This review describes the clinical and basic research that led to the description of Flammer syndrome. It is narrated from a personal perspective. This research was initiated by the observation of an increased long-term fluctuation of visual fields in a subgroup of glaucoma patients. As these patients had strikingly cold hands, peripheral blood flow was tested with a capillary microscopy, and vasospastic syndrome (VS) was diagnosed. Further studies on these patients revealed frequently weakened autoregulation of ocular blood flow and increased flow resistivity in retroocular vessels. Their retinal vessels were more rigid and irregular and responded less to flickering light. Holistic investigation demonstrated low blood pressure, silent myocardial ischaemia, altered beat-to-beat variation, altered gene expression in the lymphocytes, slightly increased plasma endothelin level and increased systemic oxidative stress. This combination of signs and symptoms was better described by the term primary vascular dysregulation (PVD) than by VS. Subsequent studies showed additional symptoms frequently related to PVD, such as low body mass index, cold extremities combined with slightly increased core temperature, prolonged sleep onset time, reduced feelings of thirst, increased sensitivity to smell and also for certain drugs and increased retinal venous pressure. To better characterise this entire syndrome, the term Flammer syndrome (FS) was introduced. Most subjects with FS were healthy. Nevertheless, FS seemed to increase the risk for certain eye diseases, particularly in younger patients. This included normal-tension glaucoma, anterior ischaemic optic neuropathy, retinal vein occlusions, Susac syndrome and central serous chorioretinopathy. Hereditary diseases, such as Leber’s optic neuropathy or retinitis pigmentosa, were also associated with FS, and FS symptoms and sings occurred more frequent in patients with multiple sclerosis or with acute hearing loss. Further research should lead to a more concise definition of FS, a precise diagnosis and tools for recognizing people at risk for associated diseases. This may ultimately lead to more efficient and more personalised treatment. Flammer syndrome (FS)  describe2 [Interestingly, the very first roots of FS originated from research in perimetry in the early 80s when quantification of ocular blood flow (OBF) was difficult to obtain. To explain this, we must first highlight some steps in the development of perimetry. One of the authors (JF) was trained at the university of Bern, where Hans Goldmann had developed the Goldmann perimetry  Fig. 1a1a and Fr2  or treat2 , 63 also2 . What weIn the early 80s, a 45-year-old, slim, intellectual and sportive lady with progressive normal-tension glaucoma (NTG) came to see JF for a second opinion. She reported that her internist attested her to be of excellent health. However, her hands were strikingly cold, and, keeping the perimetry studies in mind, we asked whether this may somehow be related to her NTG. Although she emphasised that this was totally normal for her and that her mother also had cold hands, she agreed to be tested by nailfold capillaroscopy. The cold provocation led to a prolonged flow cessation in the nailfold capillaries and the angiologist diagnosed VS  Fig. 3a3a.Fig. 3We knew now that this patient had two conditions: VS and an NTG. What we did not know was whether these two conditions were related. When treating the VS with a CCB, not only did her hands became notably warmer but the visual fields also improved. After observing additional similar cases, we postulated that VS could be a risk factor for NTG . At thatTaken together, subjects with VS responded to provocation and treatment with both finger blood flow and the visual fields. These responders also seemed to be at greater risk for NTG and potentially for other eye diseases , 71. ButWhilst we know today that arterial hypertension increases the risk for ocular hypertension and thereby also the probability for high-tension glaucoma (HTG), arterial hypotension increases the risk for GON at a given IOP. The question of the role of systemic blood pressure (BP) in glaucoma was a matter of hot debate at that time. Some authors claimed hypertension and others hypotension to be related to glaucoma, yet others claimed that BP played no role at all. We monitored 24-h blood pressure  and founIn the early 1990s, colour Doppler imaging (CDI) reached a resolution that made it possible to measure blood flow or at least flow velocity in retroocular vessels Fig. . We estaWe also studied the physiology and pharmacology of the eye –113. TheTaken together, we learned (i) that ocular vessels were highly regulated, particularly by the vascular endothelium cells, and therefore, a dysregulation due to an endotheliopathy was conceivable; (ii) that the regulation was different from one vessel to another and there was even inhomogeneity within the same vessel; and (iii) that many different drugs influenced OBF. On the one hand, this opened the door for new therapeutic strategies, but on the other hand, it made it necessary to ask patients for local and systemic drugs they were using when interpreting OBF –150.The optic nerve head (ONH) was of special interest in diseases like glaucoma. However, measuring blood flow (BF) in the ONH was difficult , 152. ItAs a rule, correlations were always present in subjects with VS but not in others. This indicated that in subjects with VS, local regulation was less efficient, and therefore, systemic factors such as perfusion pressure gained more influence.In the early 1990s, it was known that obesity was a risk factor for many diseases including an IOP increase. However, our patients with NTG tended to be rather slim , 160 andWe were confronted with a functional vascular problem, measurable in the fingers but obviously also affecting the eye. We therefore asked whether this vascular phenomenon may also affect other organs such as the heart. Episodic asymptomatic ‘silent’ myocardial ischaemia was revealed by 24-h ECGs in many patients with glaucoma, especially normal-tension glaucoma. These episodes did not occur during exercise but at rest, particularly at night, indicating that they were not due to arteriosclerosis but rather due to a functional vasoconstriction –165.Our observations raised the question of whether this vascular dysfunction could be a consequence of an autonomic nervous system dysfunction . Whilst 13 capillaries and 1019 endothelial cells with a total volume that corresponds to the liver. In the past, the vascular endothelium was believed to be just a simple semi-permeable membrane lining the inner part of arteries, veins and lymphatic vessels. Today, we know that endothelial cells interact with immune cells and regulate haemostasis, angiogenesis and, in particular, the vascular tone [Beside autonomic innervation and circulating vasoactive hormones, the vascular endothelial cells play a crucial role in the local regulation of BF. The human body has about 10lar tone . They pllar tone . In humalar tone  . Under physiological conditions ET, a potent vasoconstrictor produced by vascular endothelial cells is mainly released abluminally to regulate local vascular tone . A smallVascular dysregulation refers to the regulation of blood flow that is not adapted to the needs of the respective tissue. We determined a vascular dysregulation to be ‘primary’ if no causing disease but a certain genetic predisposition was present , 201. FoAmongst the subjects with PVD, we relatively frequently saw cases diagnosed by their neurologists as suspected MS, confirmed MS and sometimes Susac syndrome. A certain but not yet well-understood interrelationship was obvious. On the one hand, PVD could imitate some symptoms and signs of MS-like paraesthaesia, temporal pallor of the ONH, visual field defects and prolonged latency in VEP or pathological MRI. In contrast to MS, however, we did not see oligoclonal bands in the cerebrospinal fluid of PVD subjects. On the other hand, MS (like other autoimmune diseases) could lead to a secondary vascular dysregulation  with incGiven the complexity of these different parameters and their interactions, one may wonder how we found different signs and symptoms related to PVD. Patients often reported elements seemingly unrelated to their diseases. If other patients reported similar symptoms, we became suspicious and studied a potential relationship with PVD.As many of our patients suffered from low BP, we asked them whether they drank enough. Most patients said yes, but not because they were thirsty, only because they knew they had to drink. A controlled study confirmed that subjects with PVD drank more or less enough but indeed had significantly less desire to drink . We assuOlfactory dysfunction is one of the first symptoms in neurodegenerative diseases. Therefore, we asked our glaucoma patients about smell perception. Whilst patients with glaucoma and with MS had reduced olfactory function , 236, suVisually handicapped subjects, such as patients with advanced glaucoma, potentially lose their circadian rhythms due to disturbed melatonin cycles. Melatonin mediates the arousal system and is also involved in thermoregulation by fine-tuning vascular tone in selective vascular beds . To fallOur patients often reported being ‘evening persons’. Subjects with PVD exhibited a normal phase relationship between skin temperature and sleep-wake rhythms  but a phWhen shaking hands with NTG patients, cold hands were often a striking symptom Fig. . When asPatients often told us stories that we could sooner or later relate to PVD. One patient felt an earthquake when nobody else around her could feel it. It turned out that she was actually right. Indeed, sensation to vibration was increased . AnotherPVD subjects did physical exercise more often and more vigorous than the average population, and they also seemed to enjoy it more. They particularly often indicated doing running and cycling. Very rarely, however, vasospasms were induced by exercise.Most subjects with PVD were healthy and also free of eye diseases. Nevertheless, they had an altered regulation of OBF . Some PVIn the early 1990s, we observed morphological alterations resembling fine epiretinal gliosis Fig. . Unlike Patients with central serous chorioretinopathy demonstrated a localised delay in arterial filling in the area of the damaged retinal pigment epithelium, frequently associated with dilated capillaries and draining venules. In some patients, localised choroidal ischaemia could be observed in additional areas throughout the central fundus in both diseased eyes and normal fellow eyes , 251. ClThe optic nerve head, although part of the central nervous system, lacks classical blood-brain barrier properties. In glaucoma, the blood-brain barrier in and around the optic nerve head was even weaker , 253. WeThe ONH is a very vulnerable tissue. It contains non-myelinated nerve fibres consuming more energy than myelinated fibres. In addition, they are exposed to light and to mechanical forces. The ONH lacks a normal blood-brain barrier, providing circulating molecules such as ET or angiotensin direct access to the smooth muscle cells. Whilst the arterial supply stems from the ciliary circulation, the veins empty into the retinal veins, causing the ONH perfusion dependent on retinal venous pressure. The intraocular vessels do not become arteriosclerotic, but the retroocular vessels are heavily involved in arteriosclerosis, probably due to extensive movement by the rotation of the eye. Correspondingly, arteriosclerosis is a strong risk factor for anterior ischaemic optic neuropathy (AION). Nevertheless, AION also occurred in non-arteriosclerotic patients in the presence of PVD. In this case, it occurred nearly always after emotional stress , 255. WeThe classical theory was that retinal vein occlusion (RVO) was a consequence of a thrombus in the retinal vein. In the mid-1990s, we saw seven patients with RVO at the age of <45 years. Extensive evaluations revealed no pathology except increased responses to coldness in the nailfold capillaries and a history of emotional stress . We hypoWe observed a cilioretinal