Keyur B. Shah

Enhanced Interleukin-1 Activity Contributes to Exercise Intolerance in Patients with Systolic Heart Failure

Background Heart failure (HF) is a complex clinical syndrome characterized by impaired cardiac function and poor exercise tolerance. Enhanced inflammation is associated with worsening outcomes in HF patients and may play a direct role in disease progression. Interleukin-1β (IL-1β) is a pro-inflammatory cytokine that becomes chronically elevated in HF and exerts putative negative inotropic effects. Methods and Results We developed a model of IL-1β-induced left ventricular (LV) dysfunction in healthy mice that exhibited a 32% reduction in LV fractional shortening (P<0.001) and a 76% reduction in isoproterenol response (P<0.01) at 4 hours following a single dose of IL-1β 3 mcg/kg. This phenotype was reproducible in mice injected with plasma from HF patients and fully preventable by pretreatment with IL-1 receptor antagonist (anakinra). This led to the design and conduct of a pilot clinical to test the effect of anakinra on cardiopulmonary exercise performance in patients with HF and evidence of elevated inflammatory signaling (n = 7). The median peak oxygen consumption (VO2) improved from 12.3 [10.0, 15.2] to 15.1 [13.7, 19.3] mL·kg–1·min–1 (P = 0.016 vs. baseline) and median ventilator efficiency (VE/VCO2 slope) improved from 28.1 [22.8, 31.7] to 24.9 [22.9, 28.3] (P = 0.031 vs. baseline). Conclusions These findings suggest that IL-1β activity contributes to poor exercise tolerance in patients with systolic HF and identifies IL-1β blockade as a novel strategy for pharmacologic intervention. Trial Registration ClinicalTrials.gov NCT01300650

Heart failure with preserved ejection fraction: Refocusing on diastole

Heart failure (HF) with preserved ejection fraction (HFpEF) is a clinical syndrome of exercise intolerance and/or congestion, in the presence of a left ventricular (LV) ejection fraction within the normal limits (i.e. LVEF>50%). Determining the presence of impaired LV relaxation and/or filling (diastolic dysfunction) in HFpEF is needed to pragmatically to distinguish it from other cardiac and non-cardiac conditions where symptoms are not due to HF. There are multiple mechanisms for diastolic dysfunction ranging from structural abnormalities to functional derangements in HFpEF yet tailored therapies are lacking. Treatments proven effective in HF with systolic dysfunction have failed to show significant benefit in patients with HFpEF, which prognosis remains poor. This review will discuss the challenges inherent to the use of diagnostic criteria for HFpEF, differential diagnosis, prognostic evaluation, and treatment, highlighting the need for more research in this field.

Prognostic Utility of ST2 in Patients with Acute Dyspnea and Preserved Left Ventricular Ejection Fraction

BACKGROUND Soluble ST2 (sST2), an interleukin-1 receptor family member, is an emerging risk indicator for patients with cardiovascular disease. We evaluated the prognostic role of sST2 for patients presenting to the emergency department with acute dyspnea, with a focus on those with preserved left ventricular ejection fraction (LVEF ≥50%), as risk stratification is often most complex in this subgroup. METHODS We conducted a post hoc analysis of 387 patients [39% female, mean (SD) age 57.6 (14.5) years] presenting to the emergency department with dyspnea and followed for 1 year (97% complete follow-up). We examined clinical data, concentrations of serum biomarkers [sST2, amino-terminal pro-B-type natriuretic peptide (NT-proBNP)], and transthoracic echocardiography. RESULTS Patients had a median sST2 concentration of 38.4 U/mL [interquartile range (IQR) 25.5-64 U/mL]. Forty-six patients (12%) died during follow-up. Log sST2 [hazard ratio (HR) (95% CI) 2.85 (2.04-3.99), P < 0.001rsqb] and log NT-proBNP [1.28 (1.13-1.45), P < 0.001] concentrations were significant predictors of mortality at 1 year. After multivariate adjustment, only sST2 remained predictive of mortality [per log: 2.14 (1.37-3.38), P = 0.001]. In the subpopulation of individuals with normal systolic function (n = 200), only sST2 continued to predict mortality after multivariate adjustment [per log: 2.57 (1.12-5.91), P = 0.03]. Only NT-proBNP, but not sST2, concentrations correlated with multiple echocardiographic indices of left ventricular diastolic function. CONCLUSIONS sST2 is a strong predictor of mortality in patients presenting with acute dyspnea, particularly those with preserved LVEF, and may be useful for triage and risk stratification of this challenging group.

Preoperative endogenous ouabain predicts acute kidney injury in cardiac surgery patients.

