Stephanie Kiencke

Pre-clinical diabetic cardiomyopathy: prevalence, screening, and outcome.

Diabetic cardiomyopathy, characterized by left ventricular (LV) dysfunction and LV hypertrophy independent of myocardial ischaemia and hypertension, could contribute to the increased life‐time risk of congestive heart failure seen in patients with diabetes. We assessed prospectively the prevalence, effectiveness of screening methods [brain natriuretic peptide (BNP) and C‐reactive protein in combination with clinical parameters], and outcome of pre‐clinical diabetic cardiomyopathy.

Dexamethasone But Not Tadalafil Improves Exercise Capacity in Adults Prone to High-Altitude Pulmonary Edema

RATIONALE Whether pulmonary hypertension at high altitude limits exercise capacity remains uncertain. OBJECTIVES To gain further insight into the pathophysiology of hypoxia induced pulmonary hypertension and the resulting reduction in exercise capacity, we investigated if the reduction in hypoxic pulmonary vasoconstrictive response with corticosteroids or phosphodiesterase-5 inhibition improves exercise capacity. METHODS A cardiopulmonary exercise test and echocardiography to estimate systolic pulmonary artery pressure were performed in 23 subjects with previous history of high altitude pulmonary edema, known to be associated with enhanced hypoxic vasoconstriction. Subjects were randomized to dexamethasone 8 mg twice a day, tadalafil 10 mg twice a day, or placebo (double-blinded), starting the day before ascent. MEASUREMENTS AND MAIN RESULTS Measurements were performed at low and high (i.e., 4,559 m) altitude. Altitude exposure decreased maximum oxygen uptake and oxygen saturation, increased pulmonary artery pressure, and altered oxygen uptake kinetics. Compared with placebo, dexamethasone improved maximum oxygen uptake (% predicted 74 +/- 13%; tadalafil 63 +/- 13%, placebo 61 +/- 11%; P < 0.05), oxygen kinetics (mean response time 41 +/- 13 s; tadalafil 46 +/- 6 s, placebo 45 +/- 10 s; P < 0.05), and reduced the ventilatory equivalent for CO(2) (42 +/- 4; tadalafil 49 +/- 4, placebo 50 +/- 5; P < 0.01). Peak oxygen saturation did not differ significantly between the three groups (dexamethasone 66 +/- 7%, placebo 62 +/- 7%, tadalafil 69 +/- 5%; P = 0.08). During echocardiography at low-intensity exercise (40% of peak power), dexamethasone compared with placebo resulted in lower pulmonary artery pressure (47 +/- 9 mm Hg; tadalafil 57 +/- 11 mm Hg, placebo 68 +/- 23 mm Hg; P = 0.05) and higher oxygen saturation (74 +/- 7%; tadalafil 67 +/- 3%, placebo 61 +/- 20; P < 0.02). CONCLUSIONS Corticosteroids, but not phosphodiesterase-5 inhibition, partially prevented the limitation of exercise capacity in subjects with intense hypoxic pulmonary vasoconstriction at high altitude.

Incidence, clinical predictors, and prognostic impact of worsening renal function in elderly patients with chronic heart failure on intensive medical therapy

BACKGROUND Incidence, predictors, and prognostic impact of worsening renal function (WRF) in elderly patients with chronic heart failure (HF) undergoing intensive contemporary medical therapy are unknown. METHODS AND RESULTS In 566 patients (age 77 ± 8 years) included in the TIME-CHF, serum creatinine (sCr) was repeatedly measured up to 6 months. Worsening renal function was classified as increase in sCr by 0.2 to 0.3 (WRFI), 0.3 to 0.5 (WRFII), or ≥0.5 mg/dL (WRFIII) within the first 6 months. Outcome events were assessed for 18 months. RESULTS The incidence of WRF I, II, and III was 12%, 19%, and 22%, respectively. Worsening renal function III was associated with increased mortality (hazard ratio 1.98 [95% CI 1.27-3.07, P = .002] vs no WRF), whereas WRF I/II was not. History of renal failure, spironolactone treatment, higher baseline dose, and higher maximal increase in loop diuretic dose were independently associated with the occurrence of WRF III, whereas angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, and β-blocker use and allocation to N-terminal pro-B-type natriuretic peptide-guided management were not. Worsening renal function III was an independent predictor of death, death or hospitalization, and death or HF hospitalization also after adjusting for baseline characteristics. CONCLUSIONS One fifth of elderly patients with chronic HF experienced WRF III on 6-month intensive HF treatment. These patients had higher mortality, whereas patients with smaller sCr rises did not. Occurrence of WRF III was associated with high doses of loop diuretics and spironolactone use but not with other treatments.

