Anjali Tiku Owens

Blood Urea Nitrogen/Creatinine Ratio Identifies a High-Risk but Potentially Reversible Form of Renal Dysfunction in Patients With Decompensated Heart Failure

Background—Identifying reversible renal dysfunction (RD) in the setting of heart failure is challenging. The goal of this study was to evaluate whether elevated admission blood urea nitrogen/creatinine ratio (BUN/Cr) could identify decompensated heart failure patients likely to experience improvement in renal function (IRF) with treatment. Methods and Results—Consecutive hospitalizations with a discharge diagnosis of heart failure were reviewed. IRF was defined as ≥20% increase and worsening renal function as ≥20% decrease in estimated glomerular filtration rate. IRF occurred in 31% of the 896 patients meeting eligibility criteria. Higher admission BUN/Cr was associated with in-hospital IRF (odds ratio, 1.5 per 10 increase; 95% confidence interval [CI], 1.3–1.8; P<0.001), an association persisting after adjustment for baseline characteristics (odds ratio, 1.4; 95% CI, 1.1–1.8; P=0.004). However, higher admission BUN/Cr was also associated with post-discharge worsening renal function (odds ratio, 1.4; 95% CI, 1.1–1.8; P=0.011). Notably, in patients with an elevated admission BUN/Cr, the risk of death associated with RD (estimated glomerular filtration rate <45) was substantial (hazard ratio, 2.2; 95% CI, 1.6–3.1; P<0.001). However, in patients with a normal admission BUN/Cr, RD was not associated with increased mortality (hazard ratio, 1.2; 95% CI, 0.67–2.0; P=0.59; p interaction=0.03). Conclusions—An elevated admission BUN/Cr identifies decompensated patients with heart failure likely to experience IRF with treatment, providing proof of concept that reversible RD may be a discernible entity. However, this improvement seems to be largely transient, and RD, in the setting of an elevated BUN/Cr, remains strongly associated with death. Further research is warranted to develop strategies for the optimal detection and treatment of these high-risk patients.

Ventilatory Inefficiency Reflects Right Ventricular Dysfunction in Systolic Heart Failure

BACKGROUND An increased minute ventilation (VE)/carbon dioxide production (VCO2) relationship, an expression of ventilatory inefficiency (VI), is associated with increased morbidity and mortality in patients with left ventricular systolic dysfunction (LVSD). A direct link between VI and a specific cardiac abnormality has not been established. METHODS We analyzed cardiopulmonary exercise test (CPET) data from patients (N=83) with severe LVSD (ischemic and nonischemic; left ventricular ejection fraction [LVEF] 19%±7%) and at least moderate exercise intolerance. Subjects were stratified into two groups based on the (VE/VCO2 ratio at anaerobic threshold (VE/VCO2@AT) (group 1 VE/VCO2@AT≤34; group 2 VE/VCO2@AT>34). Clinical, CPET, echocardiographic, and hemodynamic data were compared between groups. RESULTS Group 2 subjects had lower exercise capacity (peak (VO2, 45.7%±11.8% vs 50.4±8.9% predicted; P<.05), with a significantly lower oxygen pulse (71.6%±24.5% vs 85.4±18.5% predicted) and maximum systolic BP (122±19 mm Hg vs 138±22 mm Hg; P<.001 for both), suggesting a more blunted stroke volume to exercise vs group 1. There were no differences in left ventricular (LV) size, LVEF, or mitral regurgitation between the two groups. In sharp contrast, group 2 had larger right ventricular (RV) dimensions (4.5±1.1 cm vs 3.9±0.8 cm) and more severe RV systolic dysfunction (RV fractional area change 26%±11% vs 33%±12%; tricuspid annular plane systolic excursion [TAPSE] 1.6±0.5 cm vs 2.0±0.5 cm; all P<.001) vs group 1. Multivariable analysis revealed that only TAPSE and Doppler-estimated pulmonary artery systolic pressure were independently associated with VE/VCO2@AT and the (VE/VCO2slope. The VE/VCO2@AT, VE/VCO2 slope, and TAPSE had nearly identical predictive value for death or transplant. CONCLUSIONS The present study suggests that VI is a functional, noninvasive marker of more advanced right-sided heart dysfunction in patients with severe LVSD.

The Year in Heart Failure

In this landmark year for the U.S. healthcare system, during which the Affordable Care Act was signed into law, there have been many notable advances in the area of heart failure (HF) and heart transplantation. In addition to scientific discoveries reviewed here and the publication of important

New Management Strategies in Heart Failure.

