Advanced (stage D) heart failure: a statement from the Heart Failure Society of America Guidelines Committee.

We propose that stage D advanced heart failure be defined as the presence of progressive and/or persistent severe signs and symptoms of heart failure despite optimized medical, surgical, and device therapy. Importantly, the progressive decline should be primarily driven by the heart failure syndrome. Formally defining advanced heart failure and specifying when medical and device therapies have failed is challenging, but signs and symptoms, hemodynamics, exercise testing, biomarkers, and risk prediction models are useful in this process. Identification of patients in stage D is a clinically important task because treatments are inherently limited, morbidity is typically progressive, and survival is often short. Age, frailty, and psychosocial issues affect both outcomes and selection of therapy for stage D patients. Heart transplant and mechanical circulatory support devices are potential treatment options in select patients. In addition to considering indications, contraindications, clinical status, and comorbidities, treatment selection for stage D patients involves incorporating the patient's wishes for survival versus quality of life, and palliative and hospice care should be integrated into care plans. More research is needed to determine optimal strategies for patient selection and medical decision making, with the ultimate goal of improving clinical and patient centered outcomes in patients with stage D heart failure.

Survival in elderly patients supported with continuous flow left ventricular assist device as bridge to transplantation or destination therapy.

BACKGROUND: Published data on mechanical circulatory support for elderly patients in continuous flow devices are sparse and suggest relatively poor survival. This study investigated whether LVADs can be implanted in selected patients over the age of 65 years with acceptable survival compared with published outcomes. METHODS AND RESULTS: A single-center retrospective analysis was conducted in 64 consecutive patients ≥65 years of age implanted with a continuous-flow left ventricular assist device (CF-LVAD) as either bridge to transplantation or destination therapy from August 2005 to January 2012. Baseline laboratory and hemodynamic characteristics and follow-up data were obtained. Median survival was 1,090 days. Survival was 85%, 74%, 55%, and 45% at 6 months and 1, 2, and 3 years, respectively. Our cohort had a baseline mean Seattle Heart Failure Model (SHFM) score of 2.6 ± 0.9. Observed survival was significantly better than SHFM-predicted medical survival. Stratification by age subsets, renal function, SHFM, implantation intention, or etiology did not reveal significant differences in survival. The most common cause of death was sepsis and nonlethalcomplication was bleeding. CONCLUSIONS: Our experience with patients over the age of 65 receiving CF-LVADs suggests that this group demonstrates excellent survival. Further research is needed to discern the specific criteria for risk stratification for LVAD support in the elderly.

Acute decompensated heart failure: update on new and emerging evidence and directions for future research.

Acute decompensated heart failure (ADHF) is a complex clinical event associated with excess morbidity and mortality. Managing ADHF patients is challenging because of the lack of effective treatments that both reduce symptoms and improve clinical outcomes. Existing guideline recommendations are largely based on expert opinion, but several recently published trials have yielded important data to inform both current clinical practice and future research directions. New insight has been gained regarding volume management, including dosing strategies for intravenous loop diuretics and the role of ultrafiltration in patients with heart failure and renal dysfunction. Although the largest ADHF trial to date (ASCEND-HF, using nesiritide) was neutral, promising results with other investigational agents have been reported. If these findings are confirmed in phase III trials, novel compounds, such as relaxin, omecamtiv mecarbil, and ularitide, among others, may become therapeutic options. Translation of research findings into quality clinical care can not be overemphasized. Although many gaps in knowledge exist, ongoing studies will address issues around delivery of evidence-based care to achieve the goal of improving the health status and clinical outcomes of patients with ADHF.

Indications for cardiac resynchronization therapy: 2011 update from the Heart Failure Society of America Guideline Committee.

Cardiac resynchronization therapy (CRT) improves survival, symptoms, quality of life, exercise capacity, and cardiac structure and function in patients with New York Heart Association (NYHA) functional class II or ambulatory class IV heart failure (HF) with wide QRS complex. The totality of evidence supports the use of CRT in patients with less severe HF symptoms. CRT is recommended for patients in sinus rhythm with a widened QRS interval (≥150 ms) not due to right bundle branch block (RBBB) who have severe left ventricular (LV) systolic dysfunction and persistent NYHA functional class II-III symptoms despite optimal medical therapy (strength of evidence A). CRT may be considered for several other patient groups for whom evidence of benefit is clinically significant but less substantial, including patients with a QRS interval of ≥120 to <150 ms and severe LV systolic dysfunction who have persistent mild to severe HF despite optimal medical therapy (strength of evidence B), some patients with atrial fibrillation, and some with ambulatory class IV HF. Several evidence gaps remain that need to be addressed, including the ideal threshold for QRS duration, QRS morphology, lead placement, degree of myocardial scarring, and the modality for evaluating dyssynchrony. Recommendations will evolve over time as additional data emerge from completed and ongoing clinical trials.

