AW) and pericardial pressures. Catheter‐tip pressure manometers measured aortic, LV, left atrial, and PA pressures. The pericardium and chest were closed. At LV end‐diastolic pressure (PLVED) = 5 mmHg and 12 mmHg, PEEP was varied  during CV. Then, at airway pressures equal to those during CV, HFOV was applied at 4 Hz, 10 Hz, and 15 Hz. Increased AW decreased pulmonary vascular conductance. As cardiac output increased, conductance increased. At PLVED = 12 mmHg, conductance was greatest during HFOV at 4 Hz. LV preload  was similar during HFOV and CV for all conditions. At PLVED = 12 mmHg, SWLV was similar during CV and HFOV, but, at PLVED = 5 mmHg and AW 10 cm H2O, SWLV was lower during HFOV than CV. Compared to pulmonary vascular conductance at higher frequencies, at PLVED = 12 mmHg, conductance was greater at HFOV of 4 Hz. Effects of CV and HFOV on LV preload and performance were similar except for decreased SWLV at PLVED = 5 mmHg. These observations suggest the need for further studies to assess their potential clinical relevance.High‐frequency oscillatory ventilation (HFOV) may improve gas exchange in patients who are inadequately ventilated by conventional mechanical ventilation (CV); however, the hemodynamic consequences of switching to HFOV remain unclear. We compared the effects of CV and HFOV on pulmonary vascular conductance and left ventricular (LV) preload and performance at different airway and filling pressures. In anesthetized dogs, we measured LV dimensions, aortic and pulmonary artery (PA) flow, and mean airway  have similar effects on LV preload and performance except for worse LV performance at a low filling pressure. We also found that pulmonary vascular conductance was greater during high‐frequency oscillatory at 4 Hz at LV end‐diastolic pressure of 12 mmHg compared to at higher frequencies. Conventional mechanical ventilation (CV) may be insufficient to maintain adequate gas exchange in seriously ill patients and may also cause or aggravate lung injury. High‐frequency oscillatory ventilation (HFOV) has been used to improve gas exchange in patients who cannot be adequately ventilated by conventional means, while putatively limiting lung injury  pressure) and left ventricular (LV) preload and systolic performance.The experimental protocol was approved by the University of Calgary animal care committee, whose criteria are consistent with those of the American Physiological Society.2 and nitrous oxide. Tidal volume and respiratory rate were initially set at 17 mL/kg and 18 breaths/min, respectively , were anesthetized initially with 25 mg/kg thiopental sodium i.v.  and a 5 mg/mL i.v. bolus of midazolam  and were maintained with fentanyl citrate , which was adjusted as necessary to ensure deep sedation without spontaneous respiratory effort. The animals were intubated with a cuffed endotracheal tube (9 mm diameter) and ventilated initially with a constant‐volume respirator  with a 1:1 mixture of Os Pascoe ), and weDSLVFW) and LV anterioposterior (DLVAP) dimensions  was measured at a port on the adapter attached to the proximal end of the endotracheal tube with an air‐filled tube (2 mm diameter) connected to a pressure transducer . A single‐lead electrocardiogram (ECG) was recorded. A flat, fluid‐filled balloon transducer .A median sternotomy was performed with the animals in the supine position. For instrumentation, the heart was delivered from the pericardium via a base‐to‐apex incision. Sonomicrometry crystals  were implanted in the LV endocardium and midwall of the septum to measure minor‐axis septum‐to‐LV free wall (PAo)  and LV pressure (PLV) (inserted through a carotid artery). Catheter‐tip pressure manometers  were used to measure left atrial (PLA) , and pulmonary artery (PPA)  pressures. An intravenous line was placed in the left external jugular vein for volume loading . A left femoral arterial line was used to obtain samples for blood gas analysis . The right atrium was paced slightly faster than the intrinsic rate  to maintain a constant heart rate and to be able to compare hemodynamics without confounding differences in heart rate. Body temperature was measured with a rectal or vaginal thermometer. After instrumentation, the heart was returned to the pericardium, which was closed with single interrupted sutures to approximate normal constraint  were used to measure aortic pressure (PLVED) of 5 mmHg, positive end‐expiratory pressures (PEEP) of 6 cm H2O, 12 cm H2O, and 18 cm H2O were applied in random order during CV and the mean airway pressure (AW) at each level of PEEP was noted. All interventions were initiated only after return to baseline with stable hemodynamics for 3–5 min. HFOV  was then begun with frequencies of 4 Hz, 10 Hz, and 15 Hz applied to cover a wide, relevant range in randomized order. During ventilation at each frequency, each of the three levels of AW noted during CV was applied in randomized order. Once acceptable blood gases were achieved , data were recorded for 1 min. The protocol was then repeated at a PLVED of 12 mmHg (Pentaspan™ was infused until the desired PLVED was achieved). At the end of the experiment, the animals were sacrificed by an intravenous bolus KCl injection and the positions of the crystals were verified.After stabilization at a LV end‐diastolic pressure , passed through a low‐pass filter (100 Hz), and digitized at 200 Hz. The digitized data were analyzed using software developed in our laboratory . Five CV cycles , during which the cardiac rhythm was regular, were selected for analysis. Using a low‐pass filter, PLVEDtm) = PLVED − PPERITransmural LV end‐diastolic pressure (Cardiac output = SV × heart ratePA − LA])Pulmonary vascular conductance  = (CO/[LV) = LV stroke volume (SVLV) × (LV (systolic) − LA)LV stroke work (SWLV (systolic) = PAo (diastolic) + 2⁄3 [PAo (systolic) − PAo (diastolic)]Where, ALV) = DSLVFW × DLVAPLV area . Mean tidal volume was 18.1 mL/kg (range 16–24 mL/kg) and mean respiratory rate was 17.7 breaths/min (range 17–18 breaths/min). Five of the 10 animals died before the completion of the protocol; thus, at the highest filling pressure, n = 5.All data are shown as mean values (± SE's). At a 2O) and HFOV (AW ~ 10 cm H2O) at PLVED 5 mmHg and 12 mmHg. LV preload (ALV) was affected similarly during both methods of ventilation. However, at a PLVED of 5 mmHg, LV performance (SVLV and SWLV) was substantially lower during HFOV compared to during CV. At a PLVED of 12 mmHg, the difference in LV performance was not statistically significant.PLVED of 5 mmHg and AW ~ 10 cm H2O. The LV diastolic