A Comprehensive and Contemporary Review on Immunosuppression Therapy for Heart Transplantation.

Heart transplantation is the standard of therapy for patients with end-stage heart disease. Since the first human-to-human heart transplantation, performed in 1967, advances in organ donation, surgical techniques, organ preservation, perioperative care, immunologic risk assessment, immunosuppression agents, monitoring of graft function and surveillance of long-term complications have drastically increased recipient survival. However, there are yet many challenges in the modern era of heart transplantation in which immunosuppression may play a key role in further advances in the field. A fine-tuning of immune modulation to prevent graft rejection while avoiding side effects from over immunosuppression has been the vital goal of basic and clinical research. Individualization of drug choices and strategies, taking into account the recipient's clinical characteristics, underlying heart failure diagnosis, immunologic risk and comorbidities seem to be the ideal approaches to improve post-transplant morbidity and survival while preventing both rejection and complications of immunosuppression. The aim of the present review is to provide a practical, comprehensive overview of contemporary immunosuppression in heart transplantation. Clinical evidence for immunosuppressive drugs is reviewed and practical approaches are provided. Cardiac allograft rejection classification and up-to-date management are summarized. Expanding therapies, such as photophoresis, are outlined. Drug-to-drug interactions of immunosuppressive agents focused on cardiovascular medications are summarized. Special situations involving heart transplantation such as sarcoidosis, Chagas diseases and pediatric immunosuppression are also reviewed. The evolution of phamacogenomics to individualize immunosuppressive therapy is described. Finally, future perspectives in the field of immunosuppression in heart transplantation are highlighted.

Ultrafiltration versus diuretics for the treatment of fluid overload in patients with heart failure: a hospital cost analysis.

Background: Heart failure (HF) is a common, serious disease in the US and Europe. Patients with HF often require treatment for fluid overload, resulting in costly inpatient visits; however, limited evidence exists on the costs of alternative treatments. This study performed a cost-analysis of ultrafiltration (UF) vs diuretic therapy (DIUR-T) for patients with HF from the hospital perspective. Methods: The model used clinical data from the literature and hospital data from the Healthcare Cost and Utilization Project to follow a decision-analytic framework reflecting treatment decisions, probabilistic outcomes, and associated costs for treating patients with HF and hypervolemia with veno-venous UF or intravenous DIUR-T. A 90-day timeframe was considered to account for hospital readmissions beyond 30 days. Sensitivity and scenario analyses were performed to gauge the robustness of the results. Results: Although initial hospitalization costs were higher, fluid removal by UF reduced hospital readmission days, leading to cost savings of $3,975 (14.4%) at the 90-day follow-up (UF costs, $23,633; DIUR-T costs, $27,608). Conclusions: UF is a viable alternative to DIUR-T when treating fluid overload in HF patients because it reduces hospital readmission rates and durations, which substantially lowers costs over a 90-day period compared to DIUR-T.

Pulmonary Artery Pressure-Guided Management of Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND: Despite increased use of guideline-directed medical therapy (GDMT), some patients with heart failure and reduced ejection fraction (HFrEF) remain at high risk for hospitalization and mortality. Remote monitoring of pulmonary artery (PA) pressures provides clinicians with actionable information to help further optimize medications and improve outcomes. OBJECTIVES: CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients trial) analyzed PA pressure-guided heart failure (HF) management in patients with HFrEF based on their ability to tolerate GDMT. METHODS: CHAMPION enrolled 550 patients with chronic HF regardless of left ventricular ejection fraction. A pre-specified sub-group analysis compared HF hospitalization and mortality rates between treatment and control groups in HFrEF patients (left ventricular ejection fraction ≤40%). Post hoc analyses in patients who tolerated GDMT were also performed. Hospitalizations and mortality were assessed using Andersen-Gill and Cox proportional hazards models. RESULTS: In 456 patients with HFrEF, HF hospitalization rates were 28% lower in the treatment group than in the control group (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.59 to 0.88; p = 0.0013), with a strong trend for 32% lower mortality (HR: 0.68; 95% CI: 0.45 to 1.02; p = 0.06). A 445-patient subset received at least 1 GDMT (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, or beta-blocker) at baseline; these patients had 33% lower HF hospitalization rates (HR: 0.67; 95% CI: 0.54 to 0.82; p = 0.0002) and 47% lower mortality (HR: 0.63; 95% CI: 0.41 to 0.96, p = 0.0293) than controls. Compared with controls, patients receiving both components of optimal GDMT (n = 337) had 43% lower HF hospitalizations (HR: 0.57; 95% CI: 0.45 to 0.74; p < 0.0001) and 57% lower mortality (HR: 0.43; 95% CI: 0.24 to 0.76; p = 0.0026). CONCLUSIONS: PA pressure-guided HF management reduces morbidity and mortality in patients with HFrEF on GDMT, underscoring the important synergy of addressing hemodynamic and neurohormonal targets of HF therapy. (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients [CHAMPION]; NCT00531661).