arterial occlusion in a 17-year-old young man without any vascular risk factors except FS with an increased retinal venous pressure. With a treatment of a very low dose of nifedipine, the patient remained without relapse .Occlusions of small end arteries in the choroid with corresponding point-shaped infarctions of the pigment epithelium can frequently be observed in PVD subjects. Extended choroidal infarctions occur less frequent but have also been described .Retinitis pigmentosa (RP) refers to a group of degenerative eye diseases with a genetic background. Here, OBF seems to influence manifestation and progress. We observed reduced ocular pulse amplitude in RP patients . A revieIn optic nerve compartment syndrome (ONCS), there is proven segregation of CSF between the intracranial subarachnoid space and the subarachnoid space surrounding the optic nerve. This leads to differences of fluid composition, reduced CSF exchange and an extension of the optic nerve sheath diameter due to increased pressure , 264–274Leber's hereditary optic neuropathy (LHON) is a mitochondrial inherited retinal degeneration affecting predominantly young adult males. It leads to a subacute drop in vision with central visual field defects, starting in one eye and involving the other eye some weeks later. Most of the patients we saw also suffered from PVD . LOHN anVascular regulation is very complex and includes also alternating transient closing of microvessels. An increased ratio of temporally non-perfused vessels can also be a manifestation of a vascular dysregulation giving the impression of a reduced vessel density when blood flow is imaged, e.g. by optical coherence tomography angiography.glaucoma sometimes for an IOP increase (a risk factor for GON) and sometimes for GON. All the risk factors for arteriosclerosis were also risk factors for an IOP increase , together with some other authors, introduced in 2013 the new term Flammer syndrome. After the term had already been mentioned in different contexts , 321, itFS describes a phenotype characterised by the presence of PVD  togetherThe evolution of the present knowledge of FS stretched over several decades. It started with the observation of unexplained phenomena in the outcome of perimetry in glaucoma patients pointing towards the role of OBF. As OBF measurements were unsatisfactory at that time, nailfold capillaroscopy turned out to be a useful substitute until new methods to quantify OBF were introduced. The dynamic retinal vessel analyser finally allowed demonstrating vascular dysregulation. In vitro examinations of ocular vessels and analyses of gene expression of lymphocytes rendered an important basis for understanding the vascular dysfunction. Careful analysis of related symptoms and signs stimulated the initiation of a number of scientific studies. With growing knowledge, the terminology changed from vasospasm over vasospastic syndrome to primary vascular dysregulation and finally to Flammer syndrome.Additional research proved the involvement of FS not just in glaucoma but also in many other eye diseases such as vascular occlusions and retinitis pigmentosa, but also in systemic diseases such as MS. Establishing the risk for related diseases may lead to predictive and preventive diagnostics, and treatment tailored to the person. This may be particularly relevant for young FS individuals.U-shaped; and (e) methods to measure BF in vivo or to test blood vessels ex vivo and to quantify gene expression have been markedly improved in the last few decades.The FS is obviously not a new phenomenon. We can only speculate why it has not been recognised earlier. Several aspects may have been jointly responsible: (a) we focus often just on one organ; (b) we tend to prefer monocausal aetiologies; (c) BF dysfunction due to structural changes are easier to observe then changeable functional dysregulations; (d) we tend to extrapolate relationships, although they are often We emphasise that what we described here is only the state of present knowledge. We are convinced that the future will add additional aspects and also correct some of the present assumptions. Science is an ongoing process, and therefore, the understanding of the syndrome and its impact in medicine will further develop. However, our patients suffering from FS symptoms and FS-related diseases deserve to benefit now from the present knowledge, even though it is still limited. Patients are very pleased when they realise that they do not suffer from numerous independent symptoms and sings but rather from one syndrome. They are thankful for information on how they can improve the situation by adapting lifestyle and nutrition. A communication between the different physicians involved makes it possible to avoid unfavourable drugs and, if necessary, to replace them by a treatment adapted to FS in terms of both drug selection and dose.ABC, ATP-binding cassette; ARAMs, activated retinal astrocytes and Müller cells; BF, blood flow; BMI, body mass index; BP, systemic blood pressure; CCBs, calcium channel blockers; CDI, colour Doppler imaging; DNA, deoxyribonucleic acid; ECG, electrocardiogram; ET, endothelin; FS, Flammer syndrome; GON, glaucomatous optic neuropathy; HTG, high-tension glaucoma; IOP, intraocular pressure; LHON, Leberʼs hereditary optic neuropathy; MMP, metalloproteinase; MRI, magnetic resonance imaging; MS, multiple sclerosis; NTG, normal-tension glaucoma; OBF, ocular blood flow; OCT, optical coherence tomography; ONCS, optic nerve compartment syndrome; ONH, optic nerve head; PVD, primary vascular dysregulation; RVO, retinal vein occlusion; RVP, retinal venous pressure; VEGF, vascular endothelial growth factor; VS, vasospastic syndrome


IMPEDDANS study aims to assess the usefulness of ICG for the screening of left ventricular diastolic dysfunction (LVDD) in patients with HT.The use of impedance cardiography (ICG) may play a role in the assessment of cardiac effects of hypertension (HT), especially its hemodynamic features. Hypertensive heart disease involves structural changes and alterations in left ventricular geometry that end up causing systolic and/or diastolic dysfunction. The Patients with HT were assessed by echocardiography and ICG. Receiver-operating characteristic curve and the area under the curve were used to assess the discriminative ability of the parameters obtained by ICG to identify LVDD, as diagnosed by echocardiography.p < 0.001) with LVDD diagnosis, with good discriminative ability: PEP , LVET , STR  and presence of D wave . STR ≥ 0.30 outperformed the other parameters .ICG derived pre-ejection period (PEP), left ventricle ejection time (LVET), systolic time ratio (STR) and D wave were associated  on July 6, 2017.The study protocol was retrospectively registered as IMPEDDANS on ClinicalTrials.gov (ID:  Arterial hypertension (HT) causes high morbidity and mortality . The proIn diastolic dysfunction, there is a relative shift in LV filling to the final part of the diastole with a greater dependence on atrial contraction. These changes can be detected by Doppler echocardiography and by ICG .The phase of rapid passive ventricular filling at the onset of diastole produces the E wave and the atrial contraction produces the A wave. The E and the A waves on the Doppler sonography correspond to the O and A waves in ICG, respectively , 14. NorThe pre-ejection period (PEP), corresponding to the interval between the depolarization onset (Q-wave) and aortic valve opening that includes the excitation-contraction coupling and isovolumetric contraction of the LV, decreases with increasing LV pressure at the end of diastole, the main physiological consequence of diastolic dysfunction –18. On tThe thoracic fluid content (TFC) reflects the total volume of fluid (intravascular and extravascular) within the thoracic cavity, being inversely related to patient transthoracic electrical bioimpedance. It is therefore a reliable index of fluid overload in ambulatory patients. This parameter increases with the evolution of diastolic dysfunction being a sign of severity and has recently been proposed for monitoring diastolic heart failure patients , 21.The purpose of IMPEDDANS study is to assess the usefulness of ICG in the screening of LV diastolic dysfunction (LVDD) in patients with HT.This is a validation study of a diagnostic method (ICG) used for a new purpose (diagnosis of LVDD) comparing it with the clinical standard (echocardiography), the method currently used for this effect in usual clinical practice.Patients of either gender, aged 18–75 years, diagnosed with grade 2 or 3 HT (systolic blood pressure [BP] ≥ 160 mmHg and/or diastolic BP ≥ 100 mmHg) and/or with resistant hypertension (according the definition of ESH/ESC guidelines),  followedPatients were excluded in the presence of: pregnancy, height less than 120 cm or more than 230 cm, weight less than 30 kg or greater than 155 kg, heart failure II-IV NYHA,  heart raRecruitment began in January 2015 and was finished in July 2017.Sample size was estimated to test a hypothesized positive predictive value of 70 ± 5% of the ICG parameters with 95% confidence. Since the prevalence of LVDD in patients with HT is estimated, in most studies, , 23, 24 Considering that it would not be ethically acceptable to perform right heart catheterization of patients with grade 2 or 3 HT, we chose to design a concordance study between ICG and echocardiography, which is the clinical standard for the diagnosis of LVDD and characterization of hypertensive cardiomyopathy.Participants were invited to be systematically assessed by ICG and echocardiography, within a maximum interval of 8 days. To ensure that both tests were performed under similar conditions, evaluations matching variations greater than 10% in BP or variations more than 5% in HR were not considered. These patients were asked to repeat at least one of the exams. If the variations persisted, they were excluded.Demographic and clinical baseline data were collected from the patients’ medical records. Outpatient HT clinic protocol requires clinical evaluation, blood chemistry tests, electrocardiogram (EKG) and, eventually, 24 h ambulatory blood pressure monitoring (AMBP). Data regarding the comorbidities and medication were collected. Body mass index was calculated as weight (kg) divided by height (m) squared.ICG was carried out by an experienced cardiopneumology technician with Niccomo – Non-Invasive Continuous Cardiac Output Monitor  according the approved department protocol. According to this, patients had to present with 6 h of fasting but took their usual antihypertensive drugs. It was carried out in supine position during 20 min (continuous recording) and 70° orthostatism with the help of the tilting table (10 min in continuous recording). The test was interrupted if there was syncope or pre-syncope; dizziness, nausea and malaise associated with poorly tolerated hypotension and/or bradycardia; pain/precordial discomfort; EKG ST segment changes; systolic BP > 210 mmHg. Table 2 , always by the same three experienced cardiologists. To ensure uniformity of evaluation and correct evaluation, all exams were reviewed by one of the other cardiologists. In order to diagnose and classify diastolic dysfunction, the left atrium volume index, the velocities E, A, septal e’, lateral e’, deceleration time (DT), isovolumetric relaxation time (IRVT), atrial reverse velocity (Ar) and E/A ratio variation with Valsalva manoeuvre were recorded  as recommended by 2009 guidelines. We considered that patients had LVDD when present septal e’ < 8, lateral e’ < 10 and left atrial volume equal or greater than 34 mL/mThe estimated efficacy and effectivity measures are the positive predictive value (PPV), negative predictive value (NPV), sensitivity and specificity of the presence of the D wave and the values of PEP, LVET, STR, and TFC obtained by ICG to detect LVDD.25 - 75th percentile, P75) or amplitude (minimum - maximum).Categorical variables were described with frequencies and percentages. After evaluating the normal distributions of the continuous variables by the Kolmogorov-Smirnov test and histograms analysis, the variables that presented normal distribution were described