pressure trace during CV is characteristic of normal physiological changes during diastole. During HFOV, note the fluctuations in LV diastolic pressure due to the oscillations in airway pressure. No fluctuations are apparent during LV systolic pressure.AW during CV and HFOV at PLVED of 5 mmHg and 12 mmHg are illustrated in AW increased, conductance substantially decreased. At a PLVED of 5 mmHg, conductance decreased by ~40% when AW was increased from ~10 cm H2O to ~20 cm H2O. This decrease in conductance would seem to be a “cost” of increasing AW, regardless of the mode of ventilation. As CO increased , conductance also increased . This suggests that the lung adapts to increases in CO, increasing conductance by “recruitment” of pulmonary vasculature. When PLVED was increased from 5 mmHg to 12 mmHg, note that conductance increased by ~50% at AW ~15 cm H2O. It is potentially important that at a PLVED of 12 mmHg, HFOV at a frequency of 4 Hz seems to be particularly advantageous. At AW ~15 cm H2O, conductance was ~15% higher at HFOV 4 Hz than at the higher frequencies; this apparent 4‐Hz “advantage” was not observed at PLVED 5 mmHg.The relations between pulmonary vascular conductance and PLVED of 5 mmHg. The HFOV data lie to the left of the CV data such that a normalized conductance of 100% is achieved at a CO of ~70% with HFOV, rather than a CO of 100% with CV. As indicated in PLVED of 12 mmHg.AW and PLVED on cardiac performance are shown in Figures AW reduced LV preload  and how volume loading increased preload. LV preload at each value of AW and PLVED was similar during both modes of ventilation. LV on ALV. As expected, SWLV increased as ALV increased.The effects of manipulating AW and LV performance [normalized SVLV (A) and normalized SWLV (B)] during CV and HFOV are illustrated in Figures LV and SWLV were greater at the higher filling pressure and decreased at higher airway pressures. At a PLVED of 12 mmHg and at each AW, SVLV and SWLV were statistically similar during CV and HFOV. However, at the lower filling pressure (PLVED = 5 mmHg) and AW ~10 cm H2O, SVLV and SWLV were significantly lower during HFOV  than during CV . The differences were not significant at higher airway pressures.The relations between LV and normalized SWLV) to AW during CV and HFOV are shown in Figures PLVED of 5 mmHg. In both Figures P <0.01 for both) and a significantly different Y‐intercept , which suggests that LV performance is reduced more during HFOV than during CV at low filling pressures.The regression relationships that relate LV performance  increased as a quasi‐sigmoidal function of PLVEDtm. The scatter in that relationship was minimal and the sigmoidal shape was expected, the LV being a structure with an unstressed volume that becomes stiffer as volume increases.The relations between RV) and SWLV during CV  and HFOV  . At PLVED = 5 mmHg, both SWRV and SWLV decreased during CV with increasing airway pressure; however, during HFOV, while SWLV decreased, SWRV generally increased with increased AW. This reciprocal relationship may explain the apparent differences in LV performance during the two modes of ventilation – see Instrumentation. At the higher filling pressure, both SWRV and SWLV decreased with increasing airway pressure during both CV and HFOV .In this study, we made two important observations. First, we observed that pulmonary vascular conductance, the amount of flow that the lungs will accept per unit driving (blood) pressure, varied under the different experimental conditions to a degree that may be clinically important. Second, we found that LV performance was similar during CV and HFOV at similar airway pressures, consistent with the fact that LV preload was not changed by switching to from CV to HFOV.Since the lung is a very complicated hydraulic‐pneumatic system, ventilation may have profound phase‐specific effects on cardiac and lung function through a number of complex and interactive mechanisms . Conductance is normalized flow – the rate of blood flow that an organ will accept at a given driving pressure .The observed changes in pulmonary vascular conductance are consistent with previously reported work ; as cardiac output increased, the lung was able to accept increased output  and cardiac output decreases as a result? Or, is decreased cardiac output the primary response to increased airway pressure  and conductance decreases as a result? Our study does not resolve this issue but demonstrates that regardless of the mechanism, the linear relationship differs between the two modes of ventilation at the lower filling pressure Fig. .ALV) are closely related to mean airway and filling pressures and not to the mode of ventilation  was similar and closely related to LV preload during both modes of ventilation, except, as discussed below, at the lower filling pressure  and PEEP 6 cm H2O  and systolic performance (LV stroke work) has been remarkably predictive during acute experiments in which the hemodynamic effects of mechanical ventilation have been studied  through direct ventricular interaction. We and others have shown that this is more likely at low filling pressures  on cardiac function (data not shown).Although 10 dogs were studied, five died before completion of the protocol. The cause(s) of death could not be determined, but the long, complicated protocol, which included high levels of PEEP at a low filling pressure, may have had detrimental effects on the animals. Acidosis was observed in several dogs, especially in earlier experiments, when amplitude adjustments were not adequate to maintain normal COLeft ventricular preload is sometimes difficult to assess. Although LV transmural pressure is an appropriate measure to assess LV preload  regardless of the mode of ventilation, HFOV at a frequency of 4 Hz appears to increase conductance substantially more than at the higher frequencies we studied. Also, HFOV appears to increase conductance relative to conventional ventilation at any level of cardiac output. These observations suggest that there is a need for further study in appropriate models to assess the potential clinical importance of such differences.We also conclude that switching from CV to HFOV at similar airway pressures appears to have no significant effect on LV preload and that LV performance should also be unaffected except at low filling pressures, which are generally avoided clinically.The authors appreciate the outstanding technical assistance of Cheryl Meek and the helpful suggestions of Dr. Andrei Harabor.The authors declare no conflict of interest.


