Jonas Spaak

Warfarin, Kidney Dysfunction, and Outcomes Following Acute Myocardial Infarction in Patients With Atrial Fibrillation

IMPORTANCE Conflicting evidence exists regarding the association between warfarin treatment, death, and ischemic stroke incidence in patients with advanced chronic kidney disease (CKD) and atrial fibrillation. OBJECTIVE To study outcomes associated with warfarin treatment in relation to kidney function among patients with established cardiovascular disease and atrial fibrillation. DESIGN, SETTING, AND PARTICIPANTS Observational, prospective, multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry (2003-2010), which includes all Swedish hospitals that provide care for acute cardiac diseases. Participants included consecutive survivors of an acute myocardial infarction (MI) with atrial fibrillation and known serum creatinine (N = 24,317), including 21.8% who were prescribed warfarin at discharge. Chronic kidney disease stages were classified according to estimated glomerular filtration rate (eGFR). MAIN OUTCOMES AND MEASURES (1) Composite end point analysis of death, readmission due to MI, or ischemic stroke; (2) bleeding (composite of readmission due to hemorrhagic stroke, gastrointestinal bleeding, bleeding causing anemia, and others); or (3) the aggregate of these 2 outcomes within 1 year from discharge date. RESULTS A total of 5292 patients (21.8%) were treated with warfarin at discharge, and 51.7% had manifest CKD (eGFR <60 mL/min/1.73 m2 [eGFR<60]). Compared with no warfarin use, warfarin was associated with a lower risk of the first composite outcome (n = 9002 events) in each CKD stratum for event rates per 100 person-years: eGFR>60 event rate, 28.0 for warfarin vs 36.1 for no warfarin; adjusted hazard ratio (HR), 0.73 (95% CI, 0.65 to 0.81); eGFR>30-60: event rate, 48.5 for warfarin vs 63.8 for no warfarin; HR, 0.73 (95% CI, 0.66 to 0.80); eGFR>15-30: event rate, 84.3 for warfarin vs 110.1 for no warfarin; HR, 0.84 (95% CI, 0.70-1.02); eGFR≤15: event rate, 83.2 for warfarin vs 128.3 for no warfarin; HR, 0.57 (95% CI, 0.37-0.86). The risk of bleeding (n = 1202 events) was not significantly higher in patients treated with warfarin in any CKD stratum for event rates per 100 person-years: eGFR>60 event rate, 5.0 for warfarin vs 4.8 for no warfarin; HR, 1.10 (95% CI, 0.86-1.41); eGFR>30-60 event rate, 6.8 for warfarin vs 6.3 for no warfarin; HR, 1.04 (95% CI, 0.81-1.33); eGFR>15-30 event rate, 9.3 for warfarin vs 10.4 for no warfarin; HR, 0.82 (95% CI, 0.48-1.39); eGFR≤15 event rate, 9.1 for warfarin vs 13.5 for no warfarin; HR, 0.52 (95% CI, 0.16-1.65). Warfarin use in each CKD stratum was associated with lower hazards of the aggregate outcome (n = 9592 events) for event rates per 100 person-years: eGFR>60 event rate, 32.1 for warfarin vs 40.0 for no warfarin; HR, 0.76 (95% CI, 0.69-0.84); eGFR>30-60 event rate, 53.6 for warfarin vs 69.0 for no warfarin; HR, 0.75 (95% CI, 0.68-0.82); eGFR>15-30 event rate, 90.2 for warfarin vs 117.7 for no warfarin; HR, 0.82 (95% CI, 0.68-0.99); eGFR≤15 event rate, 86.2 for warfarin vs 138.2 for no warfarin; HR, 0.55 (95% CI, 0.37-0.83). CONCLUSIONS AND RELEVANCE Warfarin treatment was associated with a lower 1-year risk for the composite outcome of death, MI, and ischemic stroke without a higher risk of bleeding in consecutive acute MI patients with atrial fibrillation. This association was not related to the severity of concurrent CKD.

Inverse relationship of subjective daytime sleepiness to sympathetic activity in patients with heart failure and obstructive sleep apnea.