Update on aldosterone antagonists use in heart failure with reduced left ventricular ejection fraction. Heart Failure Society of America Guidelines Committee.

Aldosterone antagonists (or mineralocorticoid receptor antagonists [MRAs]) are guideline-recommended therapy for patients with moderate to severe heart failure (HF) symptoms and reduced left ventricular ejection fraction (LVEF), and in postmyocardial infarction patients with HF. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial evaluated the MRA eplerenone in patients with mild HF symptoms. Eplerenone reduced the risk of the primary endpoint of cardiovascular death or HF hospitalization (hazard ratio [HR] 0.63, 95% confidence interval [CI] 0.54-0.74, P < .001) and all-cause mortality (adjusted HR 0.76, 95% CI 0.62-0.93, P < .008) after a median of 21 months. Based on EMPHASIS-HF, an MRA is recommended for patients with New York Heart Association (NYHA) Class II-IV symptoms and reduced LVEF (<35%) on standard therapy (Strength of Evidence A). Patients with NYHA Class II symptoms should have another high-risk feature to be consistent with the EMPHASIS-HF population (age >55 years, QRS duration >130 msec [if LVEF between 31% and 35%], HF hospitalization within 6 months or elevated B-type natriuretic peptide level). Renal function and serum potassium should be closely monitored. Dose selection should consider renal function, baseline potassium, and concomitant drug interactions. The efficacy of eplerenone in patients with mild HF symptoms translates into a unique opportunity to reduce morbidity and mortality earlier in the course of the disease.

Cardiac allograft vasculopathy: current knowledge and future direction.

Cardiac allograft vasculopathy (CAV) is a unique form of coronary artery disease affecting heart transplant recipients. Although prognosis of heart transplant recipients has improved over time, CAV remains a significant cause of mortality beyond the first year of cardiac transplantation. Many traditional and non-traditional risk factors for the development of CAV have been described. Traditional risk factors include dyslipidemia, diabetes and hypertension. Non-traditional risk factors include cytomegalovirus infection, HLA mismatch, antibody-mediated rejection, and mode of donor brain death. There is a complex interplay between immunological and non-immunological factors ultimately leading to endothelial injury and exaggerated repair response. Pathologically, CAV manifests as fibroelastic proliferation of intima and luminal stenosis. Early diagnosis is paramount as heart transplant recipients are frequently asymptomatic owing to cardiac denervation related to the transplant surgery. Intravascular ultrasound (IVUS) offers many advantages over conventional angiography and is an excellent predictor of prognosis in heart transplant recipients. Many non-invasive diagnostic tests including dobutamine stress echocardiography, CT angiography, and MRI are available; though, none has replaced angiography. This review discusses the risk factors, pathogenesis, and diagnosis of CAV and highlights some current concepts and recent developments in this field.

Isosorbide dinitrate-hydralazine improves outcomes in African Americans with heart failure.

The African American Heart Failure Trial (A-HeFT) found that African American patients with advanced heart failure fared better if the fixed-dose combination of isosorbide dinitrate and hydralazine was added to their regimen, which for most of them already included an angiotensin-converting enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB), a beta-blocker, and a diuretic (N Engl J Med 2004; 351:2049-2057). This placebo-controlled trial was the first to evaluate a therapy in a specific racial group, and it points the way to a more individualized approach to heart failure therapy.

Echocardiographic Ramp test for continuous-flow left ventricular assist devices: do loading conditions matter?