If myocardial infarction remains silent, only clinical signs of complications may unveil its presence. Life-threatening complications include myocardial rupture, thrombus formation, or arterial embolization. In the presented case, a 76-year-old patient was admitted with left-sided hemiparesis. In duplex sonography, a critical stenosis of the right internal carotid artery was identified and initially but retrospectively incorrectly judged as the potential cause for ischemia. During operative thromboendarterectomy, arterial embolism of the right leg occurred coincidentally, more likely pointing towards a cardioembolic origin. Percutaneous interventions remained unsuccessful and local fibrinolysis was applied. Delayed bedside echocardiography by an experienced cardiologist demonstrated a discontinuity of the normal myocardial texture of the left ventricular apex together with an echodense, partly floating structure merely attached by a thin bridge not completely sealing the myocardial defect, accompanied by pericardial effusion. The patient was immediately transferred to emergency cardiac surgery with extirpation of the thrombus, aortocoronary bypass graft placement, and aneurysmectomy. This didactic case reveals decisive structural shortcomings in patient's admission and triage processes and underlines, if performed timely and correctly, the value of transthoracic echocardiography as a noninvasive and cost-effective tool allowing immediate decision-making, which, in this case, led to the correct but almost fatally delayed diagnosis. Myocardial infarction is one of the major causes of death in the industrialized world. It is characterized as an ischemic necrosis of cardiac cells in a clinical setting consistent with acute myocardial ischemia . PatientIf performed and adequately interpreted, transthoracic echocardiography is an adequate diagnostic tool to visualize ventricular thrombi , 6. HoweA 76-year-old patient presented with left-sided hemiparesis to our neurologic department. Clinical assessment revealed a NIH Stroke Scale of eight. Electrocardiogram at admission showed atrial fibrillation concomitant with ST elevation in the anterior leads V3–V6 . The iniIn the following days, the perfusion of the right leg remained critically impaired despite reoperation. Ultimately, an amputation of the right lower limb got necessary. A hemiparesis persisted. Transthoracic echocardiographic follow-up before discharge revealed that the patients' left ventricular ejection fraction had improved without any more thrombus formation.Often, clinical signs of myocardial infarction are unspecific, particularly in females, elderly, diabetics, and patients with dementia or suffering from chronic renal disease , 7. As aParticularly, myocardial infarction of the anterior wall can lead to thrombus formation because of apical aneurysm and, thus, stagnant blood flow in the apex. In a multicenter trial on patients after acute myocardial infarction who were considered in low to medium risk for left ventricular thrombi, in 5.1%, a thrombus could be diagnosed within predischarge echocardiogram. In anterior myocardial infarction, there was even an incidence of 11.5% . If the Nonetheless, it would be inappropriate to blame rescue fibrinolytic therapy initiating this sort of medical nightmare. By contrast, the presented case initiated internal discussions and review of procedural shortcomings in the aforementioned common patient population, thereby helping us to improve processes in our hospital. We learned that echocardiography has to be performed early in the clinical course in patients with seemingly unrelated clinical symptoms and integrated early ECG and echocardiography assessment within our stroke unit protocols. Even in acute and urgent cases, where a delay of operative treatment may potentially lead to more neurological damage, at least a short cardiologic consultation should be prompted whenever there are hints for a cardioembolic origin. Otherwise, potentially life-threatening illnesses may be missed.


What is the central question of this study?Rate–pressure product (RPP) is commonly used as an index of cardiac ‘effort’. In canine and human hearts (which have a positive force–frequency relationship), RPP is linearly correlated with oxygen consumption and has therefore been widely adopted as a species‐independent index of cardiac work. However, given that isolated rodent hearts demonstrate a negative force–frequency relationship, its use in this model requires validation.What is the main finding and its importance?Despite its widespread use, RPP is not correlated with oxygen consumption (or cardiac ‘effort’) in the Langendorff‐perfused isolated rat heart. This lack of correlation was also evident when perfusions included a range of metabolic substrates, insulin or β‐adrenoceptor stimulation.MV˙O2). Despite its widespread use, the application of this index to rat or mouse hearts  has not been characterized. The aim of this study was to examine the relationship between RPP and MV˙O2 in Langendorff‐perfused rat hearts. Paced hearts (300–750 beats min−1) were perfused either with Krebs–Henseleit (KH) buffer (11 mm glucose) or with buffer supplemented with metabolic substrates and insulin. The arteriovenous oxygen consumption (MV˙O2) was recorded. Metabolic status was assessed using 31P magnetic resonance spectroscopy and lactate efflux. Experiments were repeated in the presence of isoprenaline and in unpaced hearts where heart rate was increased by cumulative isoprenaline challenge. In KH buffer‐perfused hearts, MV˙O2 increased with increasing heart rate, but given that left ventricular developed pressure decreased with increases in rate, RPP was not correlated with MV˙O2, lactate production or phosphocreatine/ATP ratio. Although the provision of substrates or β‐adrenoceptor stimulation changed the shape of the RPP–MV˙O2 relationship, neither intervention resulted in a positive correlation between RPP and oxygen consumption. Rate–pressure product is therefore an unreliable index of oxygen consumption or ‘cardiac effort’ in the isolated rat heart.Langendorff perfusion of hearts isolated from rats and mice has been used extensively for physiological, pharmacological and biochemical studies. The ability to phenotype these hearts reliably is, therefore, essential. One of the commonly used indices of function is rate–pressure product (RPP); a rather ill‐defined index of ‘work’ or, more correctly, ‘effort’. Rate–pressure product, as originally described in dog or human