Despite >100 clinical trials, only 2 new drugs had been approved by the US Food and Drug Administration for the treatment of chronic heart failure in more than a decade: the aldosterone antagonist eplerenone in 2003 and a fixed dose combination of hydralazine-isosorbide dinitrate in 2005. In contrast, 2015 has witnessed the Food and Drug Administration approval of 2 new drugs, both for the treatment of chronic heart failure with reduced ejection fraction: ivabradine and another combination drug, sacubitril/valsartan or LCZ696. Seemingly overnight, a range of therapeutic possibilities, evoking new physiological mechanisms, promise great hope for a disease that often carries a prognosis worse than many forms of cancer. Importantly, the newly available therapies represent a culmination of basic and translational research that actually spans many decades. This review will summarize newer drugs currently being used in the treatment of heart failure, as well as newer strategies increasingly explored for their utility during the stages of the heart failure syndrome.

Should Left Ventricular Assist Device Be Standard of Care for Patients With Refractory Heart Failure Who Are Not Transplantation Candidates? Left Ventricular Assist Devices Should Not Be Standard of Care for Transplantation-Ineligible Patients

At 40 years of age, the lifetime risk of developing heart failure (HF) is 1 in 5 for men and women in the United States. Approximately half of patients who are ultimately diagnosed with HF will die within 5 years1; the associated morbidity, hospitalization rate, and loss of functional capacity are more difficult to calculate. Among the 5 million American patients currently living with HF, it is estimated that 200 000 patients have American College of Cardiology/American Heart Association stage D or refractory HF, resulting in markedly diminished functional status and survival.1,2 In 2012, 2 therapies are available to potentially prolong survival and to improve quality of life for end-stage HF patients: heart transplantation and long-term mechanical circulatory support in the form of a ventricular assist device (VAD). For permanent mechanical support, also referred to as destination therapy (DT), the Food and Drug Administration approved the use of the HeartMate II (Thoratec Corp, Pleasanton, CA) left ventricular assist device (LVAD) in January 2010. This device supports only the left ventricle; no biventricular device is approved for long-term therapy at this time. Response by Mehra and Domanski on p 3094 Many advanced HF patients are not appropriate candidates for transplantation or permanent LVAD because of comorbid conditions or age. After excluding these patients, clinicians must critically evaluate individual patient eligibility for transplantation or VAD. The indications for and complications expected after each procedure are increasingly recognized as distinct; the skills needed by clinicians who must care for these 2 types of patients are garnered in 2 complementary but separate experiential care settings. The therapies are neither equivalent in historical experience and outcomes nor interchangeable. Transplantation has been available for decades, with well-documented selection criteria, management protocols, and outcomes. As we begin to understand how to appropriately …At 40 years of age, the lifetime risk of developing heart failure (HF) is 1 in 5 for men and women in the United States. Approximately half of patients who are ultimately diagnosed with HF will die within 5 years1; the associated morbidity, hospitalization rate, and loss of functional capacity are more difficult to calculate. Among the 5 million American patients currently living with HF, it is estimated that 200 000 patients have American College of Cardiology/American Heart Association stage D or refractory HF, resulting in markedly diminished functional status and survival.1,2 In 2012, 2 therapies are available to potentially prolong survival and to improve quality of life for end-stage HF patients: heart transplantation and long-term mechanical circulatory support in the form of a ventricular assist device (VAD). For permanent mechanical support, also referred to as destination therapy (DT), the Food and Drug Administration approved the use of the HeartMate II (Thoratec Corp, Pleasanton, CA) left ventricular assist device (LVAD) in January 2010. This device supports only the left ventricle; no biventricular device is approved for long-term therapy at this time. Response by Mehra and Domanski on p 3094 Many advanced HF patients are not appropriate candidates for transplantation or permanent LVAD because of comorbid conditions or age. After excluding these patients, clinicians must critically evaluate individual patient eligibility for transplantation or VAD. The indications for and complications expected after each procedure are increasingly recognized as distinct; the skills needed by clinicians who must care for these 2 types of patients are garnered in 2 complementary but separate experiential care settings. The therapies are neither equivalent in historical experience and outcomes nor interchangeable. Transplantation has been available for decades, with well-documented selection criteria, management protocols, and outcomes. As we begin to understand how to appropriately …

Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy: Design and Implementation of the DCM Precision Medicine Study

Background— The cause of idiopathic dilated cardiomyopathy (DCM) is unknown by definition, but its familial subtype is considered to have a genetic component. We hypothesize that most idiopathic DCM, whether familial or nonfamilial, has a genetic basis, in which case a genetics-driven approach to identifying at-risk family members for clinical screening and early intervention could reduce morbidity and mortality. Methods— On the basis of this hypothesis, we have launched the National Heart, Lung, and Blood Institute- and National Human Genome Research Institute-funded DCM Precision Medicine Study, which aims to enroll 1300 individuals (600 non-Hispanic African ancestry, 600 non-Hispanic European ancestry, and 100 Hispanic) who meet rigorous clinical criteria for idiopathic DCM along with 2600 of their relatives. Enrolled relatives will undergo clinical cardiovascular screening to identify asymptomatic disease, and all individuals with idiopathic DCM will undergo exome sequencing to identify relevant variants in genes previously implicated in DCM. Results will be returned by genetic counselors 12 to 14 months after enrollment. The data obtained will be used to describe the prevalence of familial DCM among idiopathic DCM cases and the genetic architecture of idiopathic DCM in multiple ethnicity–ancestry groups. We will also conduct a randomized controlled trial to test the effectiveness of Family Heart Talk, an intervention to aid family communication, for improving uptake of preventive screening and surveillance in at-risk first-degree relatives. Conclusions— We anticipate that this study will demonstrate that idiopathic DCM has a genetic basis and guide best practices for a genetics-driven approach to early intervention in at-risk relatives. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT03037632.

