Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction.

BACKGROUND: Characterization of myocardial structural changes in heart failure with preserved ejection fraction (HFpEF) has been hindered by the limited availability of human cardiac tissue. Cardiac hypertrophy, coronary artery disease (CAD), coronary microvascular rarefaction, and myocardial fibrosis may contribute to HFpEF pathophysiology. METHODS AND RESULTS: We identified HFpEF patients (n=124) and age-appropriate control subjects (noncardiac death, no heart failure diagnosis; n=104) who underwent autopsy. Heart weight and CAD severity were obtained from the autopsy reports. With the use of whole-field digital microscopy and automated analysis algorithms in full-thickness left ventricular sections, microvascular density (MVD), myocardial fibrosis, and their relationship were quantified. Subjects with HFpEF had heavier hearts (median, 538 g; 169% of age-, sex-, and body size-expected heart weight versus 335 g; 112% in controls), more severe CAD (65% with ≥1 vessel with >50% diameter stenosis in HFpEF versus 13% in controls), more left ventricular fibrosis (median % area fibrosis, 9.6 versus 7.1) and lower MVD (median 961 versus 1316 vessels/mm(2)) than control (P<0.0001 for all). Myocardial fibrosis increased with decreasing MVD in controls (r=-0.28, P=0.004) and HFpEF (r=-0.26, P=0.004). Adjusting for MVD attenuated the group differences in fibrosis. Heart weight, fibrosis, and MVD were similar in HFpEF patients with CAD versus without CAD. CONCLUSIONS: In this study, patients with HFpEF had more cardiac hypertrophy, epicardial CAD, coronary microvascular rarefaction, and myocardial fibrosis than controls. Each of these findings may contribute to the left ventricular diastolic dysfunction and cardiac reserve function impairment characteristic of HFpEF.

Five-year outcomes of wide excision and Mohs micrographic surgery for primary lentigo maligna in an academic practice cohort.

BACKGROUND: Wide local excision with 5-mm margins is the standard of care for lentigo maligna (LM). Mohs micrographic surgery (MMS) is used increasingly to treat this tumor. OBJECTIVE: To study the authors' experience with these 2 approaches. MATERIALS AND METHODS: Primary LM cases treated at the authors' institution from January 1, 1995, through December 31, 2005, were studied retrospectively. Main outcome measures were recurrence and outcomes after treatment for recurrence. RESULTS: In total, 423 LM lesions were treated in 407 patients: 269 (64%) with wide excision and 154 (36%) with MMS. In the MMS group (primarily larger head and neck lesions with indistinct clinical margins), recurrence rates were 3 of 154 (1.9%). In the wide excision group (primarily smaller, nonhead and neck, or more distinct lesions), recurrence rates were 16 of 269 (5.9%). Each of the 16 recurrences was biopsy proven and treated surgically: 6 by standard excision and 10 by MMS. CONCLUSION: This follow-up study of LM surgical treatments shows excellent outcomes for wide excision and MMS. Because this is a nonrandomized retrospective study, no direct comparisons between the 2 treatments can be made. When recurrences occurred, repeat surgery, either standard excision or MMS, was usually sufficient to provide definitive cure.

Incidence of lentigo maligna in Olmsted County, Minnesota, 1970 to 2007.

BACKGROUND: The incidence of lentigo maligna (LM) may be increasing, but no population-based epidemiologic studies have been performed to our knowledge. OBJECTIVE: We sought to determine the incidence of LM in Olmsted County, Minnesota, along with overall and recurrence-free survival. METHODS: Using the Rochester Epidemiology Project, we identified all adult residents of Olmsted County, Minnesota, with a first lifetime diagnosis of LM between 1970 and 2007. Medical records were reviewed to determine demographic, clinical, and surgical data, and incidence and survival were calculated. RESULTS: Among 145 patients identified, median (range) age at diagnosis of LM was 70 (33-97) years. Treatment changed over time, with Mohs micrographic surgery becoming available after 1986. No patients died of LM; 5 had local recurrence. Estimated local recurrence-free survival at 5, 10, 15, and 20 years after diagnosis was 98%, 96%, 92%, and 92%, respectively. Overall age- and sex-adjusted incidence of LM among adults was 6.3 per 100,000 person-years, increasing from 2.2 between 1970 and 1989 to 13.7 between 2004 and 2007. LIMITATIONS: Retrospective study design and homogeneous population are limitations. CONCLUSION: The incidence of LM increased significantly among residents of Olmsted County, Minnesota, over an extended time frame, with incidence being significantly higher among men than women and increasing with age.