hearts, was shown to be correlated with myocardial oxygen consumption ( The ability to modify mice genetically has further enhanced the utility of this technique and the ability to phenotype these hearts reliably has become essential. One of the commonly used indices of function is rate–pressure product (RPP), which is frequently adopted as some rather ill‐defined index of ‘work’ or, more correctly, ‘effort’. Rate–pressure product was originally described by Katz & Feinberg  as an inet al. . Howeveret al.   as a metabolic substrate. The lack of the normal range of substrate provision is again likely to influence the relationship between metabolic efficiency, myocardial oxygen consumption and contractility, particularly when heart rate is elevated.MV˙O2 in the isolated Langendorff‐perfused rat heart and, in keeping with its original definition, to establish whether RPP is an appropriate index of cardiac effort. In order to mimic the effect of physiological conditions on the investigated RPP–MV˙O2 relationship, in addition to experiments with the most commonly used crystalloid hyperglycaemic Krebs–Henseleit (KH) buffer, perfusions were carried out with KH buffer containing physiological concentrations of exogenous metabolic substrates and in the presence of β‐adrenergic stimulation.The aim of this study was to examine the relationship between RPP and All experiments were approved by the institutional ethical review committee and conform to the UK Animals (Scientific Procedures) Act 1986 incorporating European Directive 2010/63/EU.n = 36) were purchased from Harlan Laboratories (UK). Rats were housed in pathogen‐free cages with a 12 h–12 h light–dark cycle, controlled humidity and temperature (20–22°C) and fed standard rat chow and water ad libitum.Male Wistar rats . Hearts  were rapidly excised and arrested in ice‐cold KH buffer. The aorta was cannulated and secured with sutures . Hearts were perfused at a constant perfusion pressure of 80 ± 2 mmHg using a peristaltic pump  and a feedback control system . Buffer was equilibrated with 95% O2–5% CO2 using a custom‐made counter‐current membrane oxygenator consisting of spirally wound Silastic tubing  continually flushed with gas at 37°C. A fluid‐filled balloon, attached to a pressure transducer, was inserted into the left ventricle and inflated to give an end‐diastolic pressure between 3 and 8 mmHg. Left ventricular pressure (LVP), perfusion pressure, coronary flow and arterial and venous oxygen tensions were recorded using a PowerLab recorder and LabChart 7.0 software (ADInstruments). Functional parameters were averaged for ∼80 cardiac cycles at 5 min intervals.Rats were anaesthetized by Left ventricular developed pressure (LVDP) was calculated as the difference between maximal systolic (SP) and end‐diastolic pressures. Rate–pressure product was defined as the product of heart rate (HR) and left ventricular developed pressure: RPP = (HR ×LVDP)/1000.Venous effluent samples, taken during equilibration and within the last minute of each frequency increase, were immediately frozen in liquid nitrogen and stored at −80°C for analysis of lactate concentration. Samples were then thawed on ice before analysis in triplicate with a YSI 2300 Stat Plus Lactate Analyser .2 (using the reducing agent 4% w/v sodium hydrosulphite) and 100% O2 gassed water. One probe was placed in the aortic inflow arterial line and the second, venous probe was placed in the right ventricular outflow tract inserted via the pulmonary artery. The oxygen content of arterial and venous perfusate was recorded as percentage O2 saturation. Atmospheric pressure (in millimetres of mercury) was measured daily, and MV˙O2 was then calculated according to the following equation:PB is atmospheric pressure (in millimetres of mercury), Δ%O2 is the arteriovenous difference in percentage O2 saturation, SO2 is the solubility of oxygen in Krebs‐Henseleit (KH) buffer = 1.22 ×10−3 μmol ml−1 mmHg−1 at BTSP  calibrated prior to use with 0% Om): 118 NaCl, 25 NaHCO3, 4.8 KCl, 1.2 KH2PO4, 1.2 MgSO4.7H2O, 1.4 CaCl2.7H2O and 11 glucose, pH 7.4.The standard KH buffer contained : 1 sodium l‐lactate, 0.1 sodium pyruvate, 0.5 l‐glutamic acid monosodium salt monohydrate; 5 mU l−1 insulin  and 0.3 sodium palmitate with 3% (w/v) bovine serum albumin : 118 NaCl and 2.5 CaCl2.7H2O. Visking dialysis tubing  was prepared by boiling for 10 min in a solution containing (mm): 1 EDTA, 119 NaHCO3, rinsed with ddH2O and then boiled for another 10 min in 1 mmol l−1 EDTA. The tubing was given a final rinse in ddH2O before the BSA solution was transferred and left to dialyse for 48 h at 4°C against a 20‐fold larger volume of (mm): 118 NaCl and 2.5 CaCl2.7H2O. This removed molecular impurities (molecular mass cut‐off of 12–14 kDa) and saturated the Ca2+‐binding sites of BSA  in a solution containing . Appropriate corrections were made for Na−1, the frequency of the pacing was increased every 5 min in 1 Hz increments up to 720 beats min−1. Hearts were divided into the following five groups: (i) crystalloid perfusion (KH buffer); (ii) perfusion using the substrate‐enriched KHmetab buffer; (iii) crystalloid perfusion plus β‐adrenergic receptor stimulation with isoprenaline hydrochloride (10 nm); (iv) KHmetab buffer plus β‐adrenergic receptor stimulation with isoprenaline hydrochloride ; and (v) unpaced, crystalloid perfusion with stepwise logarithmic increases in ISO concentration (from 0.01 to 1000 nm). Sodium l‐ascorbate (0.05 mm) was added to both the vehicle and ISO‐containing buffer to prevent catecholamine oxidation. In group (iv), hearts were initially perfused with the vehicle buffer  for a 20 min functional equilibration and paced at 350 beats min−1 before switching to the ISO buffer. In these hearts, higher baseline pacing rates were used to account for the positive chronotropic effect of ISO. Hearts were perfused with the KHmetab buffer + ISO for a further 10 min equilibration to allow the function to stabilize before the pacing protocol was initiated and effluent samples were collected as described above.Hearts were paced via epicardial silver wire electrodes placed at the apex of the left ventricle and the right atrium. After a 20 min functional equilibration period and continuous pacing at ∼300 beats min31P Magnetic resonance spectroscopy experiments were conducted in a vertical‐bore Bruker Avance III 400 MHz wide‐bore spectrometer  with triple axis gradients, a microimaging probe and an exchangeable 15 mm 1H/31P dual tune birdcage coil . Following cannulation on a