Interventions Linked to Decreased Heart Failure Hospitalizations During Ambulatory Pulmonary Artery Pressure Monitoring.

OBJECTIVES: This study sought to analyze medical therapy data from the CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in Class III Heart Failure) trial to determine which interventions were linked to decreases in heart failure (HF) hospitalizations during ambulatory pulmonary artery (PA) pressure-guided management. BACKGROUND: Elevated cardiac filling pressures, which increase the risk of hospitalizations and mortality, can be detected using an ambulatory PA pressure monitoring system before onset of symptomatic congestion allowing earlier intervention to prevent HF hospitalizations. METHODS: The CHAMPION trial was a randomized, controlled, single-blind study of 550 patients with New York Heart Association functional class III HF with a HF hospitalization in the prior year. All patients undergoing implantation of the ambulatory PA pressure monitoring system were randomized to the active monitoring group (PA pressure-guided HF management plus standard of care) or to the blind therapy group (HF management by standard clinical assessment), and followed for a minimum of 6 months. Medical therapy data were compared between groups to understand what interventions produced the significant reduction in HF hospitalizations in the active monitoring group. RESULTS: Both groups had similar baseline medical therapy. After 6 months, the active monitoring group experienced a higher frequency of medications adjustments; significant increases in the doses of diuretics, vasodilators, and neurohormonal antagonists; targeted intensification of diuretics and vasodilators in patients with higher PA pressures; and preservation of renal function despite diuretic intensification. CONCLUSIONS: Incorporation of a PA pressure-guided treatment algorithm to decrease filling pressures led to targeted changes, particularly in diuretics and vasodilators, and was more effective in reducing HF hospitalizations than management of patient clinical signs or symptoms alone.

Pathophysiology of the cardiorenal syndromes: executive summary from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI).

Cardiorenal syndromes (CRS) have been recently classified into five distinct entities, each with different major pathophysiologic mechanisms. CRS type 1 most commonly occurs in the setting of acutely decompensated heart failure where approximately 25% of patients develop a rise in serum creatinine and a reduction of urine output after the first several doses of intravenous diuretics. Altered cardiac and renal hemodynamics are believed to be the most important determinants of CRS type 1. CRS type 2 is the hastened progression of chronic kidney disease (CKD) in the setting of chronic heart failure. Accelerated renal cell apoptosis and replacement fibrosis is considered to be the dominant mechanism. CRS type 3 is acutely decompensated heart failure after acute kidney injury from inflammatory, toxic, or ischemic insults. This syndrome is precipitated by salt and water overload, acute uremic myocyte dysfunction, and neurohormonal dysregulation. CRS type 4 is manifested by the acceleration of the progression of chronic heart failure in the setting of CKD. Cardiac myocyte dysfunction and fibrosis, so-called 'CKD cardiomyopathy', is believed to be the predominant pathophysiologic mechanism. Type 5 CRS is simultaneous acute cardiac and renal injury in the setting of an overwhelming systemic insult such as sepsis. In this scenario, the predominant pathophysiological disturbance is microcirculatory dysfunction as a result of acutely abnormal immune cell signaling, catecholamine cellular toxicity, and enzymatic activation which result in simultaneous organ injury often extending beyond both the heart and the kidneys. This paper will summarize these and other key findings from an international consensus conference on the spectrum of pathophysiologic mechanisms at work in the CRS.

Cardiorenal syndrome type 4: insights on clinical presentation and pathophysiology from the eleventh consensus conference of the Acute Dialysis Quality Initiative (ADQI).

In developed countries, the continuing rise in the prevalence of hypertension, hyperlipidemia and diabetes has contributed to an overall increase in the incidence of both cardiovascular disease (CVD) and chronic kidney disease (CKD). The observation that even modest reductions in renal function correlate with increased CVD morbidity and mortality has led to the recognition that CKD is an independent risk factor for CVD. Conversely, there is a growing recognition that many pathologic conditions that contribute to CVD, including coronary artery disease, left ventricular hypertrophy and diastolic dysfunction, can accelerate the decline in renal function. In addition, physiologic mechanisms designed to compensate for reduced glomerular filtration rate including activation of the renin-angiotensin-aldosterone axis, the release of fibroblastic growth factor 23 and other mechanisms for calcium-phosphate homeostasis as well as and the pathophysiologic effects of uremic toxins can also directly contribute to CVD. The end result of the interaction between changes in pressure and volume overload and the physiologic compensation for the loss of function in both the heart and the kidney leads to accelerated decline in both organ systems. This complex physiologic and pathophysiologic interplay between the cardiovascular and renal systems is collectively referred to as the cardiorenal syndrome. The discussion which follows is aimed at outlining the pathophysiologic mechanisms linking advanced CKD (4 and 5) to the development of cardiac abnormalities which occur with unique frequency and severity in patients with severe impairment of renal function.