OBJECTIVES: This study investigated whether continuous AI and/or elevated mean arterial pressure (MAP) were associated with false positive results for flow obstruction in echocardiographic ramp speed tests in patients with a continuous-flow left ventricular assist device. BACKGROUND: Failure to reduce the left ventricular end-diastolic diameter (LVEDD) with increasing device speeds in a ramp test is predictive of pump obstruction. Aortic insufficiency (AI) or increased MAP can diminish the ability to unload the left ventricle. METHODS: LVEDD was plotted against device speed, and a linear function slope was calculated. A flat LVEDD slope (≥-0.16) was considered abnormal (suggestive of obstruction). Ramp test results were compared in patients with or without either AI or increased MAP at baseline speed, and receiver-operator characteristic (ROC) curves were constructed for predictors of device obstruction. Device thrombosis was confirmed by direct visualization of clot at explantation or on inspection by the manufacturer. RESULTS: Of 78 ramp tests (55 patients), 36 were abnormal (18 true positive, 18 false positive), and 42 were normal (37 true negative, 5 false negative). In patients with AI, LVEDD slope was -0.14 ± 0.17, which was consistent with device obstruction (vs. -0.25 ± 0.11 in patients without AI; p < 0.001), despite no difference in mean lactate dehydrogenase concentration between the 2 groups (1,301 ± 1,651 U/l vs. 1,354 ± 1,365 U/l; p = 0.91). Area under the ROC curve (AUC) for LVEDD slope was 0.76 and improved to 0.88 after removal of patients with AI from the study. LVEDD slope in patients with MAP ≥85 mm Hg was similar to that for device obstruction (-0.18 ± 0.07) and was abnormal in 6 of the 12 ramp tests performed. Combining LVEDD slope with lactate dehydrogenase concentration increased the AUC to 0.96 as an indicator of device obstruction. CONCLUSIONS: Abnormal loading conditions due to AI or elevated MAP may result in false positive ramp tests.

Ventriculophasic sinus arrhythmia in the orthotopic transplanted heart: mechanism of disease revisited.

BACKGROUND: Several mechanisms have been proposed for ventriculophasic sinus arrhythmia: phasic changes in baroreceptor mediated vagal input to the sinus node, mechanical effects and pressure changes caused by ventricular systole, and increased blood flow to the sinus node. We attempt to elucidate the role of SA nodal blood flow in the generation of ventriculophasic sinus arrhythmia by measuring phasic changes in PP intervals from the atrial remnants of patients who have received cardiac transplant. METHODS: A total of 16 atrial electrogram recordings were obtained from the recipient atrial remnant in 12 patients who had undergone heart transplantation at the University of Miami/Jackson Memorial Hospital. Concomitant recordings of the donor surface ECG were also obtained. Recipient atrial PP intervals that contained a QRS were measured. The QP intervals were also measured and plotted against the associated PP interval to assess the relationship between varying QP intervals and the associated PP interval. RESULTS: A linear relationship between the PP intervals and the associated QP intervals was seen in all patients. Despite widely varying QP intervals, there was little change in the PP intervals suggesting absence of ventriculophasic arrhythmia. Our linear graphs are in contrast to the typical curves seen in ventriculophasic arrhythmia that have been described by Lepeschkin. CONCLUSIONS: In our study, there appeared to be absence of ventriculophasic arrhythmia despite intact vagal innervation to the atrial remnant suggesting that the lack of pulsatile SA node blood flow may contribute to the absence of ventriculophasic arrhythmia. We conclude that the transplanted heart, when performed by the standard technique, may provide a model to study mechanisms of ventriculophasic arrhythmia.

Recipient selection and management.

Cardiac transplantation remains the definitive surgical solution for Stage D heart failure. However, the lack of availability of donor organs makes patient selection crucial to appropriate resource utilization. All feasible medical and surgical alternatives should be explored before consideration of transplantation is undertaken. A cardiac transplantation evaluation should be thorough to exclude patients with preexisting serious comorbidities, with particular attention being paid to renal dysfunction, pulmonary hypertension, and panel reactive antibody levels. Once accepted for listing as a cardiac transplantation recipient, patients are assigned a priority status based on the severity of illness. Organs are allocated on the basis on status level, blood type, body size, and length of time at a given status level.

Evaluation of patients with heart failure.

Heart failure is one of the most prevalent cardiovascular diseases in the United States, and is associated with significant morbidity, mortality, and costs. Prompt diagnosis may help decrease mortality, hospital stay, and costs related to treatment. A complete heart failure evaluation comprises a comprehensive history and physical examination, echocardiogram, and diagnostic tools that provide information regarding the etiology of heart failure, related complications, and prognosis in order to prescribe appropriate therapy, monitor response to therapy, and transition expeditiously to advanced therapies when needed. Emerging technologies and biomarkers may provide better risk stratification and more accurate determination of cause and progression.

Heart failure in African Americans: disparities can be overcome.

African Americans are disproportionately affected by heart failure, with a high prevalence at an early age. Hypertension, diabetes, obesity, and chronic kidney disease are all common in African Americans and all predispose to heart failure. Neurohormonal imbalances, endothelial dysfunction, genetic polymorphisms, and socioeconomic factors also contribute. In general, the same evidence-based treatment guidelines that apply to white patients with heart failure also apply to African Americans. However, the combination of hydralazine and isosorbide dinitrate is advised specifically for African Americans.

Impact of pre-transplant pulmonary hypertension on survival after heart transplantation: a UNOS registry analysis.