specially constructed, MR‐compatible umbilical perfusion rig, the rat heart was lowered into the centre of the magnet at the position previously verified as the isocentre of the coil. Temperature calibration was performed in situ using a capillary containing ethylene glycol at the position of the heart. Shimming was carried out on the 1H signal of water, which was <50 Hz. Fully relaxed 31P spectra were acquired with an experiment duration of 13 min, 200 scans, repetition time of 3.85 s, a 90 deg flip angle, 9.8 kHz sweep width and acquisition data size of 16,384 points. After functional equilibration, hearts were perfused with the KH buffer and paced for 10 min at 350 beats min−1 followed by 10 min perfusion at 500 beats min−1. All spectra were processed with 20 Hz line broadening, and peak integrals were fitted using Bruker Top Spin version 2.1 software.r). Some relationships appeared to have two linear phases either side of an inflection. In these cases, the whole data range was fitted initially using the entire data set and a single Pearson's r value derived. Subsequently, the two linear phases were then fitted separately with the inflection arbitrarily defined. If either of these two phases reported a higher r value than the whole data range, then this double‐fit is presented rather than a single linear regression. Some data were best described by a single exponential function according to Y = (Y0 − Plateau) × exp(−K × X) + Plateau. Differences between two means were analysed using Student's unpaired t test and considered significant when P < 0.05.The results are presented as means ± SEM. Statistical significance of functional parameters was assessed using GraphPad Prism 6 software . Linear relationships were fitted by least‐squares analysis and correlation was assessed using Pearson's product–moment correlation coefficient (A shows the relationship between LVDP and heart rate. There was a negative linear relationship between increasing heart rate and LVDP (a negative FFR). Increasing the pacing rate from 300 to 750 beats min−1 resulted in a 79% decrease in LVDP from 103 to 21 mmHg and a fivefold increase in left ventricular end‐diastolic pressure from baseline levels . The slope of this negative LVDP–frequency relationship was −0.99 mmHg beat min−1. In this pacing protocol, there was a gradual increase in absolute coronary flow as heart rate increased . Interestingly, despite the gradual vasodilatation in response to increasing heart rate, coronary flow expressed per beat declined with increasing rate . Myocardial oxygen consumption as a function of heart rate and RPP are shown in Fig. C and D. Figure C shows that the combination of an increase in heart rate and the associated reduction in LVDP  results in no net change in O2 consumption over a wide range in heart rates. Hence, unlike the positive correlation originally described by Katz & Feinberg . The numbers next to the symbols in Fig. D indicate the heart rate at each point. Interestingly, the absolute arteriovenous oxygen difference remained largely constant and within a narrow range [0.17–0.18 μmol (g dry wt)−1] at all pacing frequencies (see Table S1). This is in accord with Laurent et al. , ATP and phosphocreatine (PCr) content, PCr/ATP ratios  and intracellular pH were all unaffected by increasing the heart rate from 350 to 500 beats min−1 . Figure A shows that, as in KH buffer, the LVDP–frequency relationship remained negative (slope −0.98 mmHg beat min−1). In contrast, however, baseline coronary flow was reduced at 325 beats min−1 in KHmetab buffer to 7.1 ± 0.6 ml min−1 . With increasing heart rate, absolute coronary flow (in millilitres per minute) remained relatively constant over the range 325–650 beats min−1, declining slightly over the entire frequency range (r = −0.88). As in KH perfusion, coronary flow per beat declined with increasing frequency . The relationship between heart rate and absolute coronary flow was mirrored by a similar profile of oxygen consumption . In these hearts, at baseline (325 beats min−1) the MV˙O2 was significantly lower in KHmetab‐perfused hearts compared with KH‐perfused hearts . In addition, there is some indication that the relationship between heart rate and MV˙O2 shows two phases; below 525 beats min−1MV˙O2 appears independent of heart rate, whereas above 525 beats min−1MV˙O2 declines gradually as heart rate increases .Not only is the isolated heart potentially oxygen deficient at high heart rates but it may also be substrate deficient, being typically provided only with glucose (and no insulin) as a metabolic substrate. In order to investigate whether this impacts upon metabolic efficiency and the relationship between RPP and oxygen consumption, the protocols in Fig. metab‐perfused hearts showed an apparent positive correlation between RPP and myocardial oxygen consumption , again showing some evidence of a two‐phase response. However, closer inspection reveals that this RPP–MV˙O2 relationship is, in fact, ‘upside‐down’; that is, as both LVDP and MV˙O2 decline with increasing heart rate, high rates are associated with a low RPP and a low MV˙O2 and, conversely, low heart rates with a high RPP and high MV˙O2. Figure E shows the relationship between heart rate and lactate production. This relationship again shows two phases, again with an inflection at ∼525 beats min−1, above which increases in heart rate appear to be linearly associated with increased lactate production.The KHion Fig. D, againA shows that, although ISO (10 nm) had the expected positive inotropic effect at all heart rates, the LVDP–frequency relationship remained negative (−0.97 mmHg beat min−1) . Isoprenaline at baseline (400 beats min−1) caused a 52% increase in coronary flow (18.7 ± 1.8 ml min−1) compared with KH alone (12.3 ± 0.7 ml min−1). Further increase in heart rate in the presence of ISO caused very little change in absolute coronary flow and, as previously observed, a substantial decline in flow per beat . These changes in coronary perfusion were accompanied by increased oxygen demand . The relationship between RPP and MV˙O2 is shown in Fig. D. This relationship, which was absent in KH buffer alone , was transformed into a significant negative correlation by β‐adrenoceptor stimulation. This appears to be associated with a gradually developing demand‐induced ischaemia  as indicated by a significant increase in lactate production .Figure ough ISO 0 nm had metab buffer in the presence of β‐adrenergic stimulation. In contrast to the KHmetab buffer results in the absence