with mean and standard deviation, and the variables without normal distribution were described with median and interquartile range .To compare the ICG parameters between patients with and without LVDD, Mann-Whitney test was used. Cut-off points were determined for ICG parameters  as predictors of occurrence of LVDD. Using the receiver-operating characteristic (ROC) curve cut-off points were determined regarding the diagnosis of LVDD capacity for screening purposes, thus high sensitivity was considered (>90%). The area under the curve (AUC) was estimated and 95% confidence intervals calculated using the binomial exact confidence interval method . DichotoThe study protocol was approved by the hospital’s Ethics Committee . Informed consent was obtained from each patient.ClinicalTrials.gov (ID: NCT03209141).The study protocol is registered as IMPEDDANS on IMPEDDANS study recruited 167 patients. Ten patients were excluded: three had syncope during ICG, three gave up and did not perform the tests, three had a significant dysrhythmia and one was diagnosed with atrial septal defect. From the 157 hypertensive patients included, 102 (65%) had LVDD (diagnosed by echocardiogram). Table The patients with LVDD diagnosis had significantly lower PEP and STR and higher LVET and TFC than the patients without LVDD Table . The D wp < 0.001), for LVET the AUC was 0.82 , the AUC was 0.97  for STR and for the presence D wave the AUC was 0.88   and five false positive (FP). The only FN case had STR = 0.32, which is only slightly above the cut-off value 0.31. No demographic, clinical and hemodynamic characteristics were found that differentiated the misclassified cases from the rest of the sample.In the IMPEDDANS study, the STR, with sensitivity of 99.0% and specificity of 90.9%, outperformed the other analysed variables as screening test for LVDD. This index only misclassified 5 FP cases, which determine a 95.3% PPV, and 1 FN case, which determines a 98.0% NPV.In the IMPEDDANS study, PEP ≤ 104 ms was identified as a good screening test for LVDD with sensitivity of 90.2% and PPV of 79.3%. PEP extends from the onset of ventricular depolarization to the opening of the aortic valve. It is composed of two sub-intervals, known as the period of the electromechanical coupling and the period of elevation of pressure (or isovolumetric systole). The electromechanical coupling period undergoes few changes in acute interventions, but changes in the final diastolic pressure, aortic diastolic pressure and in the mean velocity of elevation of LV pressure  in this period are the factors that determine the period of pressure rise and, consequently, PEP. Elevation of LV end-diastolic pressure (LVEDP), reduction of aortic diastolic pressure or gain in the rate of pressure increase in the pre-ejection period, lead to a time reduction. In mild LVDD, we expect a rise in LVEDP and a shortening of PEP, as we confirmed in this sample –18. Howe≥ 320 ms) was also a good LVDD screening tool with sensitivity 90.2%, and PPV 76.6%. Considering that active relaxation can be considered in the strictest sense as an early diastolic event, the time of onset of this process depends, at least in part, on systolic events such as the duration of contraction. In LVDD, increases in load during the contraction phase induce compensatory increases in duration of systole (LVET) and delayed onset of relaxation, which explain these results [Increased LVET , most of them taking diuretics . On the other hand, pulmonary congestion is more common in an advanced phase of hypertensive disease, when patients start to evidence heart failure symptoms, which were not included (only patients with mild asymptomatic LVDD were included).The diastolic properties of the LV are largely determined by the size or volume of the LV, the thickness, physical properties of the ventricular wall and the relaxation process of the myocardium. Thus, a combination of increased myocardial mass and changes in the extracellular collagen network may cause or contribute to an increase in the passive elastic rigidity of the ventricle with a diastolic pressure-volume relation represented by a steep curve. Disorders of the active myocardial relaxation process, acting alone or in conjugation with abnormal passive ventricular properties, may also cause increased ventricular rigidity. As a result, there is a reduction in the compliance and distensibility of the ventricle, the filling dynamics are changed and the final diastolic pressure increases. Under these circumstances, as the disease progresses, an increase in central blood volume may produce a substantial increase in LV diastolic pressure and, consequently, cause some degree of pulmonary congestion, which can be evidenced by an increase in TFC , 29, 30.During early diastole, the occurrence of a prominent wave may indicate diastolic dysfunction. As such, the presence of a pronounced diastolic O wave (D wave), in either upright or supine position, can be assumed as an evidence of diastolic dysfunction . Thus, iOur observational study has some weak points: the two tests were performed within a time lapse of 8 days. In order to minimize this weakness, evaluations matching variations >10% in BP or variations >5% in HR were not considered. Although sample was recruited by convenience of researchers all patients had strict inclusion and exclusion criteria, were submitted to the same evaluation protocols and patients were recruited non-consecutively. Significant strengths are the exclusion of the elderly (due to the influence of age on the physiopathology of diastolic dysfunction), and the fact that examinations have been performed in a clinical environment controlled by experienced professionals under well-defined protocols.Recommendations for the diagnosis of diastolic dysfunction were updated in 2016 (Fig. Despite all the potential demonstrated by the ICG, we must emphasize the importance of performing routine echocardiography in hypertensive patients, indispensable to provide the recommended basic echocardiographic assessments . In hypeICG can accurately screen LVDD in hypertensive patients, using its derived parameters STR, PEP, LVET and D wave. STR alone showed the highest discriminative ability. Therefore, we recommend its use as a LVDD screening tool.Future ICG studies applying the diagnostic test for LVDD will probably increase our understanding of the physiopathology/hemodynamics of HT and demonstrate that earlier detection and treatment of these hemodynamic features will favour patients’ evolution and, perhaps, reduce morbidity and mortality.


Acute kidney injury (AKI) is characterized by an acute decline in renal function and is associated to increased mortality rate, hospitalization time, and total health-related costs. The severity of this ‘fearsome’ clinical complication might depend on, or even be worsened by, the late detection of AKI, when the diagnosis is based on the elevation of serum creatinine (SCr). For these reasons, in recent years a great number of new tools, biomarkers and predictive models have been proposed to clinicians in order to improve diagnosis and prevent the development of AKI. The purpose of this narrative paper is to review the current state of the art in prediction and early detection of AKI and outline future challenges. Acute kidney injury (AKI) is an important health problem. Patients who develop AKI have markedly increased in-hospital mortality and, even if they do survive the acute phase, they still have an increased likelihood of morbidity and mortality over the long term –3. CurreFor all these reasons, over the last decade there has been considerable progress made in the discovery and development of new tools, predictive models and biomarkers of AKI; several of them have now been evaluated in different clinical settings –7. AlthoThe purpose of this narrative paper is to review the current state of the art in prediction and early detection of AKI. This shall be done by describing the most important and promising tools, biomarkers and potential innovations in this field. We will also focus on their real and potential applications in everyday clinical practice.Accessible markers of AKI can be components of serum or urine. Hopefully, one or more of these biomarkers, either alone or in combination, will prove to be useful in facilitating early diagnosis, guiding targeted interventions and monitoring the disease progression and resolution . The mosHuman neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa protein initially identified bound to gelatinase in specific granules of the neutrophil. NGAL is synthesized during a narrow window of granulocyte maturation in the bone marrow , but mayNGAL was identified as being one of the seven genes whose expression was upregulated more than tenfold within the first few hours after ischemic renal injury in a mouse model . AlthougNGAL has been one of the most widely studied biomarkers in AKI , in partNGAL shows the potential to be a simple and powerful biomarker able to provide an early (within a few hours) AKI diagnosis , and capCystatin-C (Cys-C) is a 13-kDa protein that was initially known as interalia γ-trace, post-γ-globulin, and gamma-CSF and is believed to be one of the most important extracellular inhibitors of cysteine proteases. Cys-C is freely filtered by the glomerulus, reabsorbed and catabolized, but not secreted, by the tubules. Over the past decade, serum Cys-C has been extensively studied and found to be a sensitive serum marker of the glomerular filtration rate (GFR) and a stronger predictor than SCr of risk of death and cardiovascular events in older patients , 31. TheWhen compared with (SCr), Cys-C seems to be less affected by age, gender, and body weight. Serum levels of Cys-C are a more precise indicator of kidney function than SCr levels , 38 but N-acetyl-β-d-glucosaminidase (NAG) in 201 patients with established AKI and found that elevated levels of urinary KIM-1 and NAG were significantly associated with the clinical composite endpoint of death or dialysis requirement, even after adjustment for disease severity or comorbidity [Kidney injury molecule-1 (KIM-1) is a type I cell membrane glycoprotein containing a unique six-cysteine immunoglobulin-like domain and a mucin domain in its extracellular region. KIM-1 was initially identified using representational difference analysis on kidneys following ischemia/reperfusion injury: KIM-1 mRNA levels increased more than any other known gene after kidney injury . In precorbidity .KIM-1 seems to be very useful in differentiating ATN from other forms of AKI. Furthermore, Koyner et al. also described a predictive preoperative power of KIM-1 in relation to the development of stage 1 and stage 3 AKI; this is probably due to the presence of subclinical proximal tubular injury reflected in increased KIM-1 levels .Propionibacterium acnes and lipopolysaccharide [Interleukin-18 (IL-18) is a cytokine that has been identified as an interferon-γ (IFN-γ)-inducing factor in livers of mice treated with ccharide . The preccharide . Renal Iccharide .Urinary IL-18 levels are elevated in patients with AKI and delayed graft function compared to normal subjects and patients with prerenal azotemia, chronic renal insufficiency, and nephrotic syndrome . IL-18 hFatty acid-binding proteins (FABPs) are small (15 kDa) cytoplasmic proteins abundantly expressed in all tissues with active fatty acid metabolism . Two typTissue inhibitor of metalloproteinases 2 (TIMP2) and insulin-like growth factor-binding protein 7 (IGFBP7) are markers of cellular stress in the early phase of tubular cell injury caused by a wide variety of insults  –70. Ther+  is a neuroendocrine hormone synthesized in the adrenal cortex –77. EO m calpain  with an  calpain ) or, via calpain ).Recently, a significant association has been reported of preoperative EO levels with adverse renal outcomes in cardiac surgery patients and with mortality in critically-ill patients. In one study , elevateRecently, some new potential biomarkers have been proposed for early determination of AKI in specific conditions. Clusterin , 90, ostA potential association has been described between some of the new early biomarkers of AKI