INTRODUCTION: Severe pre-transplant pulmonary hypertension (PH) has been associated with adverse short-term clinical outcomes after heart transplantation in relatively small single-center studies. The impact of pre-transplant PH on long-term survival after heart transplantation has not been examined in a large, multi-center cohort. METHODS: Adults (≥18 years) who underwent first time heart transplantation in the United States between 1987 and 2012 were retrospectively identified from the United Network for Organ Sharing registry. Pre-transplant PH was classified as mild, moderate, or severe based on pulmonary vascular resistance (PVR), trans-pulmonary gradient (TPG), and pulmonary artery (PA) mean pressure. Primary outcome was all-cause mortality. RESULTS: Data from 26,649 heart transplant recipients (mean age 52±12 years; 76% male; 76% Caucasian) were analyzed. During a mean follow-up of 5.7±4.8 years, there were 10,334 (39%) deaths. Pre-transplant PH (PVR≥2.5 WU) was a significant predictor of mortality (hazard ratio 1.10, 95% confidence interval 1.05-1.14, p<0.0001) in multivariable analysis. However, the severity of pre-transplant PH (mild/moderate vs. severe) did not affect short or long-term survival. Similarly, even in patients who were supported with either a left ventricular assist device or a total artificial heart prior to transplant, severe pre-transplant PH was not associated with worse survival when compared to patients with mild/moderate pre-transplant PH. CONCLUSION: Pre-transplant PH (PVR≥2.5 WU) is associated with a modest increase in mortality when compared to patients without pre-transplant PH. However, the severity of pre-transplant PH, assessed by PVR, TPG, or mean PA pressure, is not a discriminating factor for poor survival in patients listed for heart transplantation.

Substance abuse at the time of left ventricular assist device implantation is associated with increased mortality.

BACKGROUND: Advanced heart failure teams are often faced with the decision of whether or not to offer a left ventricular assist device (LVAD) to patients who have end-stage heart failure and recent or ongoing substance abuse. The outcomes of these patients after LVAD implantation are unknown. METHODS: Baseline predictors and outcomes were collected and analyzed from patients with active substance abuse and a cohort of patients without active substance abuse matched for age, INTERMACS profile and year of implantation. The primary outcome was all-cause mortality. Secondary outcomes included rates of listing for cardiac transplantation, transplantation and chronic drive-line infection. RESULTS: The cohort consisted of 20 consecutive LVAD recipients with active substance abuse and 40 recipients without active substance abuse. During a median follow-up period of 2.3 years (IQR 1.4 to 3.6), the substance abuse group had 3.2 times the rate (hazard) of death compared with a matched cohort (HR 3.2, 95% CI 1.2 to 8.0, p < 0.05). Furthermore, the rate of listing for transplant was 69% lower (rate ratio 0.31, p < 0.0005), rate of cardiac transplant was 89% lower (rate ratio 0.11, p < 0.0005), and risk of chronic drive-line infection was 5.4 times higher (rate ratio 5.4, p < 0.0005) in the substance abuse group. CONCLUSIONS: Active substance abuse in patients who received an LVAD was associated with increased mortality and overall poor outcomes. Larger scale data will be needed to confirm these findings and to inform decision-making in this population.

Endothelial dysfunction and cardiac allograft vasculopathy.

Cardiac allograft vasculopathy remains a major challenge to long-term survival after heart transplantation. Endothelial injury and dysfunction, as a result of multifactorial immunologic and nonimmunologic insults in the donor and the recipient, are prevalent early after transplant and may be precursors to overt cardiac allograft vasculopathy. Current strategies for managing cardiac allograft vasculopathy, however, rely on the identification and treatment of established disease. Improved understanding of mechanisms leading to endothelial dysfunction in heart transplant recipients may provide the foundation for the development of sensitive screening techniques and preventive therapies.

Postcardiac transplant survival in the current era in patients receiving continuous-flow left ventricular assist devices.