Neprilysin Inhibitors: Emerging Therapy for Heart Failure

Biologically active natriuretic peptides (NPs) are an integral part of cardiac homeostasis as they help to maintain sodium and fluid balance. When homeostasis is perturbed by neurohormonal activation in heart failure, levels of NPs rise in response. Neprilysin (NEP) is a naturally occuring enzyme that breaks down NPs. Scientists have recently discovered a novel pharmacologic agent that combines a NEP inhibitor and an angiotensin receptor blocker. In a large clinical trial, this new drug was found to reduce hospitalization and mortality in systolic heart failure. The challenges of implementing this therapy include patient selection, cost, and risk of side effects including angioedema and Alzheimers disease.

Heart Retransplant Recipients Have Better Survival With Concurrent Kidney Transplant Than With Heart Retransplant Alone

Background Heart retransplant (HRT) recipients represent a growing number of transplant patients. The impact of concurrent kidney transplants (KTs) in this population has not been well studied. We tested the hypothesis that recipients of HRT with concurrent KT (HRT‐KT) would have worse survival than recipients of HRT alone. Methods and Results A retrospective analysis of the United Network of Organ Sharing database was performed for all patients undergoing HRT from 1987 to 2011. There were 1660 HRT patients, of which 116 (7%) received concurrent KT. Those who received HRT‐KT had older age, longer wait‐list time, worse kidney function, and more known diabetes. Survival among recipients of HRT‐KT was significantly better than that of recipients of HRT alone (P=0.005). A subgroup of 323 HRT patients with severe kidney dysfunction (estimated glomerular filtration rate <30 mL/min per 1.73 m2 or on dialysis) was studied in more detail, and 76 (24%) received concurrent KT. Those on dialysis at the time of HRT had better survival with versus without concurrent KT (P<0.0001). On multivariable analysis, concurrent KT was independently associated with better outcomes for all patients with HRT and for the subgroup of patients with severe kidney dysfunction. Conclusions Recipients of HRT‐KT have better survival than recipients of HRT alone. Further research is needed to determine which HRT patients may benefit the most from concurrent KT.

Recreational Exercise in Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy, defined as unexplained left ventricular hypertrophy, has an estimated prevalence of at least 1 in 500 and is among the most common forms of inherited heart disease.1 The pathophysiology of hypertrophic cardiomyopathy is complex and involves the interplay between diastolic dysfunction, myocardial ischemia, systolic anterior motion of the mitral valve resulting in outflow tract obstruction, and arrhythmia.2 Clinical presentations are heterogeneous and range from asymptomatic to palpitations, dyspnea, exercise intolerance, chest pain, syncope, and sudden death. Although the absolute risk of cardiac mortality is less than 1% per year,3 hypertrophic cardiomyopathy remains a common cause of sudden cardiac death in the young, especially in competitive athletes.4,5 Since hypertrophic cardiomyopathy has autosomal dominant inheritance, relatives of affected individuals have substantial risk of disease. Clinical evaluation of family members and cascade screening with genetic testing can identify those affected, many of whom are asymptomatic. When properly treated, the majority of patients with hypertrophic cardiomyopathy will have a normal life span.3

Pregnancy in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is among the most common inherited forms of cardiomyopathy, with estimated prevalence of at least 1 in 500 people, affecting males and females equally given autosomal dominant transmission. The vast majority of individuals with HCM are expected to enjoy a normal lifespan and, thus, survival through child-bearing age. Despite overall favourable outcomes with modern treatment and early recognition of disease through cascade clinical screening and genotyping of often asymptomatic relatives, adverse events are known to occur during times of physiological stress including vigorous exercise and pregnancy. In this issue of the journal, Goland et al. report maternal and foetal outcomes from an international cohort of women with HCM who entered the ROPAC database. Sixty women were included, the majority of whom were relatively healthy; only a few had prior septal reduction therapy or advanced NYHA functional class. For inclusion, left ventricular wall thickness of >_15 mm was required. Unfortunately, neither genotyping nor family history information was available, and 14% of women included had antecedent hypertension, raising the possibility that not all subjects had true sarcomeric HCM. Indeed, in one case of foetal demise, the foetus was found to have cardiomyopathy as well, and a mitochondrial disease was suspected. Over a relatively short follow-up period of 6 months after delivery, there were no maternal deaths and only three women experienced pregnancy loss. However, a major adverse cardiovascular event (MACE) defined as death, heart failure, arrhythmia, or thromboembolic event occurred in 23%. As expected, those women who