and the presence of chronic subclinical kidney damage. In this way, these biomarkers should also be considered markers of progression from AKI to CKD with a prognostic value.In a cross-sectional study of 80 non-diabetic patients with CKD stages 2–4, serum NGAL was found to be elevated in those with the most advanced CKD . MoreoveIn a retrospective study of patients with non-diabetic proteinuric kidney disease, KIM-1 levels in urine were found to be elevated, but subsequently decreased when patients received treatment with angiotensin-converting enzyme inhibitors or a low-sodium diet . In a reIn two different studies (on diabetic and non-diabetic patients), urinary L-FABP was found to be more sensitive than proteinuria in predicting the progression of CKD , 104.Cys-C is considered a “functional biomarker” of AKI because it is freely filtered and reabsorbed by the proximal tubule and this process is inhibited in the presence of kidney damage . It has Although all these new molecules are promising candidate biomarkers for AKI, they are still rarely used in everyday clinical practice. Even if the primary results are really encouraging, the use of Cys-C, NGAL or other alternative makers of early AKI is still an area of ongoing research . Indeed,Furthermore, the assays for detection are not standardized and it is still under discussion whether is better to use urine or plasmatic values. Indeed, Mårtensson et al. proposed that the plasma NGAL level is a closer reflection of systemic inflammation than of the extent of renal injury inflicted . FinallySepsis represents the one of the main causes of AKI in developed countries , 114. ItNovel AKI biomarkers already have shown an ability to identify SA-AKI before SCr levels. Plasma and urine NGAL levels were significantly higher in 83 patients with SA-AKI compared to patients with nonseptic AKI . In 150 Finally, some studies have shown an association between SI-AKI and some acute phase proteins or kidney function protein. E-selectin  was associated with AKI in patients after sepsis ; microalUnfortunately, several studies reported that plasma levels of some molecules (e.g. NGAL and Cys-C) are deeply influenced by the inflammatory state , 127; thRecently several tools have been proposed to determine the severity of kidney damage and the long-term patient prognosis after kidney injury has been established . BetweenKoyner et al.  recentlyThe concept of renal functional reserve (RFR) was introduced in the 80 s . The renConsidering the ongoing issues regarding early AKI detection, it is becoming strategically important to identify subjects with an increased risk of acute renal damage after a therapeutic procedure. This is dramatically true, for example, in post-surgical AKI. More so, neither the new markers of early AKI nor, least of all, the “classic” SCr or blood-urea-nitrogen (BUN) levels are able to identify susceptible patients. All these molecules start to increase in blood and urine when the kidney damage already exists; but it is reported that poor outcomes can be observed just with an increased risk of AKI, even before the kidney damage occurs see Fig. . An accua priori” of AKI risk, not just a score for post-event outcomes.The most robust and externally validated models are for AKI requiring dialysis. However, dialysis events are rare (1–2%) and frequently occur several days after the operation, limiting the benefit of application of these scoring systems . More stpre-operative prediction power of the models is preserved.Despite all these limitations, the use of clinical prediction models for AKI is currently the only validated strategy available to identify patients with a particularly high risk. Recently, several studies  have shoA new concept—renal angina—was introduced in 2010 by Goldstein and Chawla , 148. ThIt is well known in clinical practice that two patients with identical backgrounds and clinical risk factors can react differently to the same insult. Therefore, models using traditional risk factors remain inadequate , 154–156In AKI the role of genetic variation as a determinant of both risk and outcome is not well defined . RecentlUsually in postoperative cardiac surgery, the patient’s inflammatory mediators are elevated because CPB, ischemia–reperfusion injury and endotoxemia from general hypoperfusion represent a significant systemic inflammatory trigger , 163. AsPolymorphisms of modulators of renal vascular tone have also been proposed as mediators of increased renal risk. These genes include angiotensin-converting enzyme insertion/deletion (ACE I/D), angiotensinogen, angiotensin receptor 1, and endothelial NO synthase . Only a Polymorphism ε4 apolipoprotein E (APOE), an important regulator of lipoprotein metabolism and immunomodulation, has been associated with a postoperative rise in creatinine in several studies , 166 in Oxidative stress genes (like NADPH) and haptoglobin 2–2 polymorphism have been studied as contributors to postoperative risk , 168. PrAlthough several polymorphisms have been investigated, most studies focused on a select number of individual genes in small homogenous sample populations. Overall, the results have been variable and often inconsistent across studies . The lac‘Omic’ technologies  should give researchers a holistic view of the molecules that are expressed (or overexpressed) in both physiological and pathological conditions –171. TheAcute kidney injury is a very dangerous complication. It is associated with an increased risk of mortality and morbidity, and longer hospital stay, requires additional treatment, and increases the costs of the heath care. This clinical syndrome is characterized by a progressively worsening course, being the consequence of an interplay of different pathophysiologic mechanisms. Several different factors, like hemodynamic or inflammatory status, genetic background and use of nephrotoxic compound, are all involved. Unfortunately, the heterogeneity of AKI subtypes poses a great limit for large population studies in human subjects. In this setting, the use of classic clinical predictive models associated with novel renal biomarkers  may well be the only way to refine the methods of treatment and improve the prognosis of patients. Introduction of novel independent biomarkers of AKI into the clinical setting is crucial for earlier diagnosis and improved risk assessment. The purpose of this review was to help clarify the biological basis of new AKI biomarkers that might contribute to improving the early detection or diagnosis of this pathology. But before biomarkers can be advocated for the diagnosis of AKI, further research is needed. Our understanding of how to prevent and manage AKI in an optimal way requires additional effort.


Background: Omalizumab improves asthma control in patients with uncontrolled severe allergic asthma; however, appropriate patient selection is crucial. Information in this field is sparse.Objective: We aimed to estimate whether potential omalizumab candidates were appropriately selected according to guidelines, and the clinical effect of omalizumab treatment over time.Design: We performed a retrospective observational study on adult patients with asthma treated with omalizumab during 2006–2015 at the Department of Respiratory Medicine at Odense University Hospital (OUH), Denmark. Data were obtained from the Electronic Patient Journal of OUH and Odense Pharmaco-Epidemiological Database. Guideline criteria for omalizumab treatment were used to evaluate the appropriateness of omalizumab candidate selection, and the Asthma Control Test (ACT) to assess the clinical effects of omalizumab at weeks 16 and 52 from treatment initiation.Results: During the observation period, 24 patients received omalizumab, but only 10 patients (42%) fulfilled criteria recommended by international guidelines. The main reasons for not fulfilling the criteria were inadequately reduced lung function, insufficient number of exacerbations, and asthma standard therapy below Global Initiative for Asthma (GINA) step 4–5. Seventeen and 11 patients completed treatment at weeks 16 and 52, with a statistically significant increase in ACT score of 5.1 points  and 7.7 points , respectively.Conclusion: Only 42% of the omalizumab-treated patients were appropriately selected according to current guidelines. Still, as omalizumab showed significant improvement in asthma control over time, it is important to keep this drug in mind as an add-on to asthma therapy in well-selected patients. For patients completing 52 weeks of treatment, mean ACT scores increased by 7.7 points  and nine (82%) patients had a clinically significant increase in ACT score compared with the index date. p = 0.03) and seven (p = 0.01) further patients having ACT scores of ≥ 20 after 16 and 52 weeks of omalizumab treatment, respectively.During the observation period, 18 and 12 patients completed 16 and 52 weeks of treatment, respectively. However, one patient was excluded owing to a missing ACT score at the index date. A statistically significant increase in mean ACT score by 5.1 points [95% confidence interval (CI) 3.1–7.2, p = 0.02) higher increase than men in mean ACT score from the index date to the 16 week follow-up, and the same tendency was present after 52 weeks, with a 6.39 point mean ACT score increase (p > 0.05) for women. The ACT mean scores increased in the two follow-ups in both genders, but only women had a statistically significant increase.Women had a 4.56 point  and 10 percentage points , respectively. The matching changes in mean FEV1 were 0.31 L and 0.29 L, respectively. The remaining PFT measurements showed no significant changes, and are illustrated in The mean FEVp > 0.05) exacerbations compared to the year before the index date (data not shown).The mean number of exacerbations decreased throughout the 52 weeks. However, one patient was responsible for the majority of the total number of exacerbations, corresponding to seven out of 11 (64%) and four out of seven (57%) exacerbations, respectively, after 16 and 52 weeks of omalizumab treatment. Furthermore, we found that the frequency of annual asthma exacerbations reduced by 28% or an average of 0.64  > 30 kg/mThe main finding of this study was that only 42% of the patients with severe asthma treated with omalizumab had been appropriately selected according to current guidelines ,14–16. DAccording to objective 1, previous studies have not paid much attention to the appropriateness of selecting patients for omalizumab treatment in clinical settings, which is why there is no direct frame of reference. Changes in the selection criteria during the observation period could, however, have had a negative influence on the overall proportion of well-selected patients, as the criteria used in this study are based on current guideline recommendations –16. ThusThe results of objective 2 are consistent with findings from previous studies documenting that treatment with omalizumab in patients with severe persistent asthma increases asthma control and reduces exacerbation rates . A large2 and men 28 kg/m2; data not shown), as obesity is a known predictor of poor asthma control [2014,Women had better asthma control than men at both 16 and 52 weeks. The association between gender and asthma control may be confounded by the higher BMI among women , the UK National Institute for Health and Care Excellence (NICE), and the Danish Society of Respiratory Medicine, with only two minor differences. First, in the mentioned guidelines an ACT score < 20 was not an inclusion criterion for omalizumab treatment –16. In on = 24 versus non-responders n = 5)  , which cThis study found that only 42% of the patients with severe asthma treated with omalizumab were appropriately selected according to current guidelines. Yet, omalizumab is an important add-on treatment option for well-selected asthma patients, as demonstrated by a significant improvement in asthma control. Future studies should focus on how to improve the selection of patients for omalizumab treatment and encourage identification of specific determinants of patients who are likely to benefit from the treatment, rather than the use of predetermined baseline characteristics.


