), 13 (54 %), and 7 (26 %) of the patients, respectively. Majority of neuropathies were associated with periprocedural hematomas (19, 76 %), and a quarter (19/72, 26 %) of all hematomas were associated with neuropathy. Initial treatment included warm and cold compresses followed by nonsteroidal anti-inflammatory and narcotic pain medications. In addition to the above regimen, in some patients (11, 44 %), oral gabapentin was used and it was associated with a shorter time to symptom resolution (9.4 vs. 14.1 days, p = 0.007). All patients were symptom free within 90 days of the procedure. CONCLUSION: Postprocedural neuropathy after AF ablation is rare and is frequently associated with a periprocedural hematoma. Patients typically become symptom free within 90 days of the procedure, and gabapentin may have a role in earlier symptom resolution.

Relation of systemic and urinary neutrophil gelatinase-associated lipocalin levels to different aspects of impaired renal function in patients with acute decompensated heart failure.

Both urine and serum neutrophil gelatinase-associated lipocalin (NGAL) reflect active chronic kidney disease and predict acute kidney injury. However, a direct comparison of these markers in acute decompensated heart failure has not been performed. We prospectively evaluated 93 patients admitted with acute decompensated heart failure and treated with intravenous furosemide and measured both systemic (serum) and urine NGAL levels and their corresponding markers of estimated glomerular filtration rate, natriuresis (urine sodium), and diuretic response (net output, urine sodium/furosemide ratio). In our study cohort, the median urine and serum NGAL level was 34 ng/ml (interquartile range 24 to 86) and 252 ng/ml (interquartile range 175 to 350), respectively. The urine and serum NGAL levels correlated modestly (r = 0.37, p <0.001). Higher urine (but not systemic) NGAL correlated with the markers of impaired natriuresis and reduced diuresis (p <0.005 for all). In contrast, higher serum NGAL demonstrated a stronger relation with reduced glomerular filtration function (p <0.0001). Both markers predicted acute kidney injury (urine NGAL, odds ratio 1.7, p = 0.035; serum NGAL, odds ratio 1.9, p = 0.009). In conclusion, in patients with acute decompensated heart failure, urine NGAL levels reflect renal distal tubular injury with impaired natriuresis and diuresis, and systemic NGAL levels demonstrate a stronger association with glomerular filtration function. Both systemic and urine NGAL predict worsening renal function.

Lack of significant renal tubular injury despite acute kidney injury in acute decompensated heart failure.

AIMS: Acute kidney injury (AKI) is a strong predictor of adverse events with an incompletely understood pathophysiology. Neutrophil gelatinase-associated lipocalin (NGAL) is proposed as an early marker of renal tubular injury. Our aim is to determine whether AKI during treatment of acute decompensated heart failure (ADHF) is accompanied by renal tubular injury. METHODS AND RESULTS: Urinary NGAL (uNGAL) and urinary creatinine (uCreat) levels were measured in 141 consecutive patients hospitalized for ADHF and followed for 180 days for death or re-hospitalization. AKI was defined as a rise in serum creatinine ≥0.3 mg/dl in a 48 h period. Median uNGAL/uCreat levels on Day 1 (baseline) were similar between patients who did and did not develop AKI [22.8 (12.5-106.8) µg/g vs. 20.6 (12.4-52.0) µg/g, P = 0.55]. On Day 2 and beyond, the difference between the AKI and no AKI cohorts increased, but was only significant on Day 3 [36.2 (21.7-131.8) µg/g vs. 29.4 (11.4-54.6) µg/g, P = 0.02]. The area under the receiver operating characteristic curve for Day 2 uNGAL/uCreat (≥ or <32 µg/g) to predict AKI was 0.61. There was no difference in diuretic response between 'uNGAL/uCreat + ' (≥ 27 µg/g) and 'uNGAL/uCreat-' (<27 µg/g) patients. However 'uNGAL/uCreat + ' patients had more adverse events after 180 days (66% vs. 52%, P = 0.02). CONCLUSIONS: In patients with ADHF who develop AKI following diuretic therapy, a minor rise in uNGAL precedes AKI. However, the degree of renal tubular insult was much lower than that observed in other forms of AKI.

Influence of gender on long-term mortality in patients presenting with non-ST-elevation acute coronary syndromes undergoing percutaneous coronary intervention.

Although an invasive strategy has predominately been studied in men with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs), its role in low-risk women is unclear. We sought to examine gender differences in a real-world registry of patients with NSTE-ACS who underwent percutaneous coronary intervention (PCI). Patients with NSTE-ACS undergoing PCI at the Cleveland Clinic, Cleveland, Ohio from 2003 through 2007 (n = 1,874) were included. In-hospital and long-term mortalities were assessed. Cox proportional hazards models were constructed to study the influence of gender on mortality. Interactions with age and biomarker status were examined. Women were older and had a higher incidence of co-morbid conditions compared to men. They had a smaller reference vessel diameter compared to men. Despite these characteristics there was no overall difference in in-hospital (1.4% vs 1.6%) or long-term (14.6% vs 15.8%) mortality between men and women. However, there was evidence of a significant effect modification by age (p = 0.012) and troponin status (p = 0.0073) for long-term mortality such that women <60 years of age, especially those who were troponin negative, had more than a twofold increase in long-term mortality compared to men (p = 0.007). In conclusion, although overall mortality rates are similar between men and women undergoing PCI for NSTE-ACS, women <60 years old with negative biomarkers have a higher mortality than their men peers.

Cardiogenic shock in the setting of severe aortic stenosis: role of intra-aortic balloon pump support.

OBJECTIVE: To investigate the haemodynamic effects of intra-aortic balloon pump (IABP) support in patients with severe aortic stenosis (AS) presenting in cardiogenic shock (CS). DESIGN: Observational cohort study. Setting Tertiary academic centre coronary intensive care unit (CICU). Patients Patients presenting to the CICU in CS with an established diagnosis of AS (n=25 with mean age (± SD) of 73.5 ± 9.5 years). The peak and mean Doppler AV gradients were 67 ± 26.8 mm Hg and 39.8 ± 16.8 mm Hg, respectively, with a mean baseline cardiac index of 1.77 ± 0.38 l/min/m²). Interventions Utilisation of IABP. Main outcome measures Haemodynamic impact of IABP over time. RESULTS: With the insertion of an IABP, patients' cardiac index improved from 1.77 l/min/m² to 2.18 and 2.36 l/min/m² at 6 and 24 h, respectively (p<0.001 for both times points). Systemic vascular resistance was reduced from 1331 dyn/s/cm5 to 1265 and 1051 dyn/s/cm5 at 6 and 24 h, respectively (p=0.66 and p=0.005, respectively). The central venous pressure was reduced from 14.8 mm Hg to 13.2 and 10.9 mm Hg at 6 and 24 h, respectively (p=0.12 and p=0.03, respectively). IABP insertion was associated with a complication in 3 of the 25 cases, including a deep vein thrombosis, thrombocytopenia, limb ischaemia, and technical malfunctioning of the device. CONCLUSIONS: IABP support improves the haemodynamic profile in patients with severe AS who present in CS. IABP utilisation in this critically ill population should be strongly considered as patients are being evaluated for candidacy for advanced interventions.