of ISO , as heart rate increased so did coronary flow . This increase in coronary flow resulted in increased oxygen extraction and increased oxygen consumption . The relationship between RPP and MV˙O2 is shown in Fig. D. This relationship, which was ‘upside‐down’ in KHmetab buffer , was transformed into a significant positive correlation by ISO stimulation . Coronary vasodilatation caused by ISO resulted in reduced lactate production .Figure ISO Fig. B, as helow Fig. B. This ion Fig. C. The rfer Fig. D, was tion Fig. D. Coronion Fig. E.in vivo , absolute coronary flow and flow per beat were substantially higher than in the absence of ISO but similar to that in 10 nm ISO . As heart rate was increased (with increasing ISO concentrations), absolute coronary flow remained relatively constant, whereas flow per beat declined. Oxygen consumption also declined as heart rate increased . Again, as in the KH buffer, for KH buffer + ISO, there was no correlation between RPP and MV˙O2  and no increase in lactate production .Given that electrical pacing is not the usual mechanism for increasing rate ISO Fig. B. As hesed Fig. C. Again˙O2 Fig. D and noion Fig. E.MV˙O2 or cardiac ‘effort’. Although the provision of substrates or β‐adrenergic stimulation changed the shape of the RPP–MV˙O2 relationship, neither intervention resulted in a clear positive correlation between RPP and oxygen consumption. In KH buffer alone, although MV˙O2 increased with heart rate, LVDP declined. Hence, the product of HR × pressure (RPP) remained flat.This study demonstrates that, despite its widespread use, RPP is an unreliable index of 2+ concentrations, in the absence of catecholamines or vagal tone and, not infrequently, at room temperature  Ca2+ load and fractional Ca2+ release  compared with those measured in vivo or in blood‐perfused hearts (∼1 ml min−1 g−1). These high coronary flows may limit locally derived vasoactive agents from achieving concentrations necessary to cause appropriate or sufficient dilatation in response to increases in heart rate. However, despite this, in the present study, in normal KH‐perfused hearts, the PCr/ATP ratio was not reduced at higher pacing rates. This suggests that the decline in LVDP was not attributable to progressive demand ischaemia. In isolated hearts supplied only with glucose and no insulin, it is also reasonable to consider the possibility that demand ischaemia may also be induced by inadequate substrate delivery as well as inadequate O2 delivery. However, the lack of significant frequency‐dependent lactate production and the finding that the provision of alternative substrates did not affect the negative FFR, or indeed the RPP–MV˙O2 relationship, suggests that substrate delivery is not the limiting factor in this context.In isolated hearts, as in isolated muscles, the developed pressure–frequency relationship is typically positive (or biphasic) in most larger species and is negative or flat in rats or mice , in which the FFR is reported to be positive. Likewise, no studies have measured MV˙O2 and the FFR in vivo in rats or mice, although, as discussed above, it would be teleologically surprising if the negative FFR persists in vivo. It would be interesting to repeat the present study not only in small animals in vivo but also in KH‐perfused rabbit hearts and hearts of both species perfused with erythrocytes or perfluorocarbons to improve O2 delivery.As discussed above, the lack of correlation between RPP and metab buffer) would be more stable and less prone to demand ischaemia than glucose‐fed hearts (KH buffer). Surprisingly, this was not borne out by the results. In KHmetab buffer, LVDP and coronary flow were consistently lower than in KH buffer and, on increasing heart rate, KHmetab‐perfused hearts produced more lactate. The inclusion of BSA in the perfusion solutions increased both the viscosity and the oncotic pressure of these solutions. Whether it is a change in viscosity or some effect on the tissue oedema , there is demonstrably a reduction in coronary flow in hearts perfused with the KHmetab buffer. If coronary flow is reduced for reasons of viscosity and/or changes in oedema, then as the inclusion of BSA does not alter or improve the oxygen‐carrying capacity, this may limit oxygen delivery and may explain why these KHmetab‐perfused hearts are more susceptible to demand ischaemia.When designing the present study, the assumption was made that hearts perfused with the enhanced substrate mix   and coronary flow (i.e. O2 delivery) change with changes in pacing rate and hence while MV˙O2 and coronary flow correlate, this correlation may be a undefined mixture of cause and effect.Finally, it is interesting to note that in the crystalloid‐perfused rat heart it is coronary flow (i.e. oxygen delivery) and not heart rate that is best correlated with oxygen consumption. The correlation between ry) Fig. . The corIn conclusion, although many studies use RPP in the isolated Langendorff‐perfused rat heart, the negative FFR in this preparation means that RPP is an unreliable index of oxygen consumption or ‘cardiac effort’ and should be avoided.None declared.All experiments were conducted in the laboratories of the Cardiovascular Division, King's College London. D.A.: experimental design, heart perfusions, lactate analysis, nuclear magnetic resonance spectroscopy, primary data analysis and manuscript preparation. H.R.L.: heart perfusions, lactate analysis and data analysis. M.J.S.: principal investigator and grant holder, study hypothesis, experimental design, secondary data analysis and manuscript preparation. All authors have approved the final version of the manuscript and agree to be accountable for all aspects of the work. All persons designated as authors qualify for authorship, and all those who qualify for authorship are listed.This work was supported by a British Heart Foundation Programme Grant (RG/12/4/29426) to M.J.S. and a British Heart Foundation 4 year MRes/PhD studentship (FS/13/55/30643) to H.R.L.Table S1: Absolute values of arterial and venous O2 content, A‐V oxygen consumption and coronary flow at different heart rates in KH perfused hearts. These data were used to generate the relationships shown in Figure 1. Date are mean ± SEM (n=8/group).Figure S1: Comparison of the effects of isoprenaline (ISO) on the relationship between pacing rate and left ventricular developed pressure (LVDP) in hearts perfused with KH (A) or KHmetab (B). Data are re‐plotted from Figures 1A, 3A, 4A and 5A.Click here for additional data file.