Therapeutic hypothermia for out-of-hospital ventricular fibrillation survivors: a feasibility study comparing time to achieve target core temperature using conventional conductive cooling versus combined conductive plus pericranial convective cooling.

OBJECTIVE: Mild to moderate therapeutic hypothermia (TH) has been shown to improve survival and neurologic outcome, as well as to reduce healthcare costs in patients resuscitated from out-of-hospital cardiac arrest (OHCA) with ventricular fibrillation. Accordingly, the American Heart Association has categorized this as a Class IB intervention. The therapeutic window for initiating TH is narrow, and thus, achieving target temperature expeditiously is of paramount importance to improve postresuscitative neurologic outcome. The present investigation is a feasibility study designed to assess the practicality and efficacy of including pericranial cooling in our postresuscitative TH protocol. Specifically, we compared time required to achieve target temperature (33°C) using our present standard of TH care (ie, conductive body cooling, conventional TH group) versus combined conductive body cooling plus convective (forced-air) head and neck cooling (combined TH group). DESIGN: Adult patients who experienced OHCA were included in the study provided TH could be initiated within 4 hours of resuscitation from ventricular fibrillation. Patients enrolled in both groups were cooled using the servo-controlled Arctic Sun conductive cooling system (Medivance, Inc, Louisville, CO). However, patients enrolled in the combined TH group also received forced-air pericranial cooling with an ambient temperature of approximately 13°C. In all cases, the target core (bladder) temperature was 33°C. The primary endpoint (ie, time required to achieve a core temperature of 33°C) was analyzed as a continuous variable and compared between groups using the rank sum test, whereas categorical variables were compared between groups using the chi-square test. SETTING: Cardiac intensive care unit at a major tertiary care teaching center in Rochester, MN. PARTICIPANTS: Adult patients who experienced OHCA were included in the study. INTERVENTIONS: Patients enrolled in both groups were cooled using the servo-controlled Arctic Sun conductive cooling system (Medivance, Inc, Louisville, CO). However, patients enrolled in the combined TH group also received forced-air pericranial cooling with an ambient temperature of approximately 13°C. MEASUREMENTS: Only patients admitted after January 1, 2008, were included in the analysis (28 combined TH group patients v 55 conventional TH group patients). Demographic data were similar between groups. When compared with the conventional TH group, time to achieve 33°C was significantly shorter in the combined TH group: 207 minutes (173 and 286 min) [median (25th, 75th percentile)] v 181 minutes (63 and 247 min). The magnitude and frequency of hypothermia-mediated physiologic perturbations (eg, hypokalemia) were similar for both groups. CONCLUSIONS: Both TH cooling paradigms effectively achieved 33°C; however, the combined TH technique significantly decreased the time required to achieve the target temperature. Although not evaluated in this study, such an effect may further improve postresuscitative neurologic outcomes beyond that previously described using conventional TH. Although a positive result (ie, abbreviated time taken to achieve target temperature) was observed, we maintain guarded enthusiasm for this evolving adjunctive technique until corroborative outcome-based evidence is available.

A predictive model of recurrent lower extremity cellulitis in a population-based cohort.

BACKGROUND: Cellulitis is common and recurs in some patients. The study described herein derived a predictive model for the recurrence of lower extremity cellulitis in a population-based cohort. METHODS: We conducted a retrospective, population-based cohort study using the Rochester Epidemiology Project. We reviewed the medical records of Olmsted County, Minnesota, residents with lower extremity cellulitis occurring from January 1, 1999, to June 30, 2000. Univariate and multivariate Cox proportional hazards analyses were performed to evaluate risk factors in patients who experienced recurrent lower extremity cellulitis within 2 years. A predictive model was developed to estimate risk of recurrence based on a score of risk factors identified by multivariate analysis. RESULTS: A total of 209 episodes met the definition of lower extremity cellulitis. Thirty-five patients (16.7%) experienced recurrence within 2 years. Multivariate analysis identified tibial area involvement, prior malignancy, and dermatitis affecting the ipsilateral limb as independent risk factors for recurrence, with hazard ratios of 5.02, 3.87, and 2.99 (P<.01), respectively. A score calculated from these variables (a count of 0, 1, 2, or 3) was developed to measure risk of recurrence. Based on the predictive model, the estimated probability of recurrence (95% confidence interval [CI]) within 2 years was 5.0% (95% CI, 1.6%-8.2%), 17.3% (95% CI, 11.1%-23.0%), 50.6% (95% CI, 34.2%-63.0%), or 92.8% (95% CI, 51.9%-98.9%) for a score of 0, 1, 2 or 3, respectively. CONCLUSIONS: We derived a model including tibial area involvement, history of cancer, and dermatitis to predict recurrence of lower extremity cellulitis. Potential interventions can be incorporated into treatment to diminish the proclivity for recurrence in high-risk patients.