A determinant of blood pressure is adiposity; however, there are uncertainties surrounding whether general or central adiposity is the more important determinant of blood pressure. Further, inconsistent results exist for the relationships of anthropometric measures with blood pressure and hypertension, and whether these relationships differ substantially by age and sex is unclear. We aimed to elucidate the associations of anthropometric measures of general and central adiposity with blood pressure and hypertension, and determine the effect of age and sex on these relationships.n = 7 601; age 18–59 years). We examined the associations of anthropometric measures  with blood pressure components  and hypertension within four  age groups, by sex. We adjusted all analyses for education and location, with further adjustments, variously, for either a measure of central (waist circumference) or general (body mass index) adiposity.We used cross-sectional data from the Centre for Global Health Research health check-up survey conducted during 2006–2007 of the general population in India , the associations of body mass index with blood pressure components and hypertension were greatly diminished for both sexes, and particularly in the ≥30 years age groups. By contrast, further adjustment of waist circumference for body mass index did not materially alter the associations of waist circumference with blood pressure components and hypertension.On average, every 5 kg/mOur findings indicate that central adiposity, as assessed with anthropometric measures, may be a more important determinant of blood pressure and hypertension than general adiposity for adults in India. India is undergoing a rapid health transition with substantial increases in chronic non-communicable diseases, such as cardiovascular disease (CVD) , 2, wherA main determinant of blood pressure is adiposity –10, and Reliable assessment of the relationships of anthropometric measures with blood pressure and hypertension in India and other LMICs is of particular importance. Clarification of these associations will contribute additional evidence to aid in facilitating the allocation of resources for public health promotion and prevention of hypertension and CVD. Additionally, by improving our understanding of whether a simple measure of general or central adiposity is more strongly associated with blood pressure and hypertension may help focus screening efforts and risk stratification of clinical populations where the measurement of blood pressure is not feasible. However, most previous studies from India are small, from one region, provide conflicting evidence, and do not fully investigate the effect of age and sex on these relationships –14. IndeWe therefore examine the independent and joint association of anthropometric measures of general and central adiposity with various blood pressure components and hypertension, and determine the effect of age and sex on these relationships in a sample of adults from the general population of India.n = 7 784). Of these participants, 119 were excluded because of pregnancy, and 64 due to missing data for either level of education, SBP, DBP, height, weight, WC, or HC.We conducted a cross-sectional study investigating the relationships between anthropometric measures of adiposity, blood pressure, and hypertension in India. In order to aid in the characterization of disease and death of individuals, households and communities, the Centre for Global Health Research health check-up survey of the general population of India was conducted during 2006 and 2007. Participants were recruited in four states  and two union territories  from randomly selected sampling units , which were based on the 1991 census . We usedField teams consisting of trained surveyors visited houses identified in their respective sampling units to obtain consent and enroll participants (surveyors made at least three visits to each household). All data collection was done in the household following a standardized protocol. In addition to physical measurements, participants were interviewed to obtain information on demographic, socioeconomic, lifestyle characteristics and antihypertensive medication use.Blood pressure was measured twice at heart level, in a seated position after 5 min of rest using the Omron  digital automatic blood pressure monitor. SBP and DBP were calculated as the average of the two readings, pulse pressure as the difference between SBP and DBP, mean arterial pressure as a third SBP plus two thirds DBP, and mid-blood pressure as half SBP plus half DBP. Hypertension was defined as SBP ≥140 mmHg or DBP ≥90 mmHg, or reported use of antihypertensive medication.Height was measured with a measuring tape to the nearest 0.1 cm. Individuals were requested to stand upright without footwear, with their head, back, buttocks and heels against a wall, arms at their sides, feet together and eyes directed forward. Height was then measured as the distance from the top of the head to the ground. Weight was measured on a hard level surface to the nearest 0.1 kg using the KRUPS  weighing scale, without footwear and only light clothing. WC was measured to the nearest 0.1 cm using a measuring tape. Measurements were taken at the midway point between the lower rib and iliac crest without clothing when possible. If participant did not want to move aside clothing, it was indicated and measurements were taken above light clothing. HC was measured to the nearest 0.1 cm using a measuring tape. Measurements were taken at the point yielding the maximum circumference over the buttocks with individuals wearing light clothing. In order to account for clothing, 1 cm was subtracted from measured values. BMI was calculated as weight in kilograms divided by the square of height in meters. WHR was calculated as WC in centimeters divided by HC in centimeters, and WHtR as WC in centimeters divided by height in centimeters.We performed all analyses separately for men and women. We calculated Pearson’s partial correlation coefficients for the relationships between anthropometric measures  and blood pressure , adjusted for age and location. We used multiple linear regression models to quantify the association between each anthropometric measure with each continuous blood pressure component, and Poisson regression models to quantify the relationship between each anthropometric measure and hypertension. We evaluated age as an effect measure modifier by including age and anthropometric measure interaction terms in regression models, and by examining the stratum-specific estimates by age groups .We estimated the means of each blood pressure component, and calculated the prevalence ratios (PR) for hypertension per sub-group specific standard deviation (SD) change in anthropometric measures within each age group. 235 individuals  who reported current use of antihypertensive medication were excluded from the continuous blood pressure analyses. We used two models for all analyses, model 1 adjusted for level of education  and location , and in model 2 additional adjustments were made for either WC or BMI. Further adjustment for alcohol  and tobacco  use did not materially affect these estimates (results not presented). We performed all statistical analyses using SAS version 9.3 , and provide estimates with their respective 95% confidence intervals (CI).Distribution of the mean (SD) anthropometric measures, blood pressure components, and hypertension prevalence by sex and age groups are presented in Table The means for all anthropometric measures were lowest in the youngest age group (18–29 years) and increased in older age groups for both men and women. BMI and HC were similar between both sexes in the youngest age group, and slightly higher among women in the older age groups. By contrast, mean WC and WHR were higher (~6–7 cm and 0.08–0.1 respectively) for men than women across all age groups. There were no discernible differences for mean WHtR between the sexes.The intercorrelations of anthropometric measures and blood pressure components are shown in Table 2 greater BMI or 10 cm wider WC was associated with a 5 and 4 mmHg higher SBP, and a 4 and 3 mmHg higher DBP, respectively. Independently, each measure was strongly and positively associated with SBP and DBP for both sexes across all age groups (model 1). However, after additional adjustment for WC or BMI, the association of each anthropometric measure with SBP and DBP were markedly different, and largely dependent on the age group (model 2).The changes in SBP and DBP [mmHg per SD (95% CI)] for each anthropometric measure by sex and age groups are presented in Tables Among men in the 18–29 and 30–39 years age groups, the association between WC and SBP was slightly weaker than the relationship between BMI and SBP. By contrast, the association between WC and DBP was stronger than the relationship between BMI and DBP. Further, in the 30–39 years age group, the association between BMI and DBP was largely diminished (3.44 to 0.52 mmHg) with the additional adjustment for WC. In comparison, additional adjustment for BMI did not materially alter the relation between WC and DBP. Among women in the 18–29 years age group, BMI remained significantly associated with both SBP and DBP after adjusting for WC. However, further adjustment for BMI greatly reduced the strength of association of WC with SBP and DBP, from 3.05 mmHg to 1.01 mmHg and 2.40 mmHg to 0.53 mmHg, respectively.p < 0.05) after further adjustment for BMI. Overall, the relationship of HC and WHR with SBP and DBP diminished with additional adjustment for BMI for both sexes across all age groups. Comparably, the associations of WHtR with SBP and DBP were also weakened after adjustment for BMI, with the exception of WHtR with SBP in the 50–59 years age group for both sexes.The additional adjustment for WC greatly attenuated the relationship of BMI with SBP and DBP in the two older age groups  for both men and women. By contrast, the association of WC with SBP and DBP for men, and WHtR and SBP, and WC and DBP for women were only slightly attenuated and remained significant (p < 0.05) negative association between WHtR and pulse pressure after adjustment for BMI for men in the 18–29 [−1.53 ] and 30–39 [−1.25 ] years age groups  associated with hypertension when considered separately (model 1). Overall, the associations of central adiposity measures (mainly WC or WHtR) with hypertension were slightly stronger than between BMI and hypertension for both sexes. The relationships of HC and WHR with hypertension were somewhat weaker than those observed with WC and WHtR.Figures p = 0.37), there was a slight negative association between HC and hypertension for women in the youngest age group.After additional adjustment for WC, the relationship between BMI and hypertension was largely diminished across all age groups, particularly for men (model 2). Conversely, with a few exceptions, the relationship of WC and WHtR with hypertension remained predominantly unaffected after the additional adjustment for BMI. However, for women in the youngest (18–29 years) age group, additional adjustment for BMI reduced the association of WC and WHtR with hypertension. In addition, although not statistically significant  age groups, the relation between WC and SBP was somewhat weaker than between BMI and SBP. Nevertheless, in the same age groups, WC was more strongly associated with DBP than BMI. Indeed, DBP may be a more important component of blood pressure than SBP in these age groups; since many studies have shown the significance of DBP over SBP as the main driver of vascular risk in young adults . MoreoveApart from the youngest (18–29 years) age group, the associations between anthropometric measures and blood pressure among women were similar to those for men. The observed difference for younger women may be explained, at least in part, by the marked heterogeneity in body fat distribution between men and women, and differences in the rate of abdominal fat accumulation. For instance, women generally have a higher percentage of body fat with a more peripheral distribution as compared to men, who have a more central distribution . Hence, The associations of anthropometric measures with hypertension were, for the most part, comparable to those observed with continuous blood pressure. A slight negative  relationship was present between HC and hypertension after adjusting for BMI among women in the youngest age group. This may be due, in part, to the protective effects of an increased HC. A larger HC for a given BMI may be indicative of increased gluteofemoral fat, which has been shown to be independently associated with a better metabolic profile, and decreased odds of diabetes, dyslipidemia, and hypertension , 23. FurRelative to the other anthropometric measures considered in our study, the association of WHR with all blood pressure components and hypertension was weak. The comparative differences in central body fat distribution may not be indicated by the WHR. For example, a similar WHR can be obtained by having both a large WC and HC or a small WC and HC. Moreover, differences in abdominal fat, specifically visceral adiposity may not be aptly reflected by changes in WHR . This maSeveral mechanisms that link greater adiposity to elevated blood pressure and risk of hypertension have been proposed , 10. In Our study has some limitations that should be considered when interpreting the results. First, the cross-sectional design does not allow for causal inferences to be made about the relationships of adiposity with blood pressure and hypertension. Second, there may be other confounding factors than those available for consideration in our study. However, the largely causal association between adiposity and blood pressure is well established . Thus, iIn summary, we provide evidence for the discrete relationships between anthropometric measures of general and central adiposity with various blood pressure components and hypertension in India. Greater emphasis should be placed on measures of central adiposity, such as WC and WHtR for both sexes, than BMI as an adiposity measure in future studies investigating the associations between risk factors for high blood pressure and CVD outcomes.