Accurate measurements of autonomic nerve regulation in heart failure (HF) were unresolved. The discriminating performance of deceleration and acceleration capacities of heart rate in HF was evaluated in 130 HF patients and 212 controls. Acceleration capacity and deceleration capacity were independent risk factors for HF in males, evaluated by multiple logistic regression analysis, with odds ratios (ORs) of 5.94 and 0.13, respectively. Acceleration capacity was also an independent risk factor for HF in females, with an OR of 8.58. Deceleration capacity was the best cardiac electrophysiological index to classify HF in males, with an area under the receiver operating characteristic curve (AUC) of 0.88. Deceleration capacity was the best classification factor of HF in females with an AUC of 0.97, significantly higher than even left ventricular ejection fraction (LVEF). Acceleration capacity also showed high performance in classifying HF in males (0.84) and females (0.92). The cut-off values of deceleration capacity for HF classification in males and females were 4.55 ms and 4.85 ms, respectively. The cut-off values of acceleration capacity for HF classification in males and females were −6.15 ms and −5.75 ms, respectively. Our study illustrates the role of acceleration and deceleration capacity measurements in the neuro-pathophysiology of HF. Heart failure (HF) refers to structural or functional impairment in the ventricular filling or ejection of blood, which may lead to fluid retention, pulmonary congestion, peripheral edema, and a complex clinical syndrome1The physiological activity of the heart is controlled and modulated by the parasympathetic and sympathetic nervous systems67667678910The real-time roles of the parasympathetic and sympathetic nervous systems on the heart are difficult to monitor. However, increasing numbers of studies have shown that these roles are reflected in cardiac electrophysiology67891012et al. established an approach to distinguish between vagal and sympathetic nervous system roles that affect cardiac electrophysiology using a signal processing algorithm to separately characterize the deceleration and acceleration capacities of the heart rate14In 2006, Baver Although elevated sympathetic activity is associated with an adverse prognosis, and a high level of parasympathetic activation confers cardioprotectionOutpatients and inpatients who visited our Cardiology Department from February 2012 to April 2014 were enrolled in the study. HF was diagnosed by disease history, symptoms, and signs, in combination with chest X-ray, electrocardiography, and transthoracic echocardiography results according to the Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines (2013 ACCF/AHA Guideline for the Management of Heart Failure)The review board of the Center Hospital of Minhang District approved this protocol in accordance with the amended Declaration of Helsinki. Written informed consent regarding the procedures and medical data to be used was obtained from all patients according to the guidelines of the Chinese National Ethics Regulation Committee.To calculate the deceleration capacity and acceleration capacity of the patients and controls, original electrocardiogram information for all participants was obtained from 24-h ambulatory electrocardiogram monitoring using a Holter monitoring DigiTrak XT System .The heart rate deceleration and acceleration capacities were calculated according to Baver14All HRV indexes were calculated from 24-h ambulatory electrocardiograms that were recorded under fairly similar conditions and in a fairly similar environment. Abnormal RR intervals, defined as RR intervals that change by more than 20% from the previous RR interval, such as premature atrial contraction (PAC) or premature ventricular contraction (PVC), atrial fibrillation, ventricular tachycardia and etc, were removed from the RR interval serieset al.The following parameters related to HRV were determined according to the Task Force of the European Society of Cardiology and the North American Society of Pacing Electrophysiology recommendationAn echocardiographic examination was performed using a Sonos 5500 type ultrasound machine  with a 2.5-Hz transducer. Measurement of the left ventricular ejection fraction  was performed using Simpson’s biplane method. The measured parameters using the M-mode technique included end-systolic diameter , left ventricular end-diastolic , and left atrial diameter .All of the above measurements and the echocardiographic examinations for each patient were performed and analyzed by experienced technicians who were blinded to the clinical data and experimental design. Any uncertainties regarding results were resolved by discussion among senior technicians of the Department of Echocardiography and Department of Electrocardiograms.Resting 12-lead surface ECG was obtained in the supine position. For greater accuracy, measurements were performed with calipers and a magnifying lens. The Q-, R-, and S-wave complex (QRS) duration was calculated using the first to last sharp vector crossing the isoelectric line in leads V3–V6. Three continuous QRS duration values were detected, and their average value was defined as QRS duration. QT interval durations were recorded for three consecutive beats through leads II and V4, each QT interval was measured from the beginning of the QRS complex to the visual return of the T wave to the isoelectric line. When the T wave was interrupted by the U wave, the end of the T wave was defined as the nadir between the T and the U waves. Heart rate corrected QT interval (QTc) was performed by the Bazett formula, and QTc interval duration was defined as the mean duration of all QTc intervals measured. ST amplitude (ST J-point amplitudes) was measured in standard 12-lead ECG and also in special monitoring leads with right arm and left arm electrodes placed in subclavicular fossae and all chest lead electrodes placed at the level of V1 and V2 positions. Presences of atrial fibrillation and/or ventricular tachycardia were screened by the 24-h ambulatory electrocardiogram monitoring. Subject with one or more runs of nonsustained ventricular tachycardia of at least three beats in duration were recorded as positive for ventricular tachycardia. Electrocardiography was performed and analyzed by the same experienced technician, the final electrocardiographic result for each patient was reviewed by the chief technician.t-tests were used for comparisons