OBJECTIVES: Continuous-flow left ventricular assist devices have become the standard of care for patients with heart failure requiring mechanical circulatory support as a bridge to transplant. However, data on long-term post-transplant survival for these patients are limited. We evaluated the effect of continuous-flow left ventricular assist devices on postcardiac transplant survival in the current era. METHODS: All patients who received a continuous-flow left ventricular assist device as a bridge to transplant at a single center from June 2005 to September 2011 were evaluated. RESULTS: Of the 167 patients who received a continuous-flow left ventricular assist device as a bridge to transplant, 77 (46%) underwent cardiac transplantation, 27 died before transplantation (16%), and 63 (38%) remain listed for transplantation and continued with left ventricular assist device support. The mean age of the transplanted patients was 54.5 ± 11.9 years, 57% had an ischemic etiology, and 20% were women. The overall mean duration of left ventricular assist device support before transplantation was 310 ± 227 days (range, 67-1230 days). The mean duration of left ventricular assist device support did not change in patients who had received a left ventricular assist device in the early period of the study (2005-2008, n = 62) compared with those who had received a left ventricular assist device later (2009-2011, n = 78, 373 vs 392 days, P = NS). In addition, no difference was seen in survival between those patients supported with a left ventricular assist device for fewer than 180 days or longer than 180 days before transplantation (P = NS). The actuarial survival after transplantation at 30 days and 1, 3, and 5 years by Kaplan-Meier analysis was 98.7%, 93.0%, 91.1%, and 88.0%, respectively. CONCLUSIONS: The short- and long-term post-transplant survival for patients bridged with a continuous-flow left ventricular assist device in the current era has been excellent. Furthermore, the duration of left ventricular assist device support did not affect post-transplant survival. The hemodynamic benefits of ventricular unloading with continuous-flow left ventricular assist devices, in addition to their durability and reduced patient morbidity, have contributed to improved post-transplant survival.

Qualitative Perfusion Cardiac Magnetic Resonance Imaging Lacks Sensitivity in Detecting Cardiac Allograft Vasculopathy.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major complication after heart transplantation, requiring frequent surveillance angiography. Though cardiac angiography is the gold standard, it is insensitive in detecting transplant vasculopathy and invasive. Perfusion MRI provides a noninvasive alternative and possibly a useful modality for studying CAV. We sought to compare the accuracy of qualitative perfusion MRI to coronary angiography in detecting CAV. METHODS: A retrospective analysis was performed in 68 heart transplant recipients who had simultaneous surveillance cardiac MRI and coronary angiogram and who underwent transplantation between 2000 and 2007. We compared results of qualitative MRI to those of the cardiac angiogram. Sensitivity and specificity of MR were calculated. RESULTS: Sixty-eight patients underwent both cardiac MRI and coronary angiogram. 73.5% were male; mean age was 45.37 ± 14 years. Mean duration of heart transplantation was 7.9 ± 5.2 years. The mean ejection fraction was 55% in the patients without CAV and 57.4% in those with CAV. There were 48 normal and 24 abnormal MRI studies. The overall sensitivity was 41% and specificity was 74%. CONCLUSIONS: Qualitative assessment of perfusion cardiac MR has low sensitivity and moderate specificity for detecting CAV. The sensitivity of MRI was slightly improved with severity of disease.

Lessons learned from experience with over 100 consecutive HeartMate II left ventricular assist devices.

BACKGROUND: Continuous-flow left ventricular assist devices (LVADs) such as the HeartMate II have become the therapy of choice in patients with end-stage heart failure. The aim of this study is to report the outcomes in patients receiving the HeartMate II LVAD at a single center and review the lessons learned from this experience. METHODS: From June 2005 to June 2010, 130 consecutive patients received the HeartMate II LVAD. Of these, 102 were bridge-to-transplant (BTT), 17 destination therapy, and 11 exchanges for failed HeartMate XVE. This study focuses on the 102 BTT patients. The HeartMate II was approved by the US Food and Drug Administration (FDA) as BTT in April 2008 and 64 patients received this device as BTT since that date. We review our experience with the device as BTT and report on patient survival and adverse events as well as the impact of FDA approval on outcomes. RESULTS: Overall, mean age was 52.6 ± 12.8 years; 26 (25.5%) were female. Disease etiology was ischemic in 58, nonischemic in 36, and other in 8. Overall, 30-day, 6-month, and 1-year survival for the BTT patients was 95.1%, 83.5%, and 78.8%, respectively. The 6-month survival in 38 patients in the clinical trial (pre-FDA) was 88.8% and was not statistically significant compared with the 76.2% 6-month survival in the 64 patients in the post-FDA approval period (p value = 0.1). Major adverse events among the 102 BTT patients included right ventricular failure in 5 (4.9%), LVAD driveline infections in 25 (24.5%), neurologic events in 10 (9.8%), and gastrointestinal bleeding in 18 (17.6%) patients. In addition, 1 patient (0.98%) had pump thrombus requiring device replacement. CONCLUSIONS: Despite significant morbidity, use of the HeartMate II LVAD as BTT provides excellent hemodynamic support and is associated with excellent survival and low mortality. In addition, there needs to be improvement and focused strategies in the areas of gastrointestinal bleeding, driveline infections, and adverse neurologic events for these devices to be able to provide a real long-term alternative to heart transplantation.