However, current clinic indices for the evaluation and detection of PAD are usually focused on large vessels. Nuclear imaging approaches have superior in the assessment of muscle perfusion and have been used in quantitatively assessment of lower extremity perfusion in patients.–6 However, its clinical application is limited by the lacking of standard analysis method. Hill function is a concentration-response function, which can be candidate for simulating tissue and cellular uptake of Tc-99m 2 methoxy-isobutyl-isonitrile (99mTc-MIBI) dynamics. This study took a novel Hill function-based analysis of 99mTc-MIBI scintigraphy data, to evaluate earlier lower extremity perfusion changes in diabetic patients.Impairment of microcirculation represented by lower extremity muscle perfusion has already occurred in patients without typical clinical symptoms.22.199mTc-MIBI  were performed, and serial dynamic posterior planar images were recorded for 5 minutes in the regions of both calves. Using an image analysis device , serial summed images and time-activity curves were created from the data. Fourteen patients from the PAD_DM group who underwent CTA and performed endovascular interventions were further divided into 3 groups according to the trans-atlantic inter-society consensus document (TASC) grading method, namely a mild group (TASC A), a moderate group (TASC B), and a severe group (TASC C and D). A flow chart representing the above participants’ selection and breakdown of the group intervention was provided , diabetes group , n = 34), and diabetes with the PAD group . ABI is obtained by using the blood pressure differential between the brachial systolic blood pressure and systolic blood pressure from the posterior tibial artery, with a hand-held Doppler . For the lower extremity muscle perfusion assessment, the intravenous injection of a 370-640 MBq 10-20 mCi) bolus of 0-20 mCi  which fits concentration-response curve data. Similarly, the tissue uptake of 99mTc-MIBI is proportional to blood flow, and its cellular uptake and retention are dependent on mitochondrial and plasma membrane potentials. Hill function parameters were fitted using the greedy algorithm method implemented in Matlab software (Mathworks). Since the matching of target distribution is associated with simulating steps, we used 100,000 steps to ensure the accuracy of our parameter distributions.Originally, the Hill function was proposed to describe the in vivo concentration response relationship,The Hill function can be written as Vmax: the maximum 99mTc-MIBI perfusion counts in the tissue.t: time-dependent observed 99mTc-MIBI perfusion counts in the tissue.K: under the condition of u = v, half-saturation constant 99mTc-MIBI perfusion counts.u, v: constants of effect response, and their ratio represents the steepness of the effect-concentration curve, which is a measure of how strongly the 99mTc-MIBI perfusion counts changes in response to changes in time.. We can derive the peak time of the curve, , which is the measurement of muscle perfusion ability.Let 2.2t-test for continuous variables of 3 or 2 groups comparison respectively. A 2-sided P value of less than 0.05 was considered to indicate statistical significance. All statistical analyses were conducted with the use of SPSS software, version 13.0 (SPSS Inc.).All results were presented as mean ± SD. Differences among groups were compared by means of the chi-squared test for categorical variables, and 1-way analysis of variance (ANOVA) with Bonferroni's multiple comparison post-hoc test and Students’ 33.1hs-CRP), and low density lipoprotein cholesterol between DM and PAD_DM groups. The diabetic patients with PAD exhibited profoundly decreased ABI values (P < .001) compared with the other groups.The clinical baseline characteristics of the participants in each group are presented in Table 3.299mTc-MIBI muscle perfusion data are also provided in Table 99mTc-MIBI muscle perfusion counts compared with healthy participants , and decreased lower extremity muscle perfusion became more profoundly in the DM_PAD group. No differences were found in half saturated 99mTc-MIBI muscle perfusion counts among 3 groups, which may represent the smaller differences of the basic characteristics among groups. The peak times of the lower extremity muscle perfusion of DM and DM_PAD groups were significantly prolonged compared with the Cont group , whereas the results showed no significant relation with PAD.The estimated Hill function parameters using the 3.399mTc-MIBI muscle perfusion counts decreased dramatically with the severity of the vascular lesions represented by the TASC vascular grade increased , although the peak time of the muscle perfusion failed to reach statistical significance  curve to evaluate our method's diagnostic accuracy.This study has several limitations. First, this is an observational study, and the generality of its results to other countries is still unclear. Second, our study did not include nondiabetic patients with PAD, and the difference between them and diabetic patients with PAD needs further study. Third, due to the lack of well-documented statistical methods on analyzing 99mTc-MIBI scintigraphy analysis. Further studies of the indications for 99mTc-MIBI scintigraphy in diabetic patients are warranted.This study provided an effective and noninvasive method for the earlier evaluation of lower limb microvascular perfusion in diabetic patients via the use of Hill function based The authors thank Dan Wang from Department of Nuclear Medicine for technical assistance. They also thank all the patients and investigators for their participation.


There are limited prospective data however on progression of arterial stiffness in CKD, including evaluating associations with bone mineral markers such as fibroblast growth factor 23 (FGF23) and soluble α-klotho (sKl).Arterial stiffness is an independent predictor of allIn this prospective, single-center, observational study, arterial stiffness [measured by pulse wave velocity (PWV)] and hormones influencing mineral homeostasis, including serum FGF23 and sKl, were compared between non-dialysis CKD stages 4/5 and healthy controls at baseline and 12 months (12 m). Abdominal aortic calcification (AAC) was quantitated using lateral lumbar radiography at baseline.2] and 42 controls (mean eGFR 88.6 ± 12.9 mL/min/1.73m2) completed follow-up. There were no differences in age, gender and body mass index between groups. A significant increase in FGF23  was observed in the CKD group but serum phosphate, corrected calcium, parathyroid hormone and sKl did not change significantly over 12 m. At baseline, CKD subjects had higher AAC prevalence  and higher aortic PWV  compared to controls. At 12 m, aortic PWV increased by 1.3 m/s  in the CKD cohort, with 30% of subjects showing progression from normal aortic elasticity to stiffening (PWV > 10 m/s). Serum FGF23 was associated with AAC, abnormal PWV and progression of PWV at 12 m.Forty patients with CKD [mean estimated glomerular filtration rate (eGFR) 19.5 ± 6.7 mL/min/1.73mArterial stiffness and serum FGF23, both of which are associated with increased cardiovascular risk, increased over one year in individuals with CKD. Additionally, a significant association was found between serum FGF23 and arterial calcification and stiffness. Larger clinical studies and further experimental work are warranted to delineate the temporal relationship as well as the pathological mechanisms linking FGF23 and vascular disease.The online version of this article (10.1186/s12882-017-0705-4) contains supplementary material, which is available to authorized users. Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD) . A major2D], and is associated with regulation of parathyroid hormone (PTH) by klotho dependent and independent pathways , 1,25(OH)equation . Random Plasma FGF23 levels were measured using the Kainos intact-FGF23 ELISA kit  according to the manufacturer’s protocol. Intra-assay and inter-assay analytical coefficients of variation (CV) were 7.3% and 9.9% respectively for samples measured in duplicate. Serum sKl concentrations were measured using the IBL soluble klotho ELISA kit  according to the manufacturer’s protocol with intra-assay and inter-assay analytical CVs 4.1% and 9.3%, respectively, for samples measured in duplicate. All baseline and follow-up samples were measured concurrently.Aortic PWV (m/s) was measured by a single clinician using a non-invasive tonometer  placed over the carotid and femoral arteries at rest. Pressure signals were calibrated using brachial blood pressure and measurements were taken of the distance of the carotid and femoral pulses from a fixed point . PWV was calculated using the foot-to-foot method, gated to the cardiac cycle using a 3-lead electrocardiograph . A validThirty-six CKD and 36 control subjects agreed to undergo additional evaluation with lateral lumbar radiography. Abdominal aortic calcification (AAC) score was calculated using a validated 24 points system  by a radDescriptive statistics were used to represent characteristics between the CKD and control groups at the study entry. Results were expressed as frequencies and percentages for categorical variables, mean ± standard deviation (SD) for normally distributed variables and median (interquartile range) for non-normally distributed variables. Baseline differences between the groups were analyzed by chi-square test for categorical data, unpaired t-test for continuous normally distributed data and Wilcoxon-Mann Whitney test for continuous non-normally distributed data. PWV, FGF23, PTH and sKl were log transformed. Associations between AAC and PWV and predictor variables of interest were assessed using Pearson correlation coefficients for continuous normally distributed variables and Spearman’s correlation for categorical or non–normally distributed data.http://www.stata.com). P values of less than 0.05 were considered statistically significant for all described analyses.Changes in parameters over time were assessed by comparison between baseline and follow-up data using paired t-test and Wilcoxon signed ranks test as appropriate. Multivariate linear regression was used to evaluate the associations between bone parameters and AAC score, PWV at 0 and PWV at 12 months. In addition, logistic regression was used to evaluate the predictors of the following binary measures; AAC and abnormal PWV in the entire study population. Model diagnostics were performed for all linear regression models. Data were analyzed using standard statistical software  but not with sKl . Similarly, serum phosphate , calcium  25(OH)D , 1,25(OH)2D  and PTH  were associated with FGF23 levels but not with sKl.At baseline, eGFR strongly correlated with plasma FGF23  to 130(51–187) mg/mmol p = 0.02] were observed only in the CKD group. Three patients commenced dialysis within the one-year study period. A significant increase in FGF23 was seen in the CKD subjects [240.6(141.9–1129.8) to 396.8(160.3–997.7) pg/mL p = 0.001] compared to controls . No other significant changes were observed over the 12-month period for other BMM markers and biochemical parameters assessed including sKI and PTH, blood pressure measurements or medication use for both groups , phosphate , 1,25(OH)2D , FGF23. Presence of aortic calcification and higher AAC score were independently associated with higher FGF23 [odds ratio (OR): 7.43 95% confidence interval (CI) 1.07–51.8 for AAC ≥ 1 and adjusted coefficient of 2.61 95%CI 1.21–4.01 for AAC score] in the entire study cohort  versus (vs.) controls 1(0–5), 4 versus p = 0.047, Table p = 0.1). In