John A. Jarcho

CLINICAL ASSESSMENT IDENTIFIES HEMODYNAMIC PROFILES THAT PREDICT OUTCOMES IN PATIENTS ADMITTED WITH HEART FAILURE

OBJECTIVES This study was designed to determine the relevance of a proposed classification for advanced heart failure (HF). Profiles based on clinical assessment of congestion and perfusion at the time of hospitalization were compared with subsequent outcomes. BACKGROUND Optimal design of therapy and trials for advanced HF remains limited by the lack of simple clinical profiles to characterize patients. METHODS Prospective analysis was performed for 452 patients admitted to the cardiomyopathy service at the Brigham and Womens Hospital with a diagnosis of HF. Patients were classified by clinical assessment into four profiles: profile A, patients with no evidence of congestion or hypoperfusion (dry-warm, n = 123); profile B, congestion with adequate perfusion (wet-warm, n = 222); profile C, congestion and hypoperfusion (wet-cold, n = 91); and profile L, hypoperfusion without congestion (dry-cold, n = 16). Other standard predictors of outcome were included and patients were followed for the end points of death (n = 117) and death or urgent transplantation (n = 137) at one year. RESULTS Survival analysis showed that clinical profiles predict outcomes in HF. Profiles B and C increase the risk of death plus urgent transplantation by univariate (hazard ratio [HR] 1.83, p = 0.02) and multivariate analyses (HR 2.48, p = 0.003). Moreover, clinical profiles add prognostic information even when limited to patients with New York Heart Association (NYHA) class III/IV symptoms (profile B: HR 2.23, p = 0.026; profile C: HR 2.73, p = 0.009). CONCLUSIONS Simple clinical assessment can be used to define profiles in patients admitted with HF. These profiles predict outcomes and may be used to guide therapy and identify populations for future investigation.

Mapping a gene for familial hypertrophic cardiomyopathy to chromosome 14q1

To identify the chromosomal location of a gene responsible for familial hypertrophic cardiomyopathy, we used clinical and molecular genetic techniques to evaluate the members of a large kindred. Twenty surviving and 24 deceased family members had hypertrophic cardiomyopathy; 58 surviving members were unaffected. Genetic-linkage analyses were performed with polymorphic DNA loci dispersed throughout the entire genome, to identify a locus that was inherited with hypertrophic cardiomyopathy in family members. The significance of the linkage detected between the disease locus and polymorphic loci was assessed by calculating a lod score (the logarithm of the probability of observing coinheritance of two loci, assuming that they are genetically linked, divided by the probability of detecting coinheritance if they are unlinked). A DNA locus (D14S26), previously mapped to chromosome 14 and of unknown function, was found to be coinherited with the disease in this family. No instances of recombination were observed between the locus for familial hypertrophic cardiomyopathy and D14S26, yielding a lod score of +9.37 (theta = 0). These data indicate that in this kindred, the odds are greater than 2,000,000,000:1 that the gene responsible for familial hypertrophic cardiomyopathy is located on chromosome 14 (band q1).

Rosuvastatin pharmacokinetics in heart transplant recipients administered an antirejection regimen including cyclosporine.

Cyclosporine (INN, ciclosporin) increases the systemic exposure of all statins. Therefore rosuvastatin pharmacokinetic parameters were assessed in an open‐label trial involving stable heart transplant recipients (≥6 months after transplant) on an antirejection regimen including cyclosporine. Rosuvastatin has been shown to be a substrate for the human liver transporter organic anion transporting polypeptide C (OATP‐C). Inhibition of this transporter could increase plasma concentrations of rosuvastatin. Therefore the effect of cyclosporine on rosuvastatin uptake by cells expressing OATP‐C was also examined.

A molecular basis for familial hypertrophic cardiomyopathy: An αβ cardiac myosin heavy chain hybrid gene

Abstract An αβ cardiac myosin heavy chain (MHC) hybrid gene is coinherited with familial hypertrophic cardiomyopathy (FHC) in one kindred. FHC is a disease of the heart muscle characterized by a thickening of the left ventricular wall with myocyte and myofibrillar disarray that is inherited as an autosomal dominant trait. We demonstrate here and in the accompanying article that the cardiac MHC genes, which encode integral myofibrillar components, are mutated in all affected individuals from two unrelated familles with FHC. In one kindred, an unequal crossover event during meiosis may have produced the αβ cardiac MHC hybrid gene that is present in affected individuals. We conclude that mutations in the cardiac MHC genes can cause FHC.

Development of circulatory-renal limitations to angiotensin-converting enzyme inhibitors identifies patients with severe heart failure and early mortality ☆

OBJECTIVES This study examined the hypothesis that patients who develop angiotensin-converting enzyme inhibitor intolerance attributable to circulatory-renal limitations (CRLimit) have more severe underlying disease and worse outcome. BACKGROUND Although the renin-angiotensin system contributes to the progression of heart failure (HF), it also supports the failing circulation. Patients with the most severe disease may not tolerate inhibition of this system. METHODS Consecutive inpatient admissions to the cardiomyopathy service of the Brigham and Womens Hospital between 2000 and 2002 were reviewed retrospectively for initial profiles, discharge medications, and documented reasons for discontinuation of angiotensin-converting enzyme inhibitors. Outcomes of death and transplantation were determined. RESULTS Of the 259 patients, 86 were not on an angiotensin-converting enzyme inhibitor at discharge. Circulatory-renal limitations of symptomatic hypotension, progressive renal dysfunction, or hyperkalemia were documented in 60 patients (23%); other adverse effects, including cough, in 24 patients; and absent reasons in 2 patients. Compared with patients on angiotensin-converting enzyme inhibitors, patients with CRLimit were older (60 vs. 55 years; p = 0.006), with longer history of HF (5 vs. 2 years; p = 0.009), lower systolic blood pressure (104 vs. 110 mm Hg; p = 0.05), lower sodium (135 vs. 138 mEql/l; p = 0.002), and higher initial creatinine (2.5 vs. 1.2 mg/dl; p = 0.0001). Mortality was 57% in patients with CRLimit and 22% in the patients on angiotensin-converting enzyme inhibitors during a median 8.5-month follow-up (p = 0.0001). CONCLUSIONS Development of CRLimit to angiotensin-converting enzyme inhibitor intolerance identifies patients with severe disease who are likely to die during the next year. New treatment strategies should be targeted to this population.