Burden of sodium abnormalities in patients hospitalized for heart failure.

Hyponatremia presumably is associated with adverse clinical outcomes in patients with congestive heart failure (CHF), but risk thresholds and economic burden are less studied. The authors analyzed 115,969 patients hospitalized for CHF and grouped them by serum sodium levels (severe hyponatremia, ≤130 mEq/L; hyponatremia, 131-135 mEq/L; normonatremia, 136-145 mEq/L; hypernatremia, >145 mEq/L). Univariable and multivariable analyses on the associated clinical and economic outcomes were performed. The most common abnormality was hyponatremia (15.9%), followed by severe hyponatremia (5.3%) and hypernatremia (3.2%). Hospital mortality was highest for severe hyponatremia (7.6%), followed by hypernatremia (6.7%) and hyponatremia (4.9%) (P<.0001). Compared with normonatremia, risk-adjusted mortality was highest for severe hyponatremia (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.59-1.99), followed by hypernatremia (OR, 1.55; 95% CI, 1.34-1.80) and hyponatremia (OR, 1.29; 95% CI, 1.19-1.40; all P<.0001). Risk-adjusted hospital prolongation was greater for each level of sodium abnormality than for normonatremia, ranging from 0.42 (CI, 0.26-0.60) days for hypernatremia to 1.28 (CI, 1.11-1.47) days for severe hyponatremia. Risk-adjusted attributable hospital cost increase was highest for severe hyponatremia ($1132; CI, $856-$1425; all (P<.0001). Sodium abnormalities were common in patients hospitalized for CHF. Adverse outcomes resulted not only from severe hyponatremia, but also from mild hyponatremia and hypernatremia.

Early vasoactive drugs improve heart failure outcomes.

Vasoactive therapy is often used to treat acute decompensated heart failure (ADHF). The authors sought to determine whether clinical outcomes are temporally associated with time to vasoactive therapy (vasoactive time) in ADHF. Using the Acute Decompensated Heart Failure (ADHERE) Registry, the authors examined the relationship between vasoactive time and inpatient mortality within 48 hours of hospitalization. Vasoactive agents were used early (defined as <6 hours) in 22,788 (63.8%) patients and late in 12,912 (36.2%). Median vasoactive time was 1.7 and 14.7 hours in the early and late groups, respectively. In-hospital mortality was significantly lower in the early group (odds ratio, 0.87; 95% confidence interval, 0.79-0.96; P=.006), and the adjusted odds of death increased 6.8% for every 6 hours of treatment delay (95% confidence interval, 4.2-9.6; P<.0001). Early vasoactive initiation is associated with improved outcomes in patients hospitalized for ADHF.

Characteristics of "Stage D" heart failure: insights from the Acute Decompensated Heart Failure National Registry Longitudinal Module (ADHERE LM).

BACKGROUND: An improved understanding of the characteristics, treatment, and outcome of patients with "Stage D" heart failure (HF) may improve patient outcomes. We conducted an analysis of the ADHERE LM to enhance this understanding. METHODS: ADHERE LM is a multicenter registry designed specifically to prospectively collect observational data on chronic Stage D HF. The findings were analyzed and compared to data from ADHERE CM, a multicenter registry designed to prospectively collect data on the entire spectrum of acute decompensated HF. Descriptive statistics and Kaplan-Meier analysis were used to evaluate data from all 1433 patients in ADHERE LM. RESULTS: Compared to patients with acute decompensated HF, patients with chronic Stage D HF tended to be younger (69.6 vs 72.8 years), males (65% vs 49%), with hyperlipidemia/dyslipidemia (65% vs 41%), and with coronary artery disease (73% vs 57%). In Stage D patients, use of intravenous diuretics (73%) and vasoactive agents (84%) was common. Kaplan-Meier-estimated 1-year survival was 71.9% (95% CI 69.3%-74.5%) and estimated 1-year freedom from hospitalization or death was 32.9% (95% CI 30.2%-35.6%). CONCLUSIONS: Patients with Stage D HF are frequently males with dyslipidemia and coronary artery disease. Morbidity and mortality are high. Therapeutic decisions based on studies in HF patients with different characteristics may not be applicable; additional research is needed to determine optimal therapeutic regimens for these patients.