Incidence of lower-extremity cellulitis: a population-based study in Olmsted county, Minnesota.

OBJECTIVE: To determine the population-based incidence of lower-extremity cellulitis. METHODS: We performed a population-based survey with the resources of the Rochester Epidemiology Project in Olmsted County, Minnesota. We identified residents of Olmsted County who sought care for cellulitis from January 1, 1999, through December 31, 1999, reviewed medical records to ascertain agreement with a case definition of lower-extremity cellulitis, and calculated the population-based incidence of lower-extremity cellulitis. RESULTS: During 1999, 176 episodes met the case definition of lower-extremity cellulitis; the incidence of lower-extremity cellulitis in Olmsted County was 199 per 100,000 person-years. Sex-specific incidence was 197 per 100,000 person-years for women and 201 per 100,000 person-years for men. In a sex-adjusted model, the incidence increased 3.7% (95% confidence interval, 2.9%-4.5%) per year increment in age or 43.8% (95% confidence interval, 33.6%-54.7%) per 10-year increment. The incidence of cellulitis significantly increased with age (P<.001 in Poisson regression) but was not statistically significantly different between the sexes. CONCLUSIONS: The incidence of lower-extremity cellulitis in this population-based study was high and was affected by age. In contrast, sex did not influence infection incidence. The need for hospitalization and the prevalence of recurrence of lower-extremity cellulitis added to the burden of disease in Olmsted County.

From statistical significance to clinical relevance: A simple algorithm to integrate brain natriuretic peptide and the Seattle Heart Failure Model for risk stratification in heart failure.

BACKGROUND: Heart failure (HF) guidelines recommend brain natriuretic peptide (BNP) and multivariable risk scores, such as the Seattle Heart Failure Model (SHFM), to predict risk in HF with reduced ejection fraction (HFrEF). A practical way to integrate information from these 2 prognostic tools is lacking. We sought to establish a SHFM+BNP risk-stratification algorithm. METHODS: The retrospective derivation cohort included consecutive patients with HFrEF at the Mayo Clinic. One-year outcome (death, transplantation or ventricular assist device) was assessed. The SHFM+BNP algorithm was derived by stratifying patients within SHFM-predicted risk categories (≤2.5%, 2.6% to ≤10%, >10%) according to BNP above or below 700 pg/ml and comparing SHFM-predicted and observed event rates within each SHFM+BNP category. The algorithm was validated in a prospective, multicenter HFrEF registry (Penn HF Study). RESULTS: Derivation (n = 441; 1-year event rate 17%) and validation (n = 1,513; 1-year event rate 12%) cohorts differed with the former being older and more likely ischemic with worse symptoms, lower EF, worse renal function and higher BNP and SHFM scores. In both cohorts, across the 3 SHFM-predicted risk strata, a BNP >700 pg/ml consistently identified patients with approximately 3-fold the risk that the SHFM would have otherwise estimated, regardless of stage of HF, intensity and duration of HF therapy and comorbidities. Conversely, the SHFM was appropriately calibrated in patients with a BNP <700 pg/ml. CONCLUSION: The simple SHFM+BNP algorithm displays stable performance across diverse HFrEF cohorts and may enhance risk stratification to enable appropriate decision-making regarding HF therapeutic or palliative strategies.

Left ventricular amyloid deposition in patients with heart failure and preserved ejection fraction.