Objectives:Acute kidney injury is a frequent complication of cardiac surgery and increases morbidity and mortality. As preoperative biomarkers predicting the development of acute kidney injury are not available, we have tested the hypothesis that preoperative plasma levels of endogenous ouabain may function as this type of biomarker. Rationale and Design:Endogenous ouabain is an adrenal stress hormone associated with adverse cardiovascular outcomes. Its involvement in acute kidney injury is unknown. With studies in patients and animal settings, including isolated podocytes, we tested the above mentioned hypothesis. Patients:Preoperative endogenous ouabain was measured in 407 patients admitted for elective cardiac surgery and in a validation population of 219 other patients. We also studied the effect of prolonged elevations of circulating exogenous ouabain on renal parameters in rats and the influence of ouabain on podocyte proteins both “in vivo” and “in vitro.” Main Results:In the first group of patients, acute kidney injury (2.8%, 8.3%, 20.3%, p < 0.001) and ICU stay (1.4±0.38, 1.7±0.41, 2.4±0.59 days, p = 0.014) increased with each incremental preoperative endogenous ouabain tertile. In a linear regression analysis, the circulating endogenous ouabain value before surgery was the strongest predictor of acute kidney injury. In the validation cohort, acute kidney injury (0%, 5.9%, 8.2%, p < 0.0001) and ICU stay (1.2±0.09, 1.4±0.23, 2.2±0.77 days, p = 0.003) increased with the preoperative endogenous ouabain tertile. Values for preoperative endogenous ouabain significantly improved (area under curve: 0.85) risk prediction over the clinical score alone as measured by integrate discrimination improvement and net reclassification improvement. Finally, in the rat model, elevated circulating ouabain reduced creatinine clearance (–18%, p < 0.05), increased urinary protein excretion (+ 54%, p < 0.05), and reduced expression of podocyte nephrin (–29%, p < 0.01). This last finding was replicated ex vivo by incubating podocyte primary cell cultures with low-dose ouabain. Conclusions:Preoperative plasma endogenous ouabain levels are powerful biomarkers of acute kidney injury and postoperative complications and may be a direct cause of podocyte damage.

Exercise blood pressure response during assisted circulatory support: Comparison of the total artifical heart with a left ventricular assist device during rehabilitation

BACKGROUND The total artificial heart (TAH) consists of two implantable pneumatic pumps that replace the heart and operate at a fixed ejection rate and ejection pressure. We evaluated the blood pressure (BP) response to exercise and exercise performance in patients with a TAH compared to those with a with a continuous-flow left ventricular assist device (LVAD). METHODS We conducted a single-center, retrospective study of 37 patients who received a TAH and 12 patients implanted with an LVAD. We measured the BP response during exercise, exercise duration and change in tolerated exercise workload over an 8-week period. RESULTS In patients with a TAH, baseline BP was 120/69 ± 13/13, exercise BP was 118/72 ± 15/10 and post-exercise BP was 120/72 ± 14/12. Mean arterial BP did not change with exercise in patients with a TAH (88 ± 10 vs 88 ± 11; p = 0.8), but increased in those with an LVAD (87 ± 8 vs 95 ± 13; p < 0.001). Although the mean arterial BP (MAP) was negatively correlated with metabolic equivalents (METs) achieved during exercise, the association was not statistically significant (β = -0.1, p = 0.4). MAP correlated positively with METs achieved in patients with LVADs (MAP: β = 0.26, p = 0.04). Despite the abnormal response to exercise, patients with a TAH participated in physical therapy (median: 5 days; interquartile range [IQR] 4 to 7 days) and treadmill exercise (19 days; IQR: 13 to 35 days) early after device implantation, with increased exercise intensity and duration over time. CONCLUSIONS During circulatory support with a TAH, the BP response to exercise was blunted. However, aerobic exercise training early after device implantation was found to be safe and feasible in a supervised setting.

Octreotide for left ventricular assist device-related gastrointestinal hemorrhage: can we stop the bleeding?

Left ventricular support devices (LVADs) are associated with a propensity toward gastrointestinal bleeding. A postulated mechanism is related to gastrointestinal arteriovenous malformations secondary to nonpulsatile flow. We describe a case of LVAD-related, gastrointestinal bleeding successfully treated with a combination of subcutaneous and intramuscular depot formulations of octreotide.