BACKGROUND Patients with heart failure (HF) and obstructive sleep apnea (OSA) are less sleepy than patients with OSA but without HF. Furthermore, unlike the non-HF population, in the HF population, the degree of daytime sleepiness is not related to the apnea-hypopnea index (AHI). The sympathetic nervous system plays a critical role in alertness. HF and OSA both increase sympathetic nervous system activity (SNA) during wakefulness. We hypothesized that in patients with HF and OSA, the degree of subjective daytime sleepiness would be inversely related to SNA. METHODS Daytime muscle SNA (MSNA) was recorded in patients with HF and OSA. Subjective daytime sleepiness was assessed by the Epworth Sleepiness Scale (ESS). RESULTS We studied 27 patients with HF and OSA and divided them into two groups based on the median ESS score: a less sleepy group, with an ESS score < 6 (n = 13), and a sleepier group, with an ESS score ≥ 6 (n = 14). The less sleepy group had higher MSNA than did the sleepier group (82.5 ± 9.9 bursts/100 cardiac cycles vs 69.3 ± 18.6 bursts/100 cardiac cycles; P = .037) and a longer sleep-onset latency (33 ± 29 min vs 14 ± 13 min; P = .039). The ESS score was inversely related to MSNA (r = -0.63; P < .001) but not to the AHI, arousal index, or indices of oxygen desaturation. CONCLUSIONS In patients with HF and OSA, the degree of subjective daytime sleepiness is inversely related to MSNA. This relationship is likely mediated via central adrenergic alerting mechanisms. These findings help to explain the previously reported lack of daytime hypersomnolence in patients with HF and OSA.

Dose-related effects of red wine and alcohol on heart rate variability

In healthy subjects a standard drink of either red wine (RW) or ethanol (EtOH) has no effect on muscle sympathetic nerve activity or on heart rate (HR), whereas two drinks increase both. Using time- and frequency-domain indexes of HR variability (HRV), we now tested in 12 subjects (24-47 yr, 6 men) the hypotheses that 1) this HR increase reflects concurrent dose-related augmented sympathetic HR modulation and 2) RW with high-polyphenol content differs from EtOH in its acute HRV effects. RW, EtOH, and water were provided on 3 days, 2 wk apart according to a randomized, single-blind design. Eight-minute segments were analyzed. One alcoholic drink increased blood concentrations to 36 + or - 2 mg/dl (mean + or - SE), and 2 drinks to 72 + or - 4 (RW) and 80 + or - 2 mg/dl (EtOH). RW quadrupled plasma resveratrol (P < 0.001). HR fell after both water drinks. When compared with respective baselines, one alcoholic drink had no effect on HR or HRV, whereas two glasses of both increased HR (RW, +5.4 + or - 1.2; and EtOH, +5.7 + or - 1.2 min(-1); P < 0.001), decreased total HRV by 28-33% (P < 0.05) and high-frequency spectral power by 32-42% (vagal HR modulation), and increased low-frequency power by 28-34% and the ratio of low frequency to high frequency by 98-119% (sympathetic HR modulation) (all, P < or = 0.01). In summary, when compared with water, one standard drink lowered time- and frequency-domain markers of vagal HR modulation. When compared with respective baselines, two alcoholic drinks increased HR by diminished vagal and augmented sympathetic HR modulation. Thus alcohol exerts dose-dependent HRV responses, with RW and EtOH having a similar effect.

Paricalcitol, Microvascular and Endothelial Function in Non-Diabetic Chronic Kidney Disease: A Randomized Trial

Background: Vitamin D deficiency, sympathetic activation and endothelial dysfunction are associated with increased cardiovascular risk in patients with chronic kidney disease (CKD). Studies have so far failed to establish the role of vitamin D and vitamin D receptor activator (VDRA) treatment in moderate CKD. This trial was designed to assess whether VDRA treatment can ameliorate sympathetic activation and macro- and microvascular dysfunction in non-diabetic patients with moderate CKD. Methods: We conducted a randomized controlled double-blind trial using placebo, 1 or 2 μg of paricalcitol, a VDRA, for 3 months. We assessed muscle sympathetic nerve activity (MSNA) by microneurography, pulse wave velocity (PWV) by tonometry, flow mediated vasodilatation (FMD) by brachial ultrasound, skin microcirculation assessed by iontophoresis and capillary blood velocity (CBV) by videophotometric capillaroscopy. Results: Thirty-six patients with a mean age of 65 years and mean estimated glomerular filtration rate of 40 ml/min/1.73 m2 were included. We found a significant decline in endothelial function after 3 months, except in the group receiving 2 μg of paricalcitol. The higher dose (2 μg) seemed to attenuate the decline in microvascular endothelial function, assessed by iontophoresis of acetylcholine (p = 0.06 for all groups, p = 0.65 for the 2 μg group) and for FMD (p = 0.006 for all groups, p = 0.54 for the 2 μg group). We found a borderline significance (p = 0.05) for improved CBV in the treated groups. We found no significant changes between treatments in MSNA, PWV or albuminuria. Conclusions: Endothelial function declined significantly over 3 months in patients with moderate CKD, and this decline could be ameliorated by VDRA treatment (NCT01204528).