Safety and tolerability of intensified, N-terminal pro brain natriuretic peptide-guided compared with standard medical therapy in elderly patients with congestive heart failure: results from TIME-CHF.

NT‐proBNP‐guided therapy results in intensification of medical heart failure (HF) therapy and is suggested to improve outcome. However, it is feared that an intensified, NT‐proBNP‐guided therapy carries a risk of adverse effects. Therefore, the safety and tolerability of NT‐proBNP‐guided therapy in the Trial of Intensified vs standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME‐CHF) was assessed.

Exercise-Induced Pulmonary Artery Hypertension : A Rare Finding?

To the Editor: When exposed to hypoxia at high altitude without acclimatization, susceptible individuals may develop pulmonary edema. Although the mechanisms are not completely understood, a disproportionate hypoxia-induced rise in pulmonary artery pressure (PAP) is a key factor. Those susceptible

Interaction between pulmonary hypertension and diastolic dysfunction in an elderly heart failure population.

BACKGROUND Pulmonary hypertension due to left heart disease is very common. Our aim was to investigate the relationship of the severity of left ventricular diastolic dysfunction with precapillary and postcapillary pulmonary hypertension (PH) in an elderly heart failure (HF) population. METHODS AND RESULTS A post hoc analysis of the Trial of Intensified Medical Therapy in Elderly Patients With Congestive Heart Failure data was done. Baseline transthoracic echocardiography was used to categorize diastolic function, estimate pulmonary artery pressure and pulmonary capillary wedge pressure, and calculate the transpulmonary pressure gradient (TPG). Among 392 HF patients, PH was present in 31% of patients with grade 1, in 37% of patients with grade 2, and in 65% of patients with grade 3 diastolic dysfunction; 54% of all HF patients with PH had a TPG >12 mm Hg, suggesting not only a postcapillary but also an additional precapillary component of PH. Survival was not related to the severity of diastolic dysfunction, but was worse in patients with PH (hazard ratio 1.63, 95% confidence interval 1.07-2.51; P = .024). CONCLUSIONS Our data indicate that HF patients with even mild diastolic dysfunction often have PH. Echocardiographic assessment suggest that the presence of PH might not simply be due to increased PCWP, but in part due to a precapillary component.

Evidence supportive of impaired myocardial blood flow reserve at high altitude in subjects developing high-altitude pulmonary edema

An exaggerated increase in pulmonary arterial pressure is the hallmark of high-altitude pulmonary edema (HAPE) and is associated with endothelial dysfunction of the pulmonary vasculature. Whether the myocardial circulation is affected as well is not known. The aim of this study was, therefore, to investigate whether myocardial blood flow reserve (MBFr) is altered in mountaineers developing HAPE. Healthy mountaineers taking part in a trial of prophylactic treatment of HAPE were examined at low (490 m) and high altitude (4,559 m). MBFr was derived from low mechanical index contrast echocardiography, performed at rest and during submaximal exercise. Among 24 subjects evaluated for MBFr, 9 were HAPE-susceptible individuals on prophylactic treatment with dexamethasone or tadalafil, 6 were HAPE-susceptible individuals on placebo, and 9 persons without HAPE susceptibility served as controls. At low altitude, MBFr did not differ between groups. At high altitude, MBFr increased significantly in HAPE-susceptible individuals on treatment (from 2.2 +/- 0.8 at low to 2.9 +/- 1.0 at high altitude, P = 0.04) and in control persons (from 1.9 +/- 0.8 to 2.8 +/- 1.0, P = 0.02), but not in HAPE-susceptible individuals on placebo (2.5 +/- 0.3 and 2.0 +/- 1.3 at low and high altitude, respectively, P > 0.1). The response to high altitude was significantly different between the two groups (P = 0.01). There was a significant inverse relation between the increase in the pressure gradient across the tricuspid valve and the change in myocardial blood flow reserve. HAPE-susceptible individuals not taking prophylactic treatment exhibit a reduced MBFr compared with either treated HAPE-susceptible individuals or healthy controls at high altitude.

