Use of proteomics to identify biomarkers associated with chronic kidney disease and long-term outcomes in patients with myocardial infarction.

BACKGROUND: Patients with chronic kidney disease (CKD) have poor outcomes following myocardial infarction (MI). We performed an untargeted examination of 175 biomarkers to identify those with the strongest association with CKD and to examine the association of those biomarkers with long-term outcomes. METHODS: A total of 175 different biomarkers from MI patients enrolled in the Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies (SWEDEHEART) registry were analysed either by a multiple reaction monitoring mass spectrometry assay or by a multiplex assay (proximity extension assay). Random forests statistical models were used to assess the predictor importance of biomarkers, CKD and outcomes. RESULTS: A total of 1098 MI patients with a median estimated glomerular filtration rate of 85 mL min-1 /1.73 m2 were followed for a median of 3.2 years. The random forests analyses, without and with adjustment for differences in demography, comorbidities and severity of disease, identified six biomarkers (adrenomedullin, TNF receptor-1, adipocyte fatty acid-binding protein-4, TNF-related apoptosis-inducing ligand receptor 2, growth differentiation factor-15 and TNF receptor-2) to be strongly associated with CKD. All six biomarkers were also amongst the 15 strongest predictors for death, and four of them were amongst the strongest predictors of subsequent MI and heart failure hospitalization. CONCLUSION: In patients with MI, a proteomic approach could identify six biomarkers that best predicted CKD. These biomarkers were also amongst the most important predictors of long-term outcomes. Thus, these biomarkers indicate underlying mechanisms that may contribute to the poor prognosis seen in patients with MI and CKD.

The value of a new cardiac magnetic resonance imaging protocol in Myocardial Infarction with Non-obstructive Coronary Arteries (MINOCA) - a case-control study using historical controls from a previous study with similar inclusion criteria.

BACKGROUND: Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA) is common with a prevalence of 6% of all patients fulfilling the diagnosis of myocardial infarction. MINOCA should be considered a working diagnosis. Cardiac Magnetic Resonance (CMR) imaging has recently been suggested to be of great value to determine the cause behind MINOCA. The objectives of this paper are to describe the rationale behind the second Stockholm Myocardial Infarction with Normal Coronaries (SMINC-2) study and to discuss the protocol for investigation of MINOCA patients in the light of the recently published position paper from the European Society of Cardiology. METHODS: The SMINC-2 study is an open non-randomised study using historical controls for comparison. The primary aim is to prove that MINOCA patients investigated with the latest CMR imaging technique can achieve a diagnosis in 70% of all cases entirely by imaging. By including 150 patients we will have >80% chance to prove that the diagnostic accuracy can be improved by 20 absolute % with a p-value of less than 0.05 when compared with CMR imaging in the SMINC-1 study. Furthermore, in addition to invasive coronary angiography, coronary arteries are evaluated by computed tomography angiography to investigate coronary causes and questionnaires are used to describe Quality-of-Life (QoL). By January 1st 2017, 75 patients have been included. DISCUSSION: Whether CMR imaging can provide a diagnosis to an adequate proportion of MINOCA patients is unknown. Well-defined inclusion and exclusion criteria will be used to compare a MINOCA cohort from the population with an appropriate control group. Positive results are likely to influence future guidelines of the management of MINOCA. Furthermore, the study will give mechanistic insights into MINOCA in particular in patients with "true" myocardial infarction and describe QoL in this vulnerable group of patients. TRIAL REGISTRATION: Clinical Trials NCT02318498 .

Novel combined management approaches to patients with diabetes, chronic kidney disease and cardiovascular disease.

Most patients we care for today suffer from more than one chronic disease, and multimorbidity is a rapidly growing challenge. Concomitant cardiovascular disease, renal dysfunction and diabetes represent a large proportion of all patients in cardiology, nephrology and diabetology. These entities commonly overlap due to their negative effects on vascular function and an accelerated atherosclerosis progression. At the same time, a progressive subspecialisation has caused the cardiologist to treat 'only' the heart, nephrologists 'only' the kidneys and endocrinologists' 'only' diabetes. Studies and guidelines follow the same pattern. This often requires patients to visit specialists for each field, with a risk of both under-diagnosis and under-treatment. From the patient's perspective, there is a great need for coordination and facilitation of the care, not only to reduce disease progression but also to improve quality of life. Person-centred integrated clinics for patients with cardiovascular disease, renal dysfunction and diabetes are a promising approach for complex chronic disease management.

Effects of deep and superficial experimentally induced acute pain on skin sympathetic nerve activity in human subjects.