univariate analysis, FGF23  versus (vs.) controls: 8.1(7.2–9.7) m/s, 1.7 versuF23 Fig. , PTH, php < 0.001) among CKD subjects but did not significantly change in controls after one year . Following adjustment for the total study population, only diabetes, higher baseline PWV and higher FGF23 remained independent predictors of PWV at 12 months , although this study was largely limited by a lag time of up to two years between the measurement of FGF23 and vascular imaging [The association between FGF23 and VC also lacks consistency in the current literature. The Chronic Renal Insufficiency Cohort (CRIC) investigators reported no association between intact-FGF23 levels and coronary/thoracic artery calcium in 1501 patients with earlier stages of CKD  the relatively small sample size in both groups and the single-center design potentially limited the generalizability of the study’s findings; 2) progression of AAC was not assessed as follow-up lumbar X-ray was not obtained; 3) a cause-effect relationship could not be identified due to the observational nature of the study; 4) several co-existing conditions, such as underlying diabetes, CVD and physical inactivity, that were prevalent in the CKD group may have confounded the observed associations in this study; 5) even though a large number of patient characteristics (including diabetic status) were adjusted for, the possibility of residual confounding cannot be excluded; 6) information on dietary phosphate intake and urinary phosphate excretion, which may directly influence change in FGF23 and sKl, was not collected in this study and 7) evaluation of cardiac function and structure was also not collected in this study and may have provided valuable information on the link between FGF23 and cardiovascular disease.FGF23 and PWV were observed to substantially increase in CKD subjects compared to controls over a year. Elevated circulating FGF23 levels were associated with aortic calcification and progression of arterial stiffness independent of other BMM markers evaluated in this study in both CKD and controls. These findings should be confirmed in large, prospective studies and in those with earlier stages of CKD. Causal relationships should be explored further in vitro with a view to interrogating mechanistic pathways and seeking potential therapies that may be useful in reducing the vascular burden in CKD.Additional file 1: Figure S1.Flow diagram of recruitment. (DOCX 35 kb)Additional file 2: Table S1.Changes in bone mineral markers, biochemical variables, blood pressure and medications over 1 year in CKD and controls. (DOCX 15 kb)


Nonspecific ST-segment and T-wave (ST-T) changes represent one of the most prevalent electrocardiographic abnormalities in hypertensive patients. However, a limited number of studies have investigated the association between nonspecific ST-T changes and unsatisfactory blood pressure (BP) control in adults with hypertension.The study population comprised 15,038 hypertensive patients, who were selected from 20,702 participants in the China Stroke Primary Prevention Trial. The subjects were examined with electrocardiogram test at the initial visit in order to monitor baseline heart activity. According to the results of the electrocardiogram (defined by Minnesota coding), the subjects were divided into 2 groups: ST-T abnormal and ST-T normal. Unsatisfactory BP control was defined as systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg following antihypertensive treatment during the 4.5-year follow-up period. Multivariate analysis was used to analyze the association between nonspecific ST-T abnormalities and unsatisfactory BP control.P = 0.005]), independent of traditional risk factors, as demonstrated by multivariate regression analysis. Notable differences were further observed in male subjects  and in patients with comorbid diabetes .Nonspecific ST-T changes were common in hypertensive adults (approximately 8.5% in the study), and more prevalent in women (10.3%) and diabetic patients (13.9%). The unsatisfactory BP control rate was high in the total population (47.0%), notably in the ST-T abnormal group (55.5%). The nonspecific ST-T abnormal group exhibited a significantly greater rate of unsatisfactory BP control (odds ratio [OR] 1.20, 95% confidence interval [CI] , Greater rates of unsatisfactory BP control in hypertensive patients with electrocardiographic nonspecific ST-T abnormalities were observed, notably in the subcategories of the male subjects and the diabetic patients. The outline of the Report on Cardiovascular Disease in China (2014) demonstrated that the hypertension control (BP <140/90 mm Hg) rate was approximately 9.3% of all patients, and/or 27.4% of treated patients, although 42.6% of hypertensive patients in China were aware of their condition and 34.1% were receiving treatment. Furthermore, the BP control rate was lower in female subjects and rural patients compared with that in male subjects and urban patients, respectively. The electrocardiogram (ECG) is a routine, accessible, cost-effective, and recommended diagnostic tool for the initial evaluation and follow-up of hypertensive patients. In the standard surface ECG, nonspecific ST-segment and T-wave (ST-T) changes are a common finding. Recently, a majority of studies have indicated that nonspecific ST-T abnormalities are significantly associated with cardiovascular morbidity and mortality.–9 However, the prognostic significance of nonspecific ST-T abnormalities for BP control has not been fully investigated.Hypertension is a common chronic disease that affects a great proportion of the population worldwide. It is considered one of the major risk factors for the development of cardiovascular diseases such as stroke, ischemic heart disease, and heart failure.The goal of the present study was to determine whether nonspecific baseline ST-T ECG abnormalities are associated with unsatisfactory BP control in hypertensive patients. The study aimed to provide information on the potential improvement of the management of hypertension.22.1 The detailed description of the stage designed and the methodology have been previously described. Eligible participants were men and women 45 to 75 years of age who had hypertension. The major exclusion criteria included the history of stroke, myocardial infarction, heart failure, coronary revascularization, and/or congenital heart disease. Individuals with a missing ECG measurement, an illegible ECG, and/or ECG abnormalities inconsistent with nonspecific ST-T changes  at baseline .ine Fig.  were furThe CSPPT protocol was approved by the ethics committee of the Institute of Biomedicine, Anhui Medical University, Hefei, China (FWA assurance number FWA00001263). All participants provided written informed consent for their participation in the study protocol. The study protocol was conducted according to the principles of the Declaration of Helsinki that ensure that the safety and well-being of the patients is protected and that the integrity of the data is preserved.2.2The CSPPT was a multicommunity, randomized, double-blinded clinical trial conducted between May 19, 2008, and August 24, 2013, in 32 communities in the Jiangsu and Anhui provinces of China. The present study was a prospective cohort study. The 15,038 participants with baseline ECG measures were stratified according to the presence and/or absence of nonspecific ST-T abnormalities using the Minnesota coding criteria. Eligible participants were subsequently divided into 2 groups: ST-T abnormal and ST-T normal. All ECGs were recorded and analyzed by 2 trained medical professionals. In the case of a disagreement regarding the interpretation of an ECG, a third reading was conducted jointly until a final interpretation of the ECG was achieved.2.32 to V6 (MC 4-3); ST-J depression ≥1.0 mm and ST-segment upward sloping or U-shaped, in any of leads I, II, aVL, or V1 to V6 (MC 4-4); T-wave amplitude zero (flat), negative, or diphasic (negative–positive type only) with <1.0-mm negative phase in leads I, II, V3 to V6, aVL when R-wave amplitude is ≥5.0 mm (MC 5-3); and T-wave amplitude positive and T- to R-wave amplitude ratio of <1:20 in any of leads I, II, aVL, or V3 to V6 when R-wave amplitude in the corresponding leads was ≥10.0 mm (MC 5-4).The Minnesota code (MC) criteria for nonspecific ST-T abnormalities were used, as described by the MC ECG classifications 4-3, 4-4, 5-3, and 5-4. The criteria were defined as follows: no ST-J depression ≥0.5 mm but ST-segment downward sloping and ST-segment or T-wave nadir at least 0.5 mm below the P-R baseline, in any of leads I, II, aVL, or VHypertension was defined as seated resting systolic blood pressure (SBP) of ≥140 mm Hg or diastolic blood pressure (DBP) of ≥90 mm Hg at both the screening and recruitment visits and/or use of antihypertensive medication. The BP of the participants was measured during the follow-up period every 3 months from 2008 to 2013. During each visit, the participants were required to rest in a seated position for at least 5 minutes prior to the measurement. BP was measured 3 times at 5-minute intervals by a trained physician with an electronic sphygmomanometer . The mean of the 3 readings was calculated for the measurement of the BP. The average of 20 measurements at 20 different visits was used as the final BP value. Overall unsatisfactory BP control was defined as SBP of ≥140 mm Hg or DBP of ≥90 mm Hg following antihypertensive treatment.Diabetes mellitus was defined as self-reported clinically diagnosed diabetes or use of hypoglycemic agents or a fasting blood glucose concentration of ≥7.0 mmol/L (≥7.0 mmol/L). Body mass index (BMI) was calculated as weight (in kilograms) divided by height (in square meters).12 at both the baseline and the exit visits were measured by a commercial laboratory kit using a chemiluminescent immunoassay . Serum homocysteine, fasting lipids, and glucose levels at the baseline and the exit visit were measured using automatic clinical analyzers  at the core laboratory of the National Clinical Research Center for Kidney Disease, in Nanfang Hospital, Guangzhou, China.Serum folate and vitamin B2.42 tests for categorical variables and t tests and/or Wilcoxon rank-sum tests for continuous variables, as appropriate. The prospective association between nonspecific ST-T changes and unsatisfactory BP control was examined using Cox proportional hazard regression models following adjustment for the covariates. Multiple linear regression was used to assess the association between ST-T abnormality and change of blood pressure under treatment. Furthermore, multivariate logistic regression analysis was used to evaluate the impact of electrocardiographic nonspecific ST-T abnormalities on unsatisfactory BP control in the subgroup analyses. A 2-tailed P-value <0.05 was considered statistically significant.Data were analyzed using the Empower Stats software. The results are presented as mean ± standard deviation for continuous variables and frequence(percentage) for categorical variables. Baseline characteristics were compared between participants in the presence and/or absence of nonspecific ST-T abnormalities using χ3The study population included 15,038 participants (62.1% women) from the CSPPT, which is representative of a low- to medium-risk Chinese hypertensive population. The BP control rate for the total population was 53.0%. The prevalence of nonspecific ST-T abnormalities in the population investigated was 8.5%, whereas prevalence was greater in women (10.3%) and diabetics (13.9%).The baseline characteristics are shown in Table 12, total cholesterol