Lack of Diagnostic and Prognostic Utility of Circulating Plasma Myeloperoxidase Concentrations in Patients Presenting with Dyspnea

BACKGROUND Plasma myeloperoxidase (MPO), an inflammatory biomarker, is associated with increased mortality in patients with acute coronary syndrome or chronic left ventricular systolic dysfunction. We sought to assess the diagnostic accuracy of MPO for acute decompensated heart failure (ADHF) and its prognostic value for patients with acute dyspnea. METHODS In a prospective, observational study conducted in 5 US centers, 412 patients [mean (SD) age, 58 (14) years; 39% women] presenting with dyspnea to the emergency department were enrolled and followed for 1 year. Clinical, serum/plasma biomarker [MPO, B-type natriuretic peptide (BNP), N-terminal proBNP (NT-proBNP)], and transthoracic echocardiographic data were obtained. RESULTS We observed no differences in MPO concentration (P = 0.07) between patients with ADHF [n = 147; median, 553 pmol/L; interquartile range (IQR), 415-738 pmol/L] and those without ADHF (n = 265; median, 576 pmol/L; IQR, 413-884 pmol/L). The diagnostic accuracy for ADHF was excellent for BNP [area under the ROC curve (AUC), 0.90; P < 0.001] and NT-proBNP (AUC, 0.90; P < 0.001) but poor for MPO (AUC, 0.46; P = 0.18). MPO appeared uncorrelated with echocardiographic measures of cardiac structure or function. The observed 1-year mortality rate was 12%. MPO concentration also appeared unrelated to mortality [hazard ratio, 1.25 (above vs below the median); 95% CI, 0.71-2.18], whereas BNP (P = 0.001) and NT-proBNP (P < 0.001) were significant predictors of mortality. MPO concentration provided no prognostic information in addition to that of BNP or NT-proBNP concentration. CONCLUSIONS Unlike natriuretic peptides, MPO concentration was not predictive of ADHF diagnosis or 1-year mortality in a heterogeneous sample of emergency department patients with acute dyspnea.

Implantable Mechanical Circulatory Support: Demystifying Patients With Ventricular Assist Devices and Artificial Hearts

Engineering advancements have expanded the role for mechanical circulatory support devices in the patient with heart failure. More patients with mechanical circulatory support are being discharged from the implanting institution and will be seen by clinicians outside the immediate surgical or heart‐failure team. This review provides a practical understanding of device design and physiology, general troubleshooting, and limitations and complications for implantable left ventricular assist devices (pulsatile‐flow and continuous‐flow pumps) and the total artificial heart.

Exercise physiology, testing, and training in patients supported by a left ventricular assist device

The left ventricular assist device (LVAD) is an accepted treatment alternative for the management of end-stage heart failure. As we move toward implantation of LVADs in less severe cases of HF, scrutiny of functional capacity and quality of life becomes more important. Patients demonstrate improvements in exercise capacity after LVAD implantation, but the effect is less than predicted. Exercise training produces multiple beneficial effects in heart failure patients, which would be expected to improve quality of life. In this review, we describe factors that are thought to participate in the persistent exercise impairment in LVAD-supported patients, summarize current knowledge about the effect of exercise training in LVAD-supported patients, and suggest areas for future research.

Psychosocial assessment of candidates and risk classification of patients considered for durable mechanical circulatory support.

BACKGROUND The psychosocial assessment of candidates for transplantation (PACT), developed to assess candidates for heart transplant, has not been routinely used to assess left ventricular assist device (LVAD) candidacy. We examined the efficacy of the PACT to assess psychosocial outcomes in LVAD patients. METHODS We reviewed patients who received LVAD implants between June 2006 and April 2011 and retrospectively applied the PACT. We determined the accuracy of identifying social success with the PACT and revised domains to reflect criteria influencing social success for LVAD patients. RESULTS Forty-eight patients (72% men, 44% non-white, 50.4 years old) were divided into high-scoring and low-scoring groups. Nine patients with low PACT scores were falsely categorized as high-risk, whereas 4 with high scores had poor social outcomes. The score had a high positive-predictive value (0.86) but low negative-predictive value (0.31). The PACT was revised (modified [m]PACT) to measure indicators, such as social support and understanding of care requirements, identified to more closely affect LVAD outcome. The mPACT exhibited improved accuracy. A reclassification table was developed, and the net reclassification index was 0.32. The percentage of patients incorrectly classified for social risk decreased from 27% with the PACT to 8% with the mPACT. Patients with higher mPACT scores had decreased 30-day readmission rates (26% vs 67%, p = 0.045) after device implantation. CONCLUSIONS By emphasizing social support, psychologic health, lifestyle factors, and device understanding, the mPACT showed improved performance in risk-stratifying candidates for LVAD therapy. Prospective validation is warranted.