There is evidence in experimental animals that deep and superficial pain exert differential effects on cutaneous sympathetic activity. Skin sympathetic nerve activity (SSNA) was recorded from the common peroneal nerve of awake human subjects and injections of 0.5 ml hypertonic saline was made into the tibialis anterior muscle (causing a deep, dull ache) or 0.2 ml into the overlying skin (causing a sharp burning pain) at unexpected times. Both deep and superficial pain caused increases in SSNA immediately on injection and preceding the onset of pain for both muscle and skin pain (10.1 +/- 2.4 vs. 15.3 +/- 5.3 s; muscle versus skin, respectively). SSNA increases were short lasting (104.2 +/- 13.4 vs. 81.8 +/- 11.7 s; muscle versus skin pain) and did not follow muscle and skin pain profiles. Sweat release occurred following both intramuscular and subcutaneous injections of hypertonic saline. While muscle or skin pain invariably caused changes in skin blood flow as well as increases in sweat release, skin blood flow increased in females and decreased in males. We conclude that both acute muscle and skin pain cause an increase in SSNA, sweat release and gender-dependent changes in skin blood flow.

Baroreflex impairment during rapid posture changes at rest and exercise after 120 days of bed rest.

Orthostatic intolerance is common after space flight and head-down tilt (HDT) bed rest. We hypothesized that HDT-induced impairments of arterial blood pressure (AP) control would be more marked during exercise and that recovery of baroreflex function after very long-term HDT would be delayed. Six subjects were studied before (BDC) during (day 60, D60; D113) and after (recovery day 0, R0; R3; R15) 120 days of HDT. Supine resting subjects were exposed to repeated 1 min passive tilts to upright at 3-min interval. During 50 W steady-state exercise corresponding tilt had a 2-min duration at 4-min interval. The amplitudes of the tilt-induced transient beat-by-beat deviations in AP and rate (HR) were determined during the gravity transients. At rest these deviations did not change over time, but during exercise the total peak-to-nadir range of deviations in systolic AP (SAP) at up-tilt and down-tilt increased to 168+/-16% (mean+/-SEM) of BDC at D113 with no clear recovery upto and including R15. Counter-regulatory HR responses were not increased proportionally and especially not tachycardic responses to up-tilt, resulting in a reduction of baroreflex sensitivity (deltaRR-interval/deltaSAP) by 55+/-9% of BDC at D113 with no recovery upto and including R15. We conclude that prolonged bed rest cause long-lasting impairments in AP control and baroreflex function in exercising humans.

Impaired pressor response after spaceflight and bed rest: evidence for cardiovascular dysfunction.

We hypothesized that impaired cardiovascular responses to isometric muscle action contribute to the cardiovascular deconditioning that occurs after space flight (SF) and head-down-tilt bed rest (HDT). Six subjects were studied before, during and after 120 days of -6 degrees HDT, and four subjects were studied before, during (two subjects) and after 179-389 days of SF. Subjects performed a sustained handgrip (SHG) at a force equivalent to 30% of maximum contraction force for 2 min, and heart-rate (HR) and pressor (mean arterial pressure, deltaMAP) responses were recorded. At the same relative force, both deltaHR and deltaMAP were significantly reduced during the first days after HDT (-54%, P<0.05 and -43%, P<0.05). In two subjects studied within 24 h after their return from SF, deltaMAP was practically absent (-79%, P<0.05) whereas in four subjects studied 1-4 days after return from SF, deltaMAP was reduced by 35% (P<0.05). deltaHR was not significantly changed. Our finding of attenuated pressor responses to SHG after HDT and SF supports the notion of impairments at both the neurocirculatory control and effector organ levels.

Haemodynamic and baroreflex responses to whole-body tilting in exercising men before and after 6 weeks of bedrest.

We sought to determine whether the cardiovascular deconditioning that occurs in exercising men after prolonged (42 days) bedrest in the head-down tilt (HDT) position is primarily related to mechanical changes in the heart or to an impaired arterial-cardiacchronotropic baroreflex. Seven subjects were studied before (C, control) and repeatedly after HDT with rapid tilting between the upright and supine positions during steady-state 50-W dynamic leg exercise. Ventricular interdependence was assumed to be an index of cardiac size; it was assessed on the basis of the initial dip of arterial pulse pressure (PP) induced by a sudden tilt from the upright to the supine position (down-tilt). Arterialcardiac-chronotropic baroreflex sensitivity (ABS) was assessed as the ratio between tilt-induced heart rate transients and the preceding (and reciprocal) transient in arterial pressure. On the first day of recovery, the initial PP dip was -4 (2) mmHg (where 1 mmHg is 0.13 kPa), less than half of the control value; on subsequent recovery days, the initial PP dip was not significantly different from the control value. When tilting from the upright to the supine position, mean ABS ranged from 1.02 to 1.06 bpm/mmHg during three separate control sessions. Tilts in the opposite direction gave lower ABS values because of the more sluggish HR response and ranged from 0.43 to 0.45 bpm/mmHg in the control situations. ABS did not change after HDT. Our results indicate that impairments of the cardiovascular system after long-term bedrest are of haemodynamic rather than baroreflex origin.

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

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 degrees) bedrest. Steady-state heart rate (fc), mean arterial blood pressure, cardiac output (Qc), 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 Qc 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 Qc 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.

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.