Task Force 4: organization of delivery systems for adults with congenital heart disease

The delivery of appropriate care to adults with congenital heart disease (ACHD) is a largely unmet challenge in the U.S. and elsewhere. To meet this challenge, a structure and process for the organization and delivery of care is proposed. We will use the “severe heart failure care model”

Familial hypertrophic cardiomyopathy is a genetically heterogeneous disease.

We demonstrate that familial hypertrophic cardiomyopathy (FHC), an autosomal dominant disorder of heart muscle, is a genetically heterogeneous disease. The locus responsible for FHC in members of one large kindred was recently mapped to chromosome 14q11-12 (FHC-1). We have characterized three additional unrelated families in which the gene for FHC segregates as an autosomal dominant trait to determine if these disease loci also map to FHC-1. All family members were clinically studied by physical examination, electrocardiogram, and two-dimensional echocardiography. Genetic studies were performed using DNA probes which are derived from loci that are closely linked to FHC-1. In one family the genetic defect maps to the previously identified FHC-1 locus. However, the loci responsible for FHC in two other families were not linked to FHC-1. We conclude that FHC can be caused by defects in at least two loci and is a genetically heterogeneous disorder.

Cardiac transplant outcome of patients supported on left ventricular assist device vs. intravenous inotropic therapy.

BACKGROUND Although the left ventricular assist device (LVAD) has been increasingly used as a bridge to transplant, its effect on post-transplant outcome is uncertain. We, therefore, designed this study using the Cardiac Transplant Research Database to compare patients supported on an LVAD before transplant with those treated with intravenous inotropic medical therapy. METHODS AND RESULTS Of the 5,880 patients transplanted between 1990 and 1997, a total of 502 received support from LVADs and 2,514 received intravenous inotropic medical therapy at the time of transplant. Kaplan-Meier analysis showed no significant difference in post-transplant survival between the LVAD and medical-therapy groups (p = 0.09). Results of a multivariate Cox regression analysis were consistent with that of the Kaplan-Meier analysis and did not identify LVAD as a significant risk factor for mortality. The percentage of patients who received LVADs as a function of total transplants increased from 2% in 1990 to 16% in 1997. Furthermore, although the number of extracorporeal LVADs remained relatively constant, the number of intracorporeal LVADs increased over time. Multivariate parametric analysis found that the risk factors for post-transplant death in the LVAD group were extracorporeal LVAD use (p = 0.0004), elevated serum creatinine (p = 0.05), older donor age (p = 0.03), increased donor ischemic time (p < 0.0001), and earlier year of transplant (p = 0.03). CONCLUSIONS Given a limited donor supply, the intracorporeal LVAD helps the sickest patients survive to transplant and provides post-transplant outcome similar to that of patients supported on inotropic medical therapy. Therefore, patients supported on LVADs before transplant may receive the greatest marginal benefit when compared with other transplant candidates.

Renal insufficiency and end-stage renal disease in the heart transplant population☆

BACKGROUND Renal insufficiency and end-stage renal disease (ESRD) are important problems in the cardiac transplant population, and are associated with significant morbidity, mortality and financial cost. We undertook this study to define pre-operative or early post-operative predictors of subsequent renal insufficiency and ESRD. METHODS We studied 370 patients at Brigham and Womens Hospital who received heart transplants between 1984 and 1999, with up to 10-year follow-up. We evaluated 2 time-dependent primary outcomes: early reduction in GFR, and development of ESRD at any timepoint. Cox proportional hazards modeling was used in both univariate and multivariate analyses. RESULTS The mean estimated glomerular filtration rate (GFR) fell 24% within the first post-transplant year, and remained stable thereafter. By actuarial analysis, 23% of patients developed a 50% reduction in GFR by the third year, and 20% developed ESRD by the tenth year of follow-up. In Cox multivariate analysis, significant predictors of post-transplant ESRD included: GFR <50 ml/min (hazards ratio [HR] 3.69, p = 0.024); high mean cyclosporine trough in the first 6 months (HR 5.10, p = 0.0059); and presence of diabetes (HR 3.53, p = 0.021). Conclusions about renal insufficiency outcome were limited by difficulties with accurate estimation of GFR and with definition of renal insufficiency. CONCLUSIONS The results of this study underscore the magnitude of the problem of renal insufficiency and ESRD in the heart transplant population. In addition, these data suggest that patients at high risk for these outcomes can be identified early, even pre-operatively, to guide post-operative management.

A pragmatic view of the new cholesterol treatment guidelines.

On November 12, 2013, updated guidelines for the treatment of high blood cholesterol levels were released by the American College of Cardiology– American Heart Association (ACC-AHA) Task Force on Practice Guidelines.1 This update represents the first major guideline revision since the National Cholesterol Education Program released its Adult Treatment Panel III report in 2002.2 The previous guidelines were widely accepted and applied with relative consistency. In contrast, the new guidelines have already been the subject of controversy, with some observers arguing that some elements of the recommendations are not evidence-based.3 Nevertheless, these recommendations may have a major effect on the clinical practice of lipid management. We therefore provide here a brief practical summary of the current cholesterol guidelines, indicating the area of dispute.