Integrating virtual patients into courses : follow-up seminars and perceived benefit

Medical Education 2012: 46: 417–425

Regression of vascular calcification in chronic kidney disease – feasible or fantasy? A review of the clinical evidence

The complex relationships between cardiovascular, renal, and bone disease are increasingly recognized but not yet clearly understood. Vascular calcification (VC) represents a common end point between these interlinked systems. It is highly prevalent in chronic kidney disease (CKD) and may be responsible for some of the excess cardiovascular events seen in this condition. There is much interest in developing therapeutic agents to stop its development or reverse its progression. Traditionally considered to be due to abnormalities in calcium and phosphate metabolism alone, VC is now known to be the product of active, dynamic processes within the vessel wall. Primary prevention of VC is possible through successful prevention or reversal of progressive renal dysfunction, hypertension and hyperlipidaemia, but is challenging given the increasing global prevalence of these risk factors. Secondary prevention of VC through tight control of calcium and phosphate, can be achieved by dietary or pharmacological means. Both the modification of haemodialysis duration or methods and the use of renal transplantation have an effect. Novel drugs such as cinacalcet were hoped to halt calcification but results have been mixed, and no intervention has yet been shown to reverse calcification reliably. A new range of experimental targets involved in the putative mediatory pathways between bone and vascular disease has emerged. Aiming to manipulate the active mechanisms involved in calcium deposition, these hold hope for reversal of calcification, but are still theoretical or in early animal or human experimentation.

Human carotid baroreflex during isometric lower arm contraction and ischemia

Our aim was to determine the roles of somatomotor activation and muscle ischemia for the tachycardia and hypertension of isometric arm contraction. Carotid-cardiac and carotid-mean arterial pressure (MAP) baroreflex response curves were determined in 10 men during rest, during isometric arm contraction at 30% of maximum, and during postcontraction ischemia. Carotid distending pressure (CDP) was changed by applying pressure and suction in a neck chamber. Pressures ranged from +40 to -80 mmHg and were applied repeatedly for 15 s during the three conditions. Maximum slopes and ranges of the response curves did not differ among conditions. The heart rate (HR) curve was shifted to a 14 ± 1.8 (mean ± SE) beats/min higher HR and a 9 ± 5.7 mmHg higher CDP during contraction and to a 14 ± 5.9 mmHg higher CDP during postcontraction ischemia with no change of HR compared with rest. The MAP curve was shifted to a 20 ± 2.8 mmHg higher MAP and to a 18 ± 5.4 mmHg higher CDP during contraction, and the same shifts were recorded during postcontraction ischemia. We conclude that neither somatomotor activation nor muscle ischemia changes the sensitivity of arterial baroreflexes. The upward shift of the MAP response curve, with no shift of the HR response curve during postexercise ischemia, supports the notion of parallel pathways for MAP and HR regulation in which HR responses are entirely caused by somatomotor activation and the pressor response is mainly caused by muscle ischemia.Our aim was to determine the roles of somatomotor activation and muscle ischemia for the tachycardia and hypertension of isometric arm contraction. Carotid-cardiac and carotid-mean arterial pressure (MAP) baroreflex response curves were determined in 10 men during rest, during isometric arm contraction at 30% of maximum, and during postcontraction ischemia. Carotid distending pressure (CDP) was changed by applying pressure and suction in a neck chamber. Pressures ranged from +40 to -80 mmHg and were applied repeatedly for 15 s during the three conditions. Maximum slopes and ranges of the response curves did not differ among conditions. The heart rate (HR) curve was shifted to a 14 +/- 1.8 (mean +/- SE) beats/min higher HR and a 9 +/- 5.7 mmHg higher CDP during contraction and to a 14 +/- 5.9 mmHg higher CDP during postcontraction ischemia with no change of HR compared with rest. The MAP curve was shifted to a 20 +/- 2.8 mmHg higher MAP and to a 18 +/- 5.4 mmHg higher CDP during contraction, and the same shifts were recorded during postcontraction ischemia. We conclude that neither somatomotor activation nor muscle ischemia changes the sensitivity of arterial baroreflexes. The upward shift of the MAP response curve, with no shift of the HR response curve during postexercise ischemia, supports the notion of parallel pathways for MAP and HR regulation in which HR responses are entirely caused by somatomotor activation and the pressor response is mainly caused by muscle ischemia.

Association between the use of fondaparinux vs low-molecular-weight heparin and clinical outcomes in patients with non-ST-segment elevation myocardial infarction.