OBJECTIVES: This study sought to determine the frequency of left ventricular amyloid in heart failure with preserved ejection fraction (HFpEF). BACKGROUND: Left ventricular amyloid deposition can cause diastolic dysfunction and HFpEF. METHODS: Autopsy of left ventricular specimens from patients with antemortem diagnosis of HFpEF without clinically apparent amyloid (n = 109) and from control subjects (n = 131) were screened with sulfated Alcian blue and subsequent Congo red staining with microdissection for mass spectrometry-based proteomics to determine amyloid type. Fibrosis was assessed with quantitative whole-field digital microscopy. RESULTS: The presence of wild-type transthyretin (wtTTR) amyloid was associated with age at death and male sex, but the age- and sex-adjusted prevalence of wtTTR amyloid was higher in HFpEF patients than in control subjects (odds ratio: 3.8, 95% confidence interval: 1.5 to 11.3; p = 0.03). Among HFpEF patients, moderate or severe interstitial wtTTR deposition, consistent with senile systemic amyloidosis as the primary etiology of HFpEF, was present in 5 (5%) patients (80% men), with mild interstitial and/or variable severity of intramural coronary vascular deposition in 13 (12%) patients. While, wtTTR deposition was often mild, adjusting for age and presence of HFpEF, wtTTR amyloid was associated with more fibrosis (p = 0.005) and lower age, sex, and body size-adjusted heart weight (p = 0.04). CONCLUSIONS: Given the age- and sex-independent association of HFpEF and wtTTR deposition and an emerging understanding of the pathophysiology of the amyloidoses, the current findings support further investigation of the role of wtTTR in the pathophysiology of HFpEF.

Comorbidity and ventricular and vascular structure and function in heart failure with preserved ejection fraction: a community-based study.

BACKGROUND: Patients with heart failure and preserved ejection fraction (HFpEF) display increased adiposity and multiple comorbidities, factors that in themselves may influence cardiovascular structure and function. This has sparked debate as to whether HFpEF represents a distinct disease or an amalgamation of comorbidities. We hypothesized that fundamental cardiovascular structural and functional alterations are characteristic of HFpEF, even after accounting for body size and comorbidities. METHODS AND RESULTS: Comorbidity-adjusted cardiovascular structural and functional parameters scaled to independently generated and age-appropriate allometric powers were compared in community-based cohorts of HFpEF patients (n=386) and age/sex-matched healthy n=193 and hypertensive, n=386 controls. Within HFpEF patients, body size and concomitant comorbidity-adjusted cardiovascular structural and functional parameters and survival were compared in those with and without individual comorbidities. Among HFpEF patients, comorbidities (obesity, anemia, diabetes mellitus, and renal dysfunction) were each associated with unique clinical, structural, functional, and prognostic profiles. However, after accounting for age, sex, body size, and comorbidities, greater concentric hypertrophy, atrial enlargement and systolic, diastolic, and vascular dysfunction were consistently observed in HFpEF compared with age/sex-matched normotensive and hypertensive. CONCLUSIONS: Comorbidities influence ventricular-vascular properties and outcomes in HFpEF, yet fundamental disease-specific changes in cardiovascular structure and function underlie this disorder. These data support the search for mechanistically targeted therapies in this disease.

Hypokalemia during the cooling phase of therapeutic hypothermia and its impact on arrhythmogenesis.

BACKGROUND: Mild to moderate therapeutic hypothermia (TH) has been shown to improve survival and neurological outcome in patients resuscitated from out-of-hospital cardiac arrest (OHCA) with ventricular fibrillation (VF) as the presenting rhythm. This approach entails the management of physiological variables which fall outside the realm of conventional critical cardiac care. Management of serum potassium fluxes remains pivotal in the avoidance of lethal ventricular arrhythmia. METHODS: We retrospectively analyzed potassium variability with TH and performed correlative analysis of QT intervals and the incidence of ventricular arrhythmia. RESULTS: We enrolled 94 sequential patients with OHCA, and serum potassium was followed intensively. The average initial potassium value was 3.9±0.7 mmol l(-1) and decreased to a nadir of 3.2±0.7 mmol l(-1) at 10 h after initiation of cooling (p<0.001). Eleven patients developed sustained polymorphic ventricular tachycardia (PVT) with eight of these occurring during the cooling phase. The corrected QT interval prolonged in relation to the development of hypothermia (p<0.001). Hypokalemia was significantly associated with the development of PVT (p=0.002), with this arrhythmia being most likely to develop in patients with serum potassium values of less than 2.5 mmol l(-1) (p=0.002). Rebound hyperkalemia did not reach concerning levels (maximum 4.26±0.8 mmol l(-1) at 40 h) and was not associated with the occurrence of ventricular arrhythmia. Furthermore, repletion of serum potassium did not correlate with the development of ventricular arrhythmia. CONCLUSIONS: Therapeutic hypothermia is associated with a significant decline in serum potassium during cooling. Hypothermic core temperatures do not appear to protect against ventricular arrhythmia in the context of severe hypokalemia and cautious supplementation to maintain potassium at 3.0 mmol l(-1) appears to be both safe and effective.