level, high-density lipoprotein cholesterol, and BMI (Table P = 0.005]), whereas with regard to the stratified categories significantly different results were obtained in male  and not in female subjects .The presence and absence of nonspecific ST-T abnormalities significantly differed among related demographic and clinical variables Table . This trP < 0.001, and β 0.50, 95% CI , P = 0.002, respectively). In addition, these patients revealed lower values in the relative percentage decrease in SBP and DBP . Importantly, the aforementioned differences were noted in male and not female subjects.The associations between baseline electrocardiographic ST-T abnormalities and changes in BP following treatment are shown in Table P = 0.002) and subjects with comorbid diabetes .Table 4The major advantage of the present study was the large sample size derived from the CSPPT. The CSPPT was a large randomized trial conducted in adult subjects with hypertension in China without a history of stroke or myocardial infarction. The results of the trial demonstrated that enalapril–folic acid therapy significantly reduced the relative risk of an initial stroke incident by 21% compared with enalapril monotherapy. Given the well-characterized population, the standardized assessment of ECGs using the MC criteria, and the 4.5-year longitudinal follow-up period, the CSPPT study provided a unique opportunity to assess the prevalence of nonspecific ST-T changes in order to identify differences between genders and to explore whether nonspecific ST-T changes were associated with increased risk of unsatisfactory BP control. The study further provided insight regarding the potential predictive value of unsatisfactory BP control. The possible explanations of the aforementioned findings may be the rigorous design of the CSPPT and the strict follow-up schedule applied by trained research staff and physicians, which ensured high adherence of patients to the prescribed treatment regimen. The control rate of the present study conducted in China was similar to that noted in 2 studies conducted in America  and Italy .In the present study, the rate for the achievement of target BP levels of the total population was 53.0% and that was considerably greater compared with that previously reported in a national survey among adult participants in China (27.4% among treated hypertensive participants).,12–16 The greater prevalence of nonspecific ST-T changes in women has been attributed to the interplay of a variety of factors of anatomic, structural, hormonal, autonomic, and genetic origin. High blood glucose is associated with comorbidities such as hypertension, hyperlipidemia, and a prothrombotic state that interact synergistically to promote cardiac changes. The latter changes in turn result in ECG abnormalities, including nonspecific ST-T changes.The current study demonstrated that nonspecific ST-T changes in the ECG of hypertensive patients can be used for the identification of a greater risk of unsatisfactory BP control, notably in male participants and patients with diabetes mellitus. The prevalence of nonspecific ST-T abnormalities was 8.5%, and the prevalence was greater in women (10.3%) and in patients with diabetes (13.9%). This finding is consistent with previous studies.,18 As a result, nonspecific ST-T changes could be considered an early indicator of poor BP management. Following adjustment for the covariables, the current study indicated that hypertensive patients with baseline nonspecific ST-T abnormalities exhibited a higher rate of unsatisfactory BP control  , and/or athletic ability.


Although pulmonary hypertension due to left heart disease (LHD-PH) accounts for the largest proportion of pulmonary hypertension, few reports on the epidemiological analysis of LHD-PH exist. Recently, pulmonary arterial capacitance (PAC) has attracted attention as a possible factor of right ventricular afterload along with pulmonary vascular resistance. We therefore investigated the clinical significance of PAC in LHD-PH.st quartile was 0.74 to 1.76 ml/mmHg, the 2nd quartile 1.77 to 2.53 ml/mmHg, the 3rd quartile 2.54 to 3.59 ml/mmHg, and the 4th quartile 3.61 to 12.14 ml/mmHg). The end-points were defined as rehospitalization due to worsening heart failure and/or cardiac death. The Cox proportional hazard regression model was used to determine what variables were associated with cardiac events.The subject consisted of 252 LHD-PH patients  diagnosed by right heart catheterization. PAC was estimated by the ratio between stroke volume and pulmonary arterial pulse pressure. Patients were classified into four groups according to the PAC . The event-free rate of the 1st quartile was significantly lower than that of the 3rd and 4th quartiles . The Cox hazard analysis revealed that PAC was significantly associated with cardiac events .The patients in the 1PAC is useful in the prediction of cardiac event risk in LHD-PH patients. In pulmonary arterial hypertension (PAH), narrowing of the vessel lumen occurs by thickening of the medial wall or growth of endothelial cells in the peripheral vessels of the lung. Pulmonary vascular resistance (PVR) is defined as (mean pulmonary artery pressure [PAP]—mean pulmonary capillary wedge pressure [Pcw])/pulmonary blood flow . PVR refPulmonary hypertension due to left heart disease (LHD-PH) is most common in pulmonary hypertension. LHD-PH was defined as mean Pcw > 15 mmHg and mean PAP ≥ 25 mmHg at rest according to the European Society of Cardiology (ESC) criteria , 7. HoweThe study subjects consisted of consecutive 252 LHD-PH patients who had been diagnosed using right heart catheterization between January 2006 and June 2015 at Fukushima Medical University. We excluded cases of acute heart failure, acute coronary syndrome, IPAH, connective tissue disease-associated pulmonary hypertension, pulmonary hypertension due to lung disease, and chronic thromboembolic pulmonary hypertension. All catheterizations were performed within 7 days after echocardiography in a resting supine position under fluoroscopic guidance. PAP, Pcw, mean right atrial pressure (RAP) and cardiac output were measured using a 7F Swan-Ganz catheter . We mainly used the thermo dilution method for the measurement of cardiac output, however, for cases of advanced tricuspid regurgitation, we used the Fick method. The diastolic pressure gradient (DPG) was defined as the difference between the mean Pcw and the diastolic PAP . The traTransthoracic echocardiography was performed by an experienced echocardiographer using standard techniques . The lef2 test for the non-continuous variables. Survival curves were estimated by the Kaplan-Meier method and compared using the log-rank test. Comparison of the area under the receiver-operating characteristic (ROC) curve (AUC) was carried out by a De Long test. A Cox proportional hazard model was used to analyze the association between clinical factors and cardiac events. The proportional hazards assumption for the model was checked by examining log minus-log transformed Kaplan-Meier estimates of the survival curves for two groups plotted against time to follow-up period. These curves help in identifying non-proportionality patterns in hazard function such as convergent (difference in risk between the 2 groups decreases with time), divergent, or crossing of the curves. In addition, Schoenfeld test for the violation of proportional hazards, which assess the correlation between scaled residuals and time, was also conducted. As the proportional-hazard assumptions were violated in the above-mentioned diagnostic test, the extended Cox hazard model was used for time-varying exposure of the adjusting variable. A P value of < 0.05 was considered significant for all comparisons. We considered the following clinical factors, which are generally known to affect the risk of cardiac events in heart failure patients: age, sex, atrial fibrillation, presence of ischemic etiology, New York Heart Association (NYHA) functional class, LVEF, levels of B-type natriuretic peptide (BNP), estimated glomerular filtration rate (eGFR), and hemoglobin. Additionally, the following hemodynamic parameters were selected based on previous studies: cardiac index, SV index, mean RAP, systolic PAP, diastolic PAP, mean PAP, mean Pcw, PP, PVR, DPG, and TPG [Normally distributed variables were presented as the mean ± SD, and non-normally distributed variables were presented as median (inter-quartile range). Categorical variables were expressed as numbers and percentages. The baseline characteristics of the groups were compared using analysis of variance for the continuous variables and the χ and TPG , 6, 9. Ast to the 4th quartiles, according to PAC. The range of PAC in the 1st quartile was 0.74 to 1.76 ml/mmHg, the 2nd quartile 1.77 to 2.53 ml/mmHg, the 3rd quartile 2.54 to 3.59 ml/mmHg, and the 4th quartile 3.61 to 12.14 ml/mmHg. Distribution of PAC in each quartiles was showed in st quartile contained a larger number of patients with valvular heart disease and a higher NYHA class compared with the 4th quartile. As for the hemodynamic parameters, the cardiac index (CI), SV index were significantly lower in 1st quartile. The systolic PAP, diastolic PAP, mean PAP, mean Pcw, PVR, and TPG were significantly higher in the 1st quartile. However, there were no significant differences in the levels of mean RAP and DPG. In the laboratory data, BNP was significantly higher in the 1st quartile. In terms of medication for heart failure, the use of diuretics, digitalis, and inotropic agents was higher in the 1st quartile. st quartile had the lowest event free rate compared to the other groups .In total, 253 patients were diagnosed with LHD-PH by right heart catheterization and 252 patients were followed-up . The medIn the Cox hazard model, PAC, NYHA classification, non-ischemic etiology, SV index, mean RAP, systolic PAP, diastolic PAP, mean PAP, mean Pcw, PP, LVEF, BNP, eGFR, and hemoglobin level were significantly associated with cardiac events .We analyzed the ROC curve of each hemodynamic index as a prognostic predictor of cardiac events and compared PAC with each hemodynamic index . The AUCIn the present study, we showed that patients with lower PAC had significantly higher cardiac event rates than those with higher PAC. PAC was significantly associated with cardiac death and worsening heart failure in LHD-PH patients.Our study indicated that NYHA classification, BNP, anemia and CKD were recognized as predictive factors for cardiac events even if the patients were limited to LHD-PH. One of the possible mechanisms might be the involvement of cardio-renal-anemia syndrome in pulmonary hypertension as reported previously . Yambe eC-pcPH is known to be associated with a worse prognosis than I-pcPH , 6. HoweThere are some potential limitations in the present study. First, we measured cardiac output by both thermo dilution method and Fick’s method. It raises the issue that there is a variability between Fick’s method and thermos dilution method. However, we used thermos dilution method in routine and the number of patients who used Fick’s method was small. Second, during this study period, volume analysis by cardiac MRI and the measurement of impedance were not performed in routine. Further investigation including these parameters is required in the future.In the present study, we showed the importance of PAC when predicting cardiac event risk in LHD-PH patients. PAC should also be considered as an important contributing factor of right ventricular afterload. Further multicenter studies are required in future to fully validate these findings.