Prognostic Value of Self-Reported Versus Objectively Measured Functional Capacity in Patients With Heart Failure: Results From the TIME-CHF (Trial of Intensified Versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure)

To the Editor: A central aspect of quality of life in patients with heart failure (HF) is their ability to perform daily activities, which may be quantified by the Duke Activity Status Index (DASI) questionnaire ([1][1]). Lower DASI scores were shown to be related independently to event-free

Prognostic Value of the Change in Heart Rate From the Supine to the Upright Position in Patients With Chronic Heart Failure

Background The prognostic value of the change in heart rate from the supine to upright position (∆HR) in patients with chronic heart failure (HF) is unknown. Methods and Results ∆HR was measured in patients enrolled in the Trial of Intensified Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME‐CHF) who were in sinus rhythm and had no pacemaker throughout the trial (n=321). The impact of ∆HR on 18‐month outcome (HF hospitalization‐free survival) was assessed. In addition, the prognostic effect of changes in ∆HR between baseline and month 6 on outcomes in the following 12 months was determined. A lower ∆HR was associated with a higher risk of death or HF hospitalization (hazard ratio 1.79 [95% confidence interval {95% CI} 1.19‐2.75] if ∆HR ≤3 beats/min [bpm], P=0.004). In the multivariate analysis, lower ∆HR remained an independent predictor of death or HF hospitalization (hazard ratio 1.75 [95% CI, 1.18‐2.61] if ∆HR ≤3 bpm, P=0.004) along with ischemic HF etiology, lower estimated glomerular filtration rate, presence and extent of rales, and no baseline β‐blocker use. In patients without event during the first 6 months, the change in ∆HR from baseline to month 6 predicted death or HF hospitalization during the following 12 months (hazard ratio=2.13 [95% CI 1.12–5.00] if rise in ∆HR <2 bpm; P=0.027). Conclusions ∆HR as a simple bedside test is an independent prognostic predictor in patients with chronic HF. ∆HR is modifiable, and changes in ∆HR also provide prognostic information, which raises the possibility that ∆HR may help to guide treatment. Clinical Trial Registration Information URL: www.isrctn.org. Unique identifier: ISRCTN43596477.

Altered Left Ventricular Geometry and Torsional Mechanics in High Altitude-Induced Pulmonary Hypertension: A Three-Dimensional Echocardiographic Study

Background: Changes in left ventricular (LV) torsion have been related to LV geometry in patients with concomitant long‐standing myocardial disease or pulmonary hypertension (PH). We evaluated the effect of acute high altitude‐induced isolated PH on LV geometry, volumes, systolic function, and torsional mechanics. Methods: Twenty‐three volunteers were prospectively studied at low altitude and after the second (D3) and third night (D4) at high altitude (4,559 m). LV ejection fraction, multidirectional strains and torsion, LV volumes, sphericity, and eccentricity were derived by speckle‐tracking on three‐dimensional echocardiographic data sets. Pulmonary pressure was estimated from the transtricuspid pressure gradient (TRPG), LV preload from end‐diastolic LV volume, and transmitral over mitral annular E velocity (E/e′). Results: At high altitude, oxygen saturation decreased by 15%–20%, heart rate and cardiac index increased by 15%–20%, and TRPG increased from 21 ± 2 to 37 ± 9 mm Hg (P < .01). LV volumes, preload, ejection fraction, multidirectional strains, and sphericity remained unaffected, but diastolic (1.04 ± 0.07 to 1.09 ± 0.09 on D3/D4, P < .05) and systolic (1.00 ± 0.06 to 1.08 ± 0.1 [D3] and 1.06 ± 0.07 [D4], P < .05) eccentricity slightly increased, indicating mild septal flattening. LV torsion decreased from 2.14 ± 0.85 to 1.34 ± 0.68 (P < .05) and 1.65 ± 0.54 (P = .08) degrees/cm on D3/D4, respectively. Changes in torsion showed a weak inverse relationship to changes in systolic (r = −0.369, P = .013) and diastolic (r = −0.329, P = .032) eccentricity but not to changes in TRPG, heart rate or preload. Conclusions: High‐altitude exposure was associated with mild septal flattening of the LV and reduced ventricular torsion at unchanged global LV function and preload, suggesting a relation between LV geometry and torsional mechanics.