IMPORTANCE Fondaparinux was associated with reduced major bleeding events and improved survival compared with low-molecular-weight heparin (LMWH) in a large randomized clinical trial involving patients with non-ST-segment elevation myocardial infarction (NSTEMI). Large-scale experience of the use of fondaparinux vs LMWH in a nontrial setting is lacking. OBJECTIVE To study the association between the use of fondaparinux vs LMWH and outcomes in patients with NSTEMI in Sweden. DESIGN, SETTING, AND PATIENTS Prospective multicenter cohort study from the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies registry involving 40,616 consecutive patients with NSTEMI who received fondaparinux or LMWH between September 1, 2006, through June 30, 2010, with the last follow-up on December 31, 2010. EXPOSURES In-hospital treatment with fondaparinux or LMWH during the hospital stay. MAIN OUTCOMES AND MEASURES In-hospital severe bleeding events and death and 30- and 180-day death, MI, stroke, and major bleeding events. Logistic regression models adjusted for calendar time, admitting hospital, baseline characteristics, and in-hospital revascularization. RESULTS In total, 14,791 patients (36.4%) were treated with fondaparinux and 25,825 (63.6%) with LMWH. One hundred sixty-five patients (1.1%) in the fondaparinux group vs 461 patients (1.8%) in the LMWH group experienced in-hospital bleeding events (adjusted odds ratio [OR], 0.54; 95% CI, 0.42-0.70). A total of 394 patients (2.7%) in the fondaparinux group died while in the hospital vs 1022 (4.0%) in the LMWH group (adjusted OR, 0.75; 95% CI, 0.63-0.89). The differences in major bleeding events and mortality between the 2 treatments were similar at 30 and 180 days. There were no significant differences in the number of recurrent MI and stroke events at 30 or 180 days among the 2 treatment groups. CONCLUSIONS AND RELEVANCE In routine clinical care of patients with NSTEMI, fondaparinux was associated with lower odds than LMWH of major bleeding events and death both in-hospital and up to 180 days afterward.

Risk Factors and Markers for Acute Myocardial Infarction With Angiographically Normal Coronary Arteries.

Myocardial Infarction with normal coronary arteries (MINCA) is common with a prevalence of 1% to 12% of all myocardial infarctions. The pathogenic mechanisms of MINCA are still unknown, but endothelial dysfunction has been suggested as a possible cause. To investigate risk factors and markers for MINCA, we conducted a case-control study. Considering the reported low prevalence of classical risk factors for coronary heart disease (CHD) in some but not all studies, our hypothesis was that endothelial function and intima-media thickness (IMT) were better, respectively lower, than CHD controls. One hundred patients with MINCA fulfilling diagnostic criteria according to the European Society of Cardiology/American Collage of Cardiology/American Heart Association universal definition of myocardial infarction with myocarditis excluded by cardiac magnetic resonance imaging were investigated. Risk factors, endothelial function (EndoPAT), and IMT were compared to gender- and age-matched patients with myocardial infarction and CHD, respectively healthy controls. Smoking, hypertension, impaired glucose tolerance and diabetes mellitus, inflammatory disease, and psychiatric disorders were more common in patients with MINCA than in healthy controls. In contrast to patients with CHD, the lipid profile was antiatherogenic with low low-density lipoprotein and high high-density lipoprotein cholesterol. There were no major differences between the groups regarding endothelial function and IMT that were in the normal range. In conclusion, the present study showed that MINCA was associated with many established cardiovascular risk factors without major differences in atherosclerosis markers. MINCA patients recalled a high prevalence of emotional stress before admission that together with previous psychiatric vulnerability and female gender speaks strongly in favor of Takotsubo syndrome being an important cause of MINCA.

Cardiovascular responses to upright and supine exercise in humans after 6 weeks of head-down tilt (-6 degrees).

Abstract Seven healthy men performed steady-state dynamic leg exercise at 50 W in supine and upright postures, before (control) and repeatedly after 42 days of strict head-down tilt (HDT) (−6°) bedrest. Steady-state heart rate (fc), mean arterial blood pressure, cardiac output (Q˙c), and stroke volume (SV) were recorded. The following data changed significantly from control values. The fc was elevated in both postures at least until 12 days, but not at 32 days after bedrest. Immediately after HDT, SV and Q˙c were decreased by 25 (SEM 3)% and 19 (SEM 3)% in supine, and by 33 (SEM 5)% and 20 (SEM 3)% in upright postures, respectively. Within 2 days there was a partial recovery of SV in the upright but not in the supine posture. The SV and Q˙c during supine exercise remained significantly decreased for at least a month. Submaximal oxygen uptake did not change after HDT. We concluded that the cardiovascular response to exercise after prolonged bedrest was impaired for so long that it suggested that structural cardiac changes had developed during the HDT period.