within groups according to the data distribution characteristics; all were performed as two-sided tests. A P value <0.05 was deemed to indicate statistical significance. Statistical analyses were performed using SPSS software . To avoid the influence among variables as much as possible, correlation patterns for each variable were analyzed quantitatively using Spearman’s rank correlation coefficient. Confounding factors and collinearity were examined by Spearman’s rank correlation coefficient array. To evaluate the performance of deceleration capacity, acceleration capacity and traditional HRV indexes in discriminating HF, HF patients and healthy controls were pooled, the area under the receiver operating characteristic curve (AUC) analysis was performed. Any differences in the AUC of indexes were examined by non-parametric tests of paired samples through bootstrapping with replicates of 10,000; the Bonferroni method was used to adjust the significance level for multiple comparisons. A multiple unconditional logistic regression model was used for our primary analysis of the independent effects of each variable. Potential associated factors for HF were selected according to univariate analyses (P < 0.1), Spearman’s rank correlation coefficient, and the principle of indexes. To determine the independent factors associated with HF, selected indexes were included in the binary multiple logistic regression analysis, in which HF was the dependent variable. The cut-off values for deceleration capacity and acceleration capacity in males and females were identified by searching the maximum log-rank statistics in ROC analysis.The distribution characteristics of all data were assessed first. Normally distributed data are presented as means ± standard deviation (SD), and skewed data are presented as medians (interquartile range). Paired or non-paired Student’s In total, 130 patients with HF and 212 controls were enrolled in this study; the proportions of males in the HF and control groups were 68.5% and 19.3%, respectively. To avoid sex bias and observe any sex differences in the following analyses, HF patients and controls were analyzed by sex. The demographic, echocardiographic and electrocardiographic data, treatment, heart rate variability, acceleration capacity and deceleration capacity indexes were compared and are summarized in Echocardiographic and cardiac electrophysiological indexes are highly correlated mutually. Although the Task Force of the European Society of Cardiology and the North American Society of Pacing Electrophysiology have recommended time and frequency domain measures of HRVP = 0.053) and LVEF were independent risk factors for HF in females  and non-treatment groups n = 170). The HRV indexes of these two groups were further compared. The acceleration capacities in treatment group and non-treatment group were −7.7  and −7.6 (−8.6 ~ −5.7), respectively; the deceleration capacities in treatment group and non-treatment group were 7.3 (6.1 ~ 8.3) and 7.2 (6.2 ~ 8.4), respectively, no significant difference was observed . Of the 0. The HRFor the effect of ACE inhibitors on autonomic nervous system, conflicting findings were reported. Sustained augmentation of parasympathetic tone and improvement of HRV were observed in HF patients after ACE inhibitor administration18The cardiac function of the heart is modulated opposingly by the sympathetic and parasympathetic nervous systems72721127122114In HF, it has been recognized that the sympathetic nervous system is activated and that an imbalance between vagal and sympathetic activities occurs232526Deceleration and acceleration capacities are new algorithm for HRV, which was based on 24-h ambulatory electrocardiogram monitoringEchocardiographic indexes are independent of cardiac electrophysiological indexes in principle, while cardiac structural changes should influence cardiac electrophysiological changesLimitations of this study included 1) the relatively small sample size for female HF patients, which might weaken the accuracy of the conclusions; and 2) since the autonomic modulation varies according to age, in this report, the age of patients with HF was significantly older than the age of controls, thus, we could not eliminate any possible impact of age difference on their cardiac electrophysiology. In this report, our goal is mainly focused on the deceleration and acceleration capacities of heart rate associated with HF, the associations between arrhythmia profile and HF were studied extensively1In conclusion, deceleration capacity and acceleration capacity are independent risk factors for HF; deceleration capacity was the best cardiac electrophysiological index to classify HF in males; deceleration capacity was the best HF-classifying index in females. Our study positions the roles of parasympathetic and sympathetic activity in HF and provides new insights into how parasympathetic and sympathetic activation affect HF.How to cite this article: Hu, W. et al. Deceleration and acceleration capacities of heart rate associated with heart failure with high discriminating performance. Sci. Rep.6, 23617; doi: 10.1038/srep23617 (2016).


This study used high-resolution 3-dimensional cardiac magnetic resonance to define the anatomical and functional left ventricular (LV) properties associated with increasing systolic blood pressure (SBP) in a drug-naïve cohort.LV hypertrophy and remodeling occur in response to hemodynamic stress but little is known about how these phenotypic changes are initiated in the general population.In this study, 1,258 volunteers  without self-reported cardiovascular disease underwent 3-dimensional cardiac magnetic resonance combined with computational modeling. The relationship between SBP and wall thickness (WT), relative WT, end-systolic wall stress (WS), and fractional wall thickening were analyzed using 3-dimensional regression models adjusted for body surface area, sex, race, age, and multiple testing. Significantly associated points in the LV model (p < 0.05) were identified and the relationship with SBP reported as mean β coefficients.There was a continuous relationship between SBP and asymmetric concentric hypertrophic adaptation of the septum and anterior wall that was associated with normalization of wall stress. In the lateral wall an increase in wall stress with rising SBP was not balanced by a commensurate hypertrophic relationship. In normotensives, SBP was positively associated with WT (β = 0.09) and relative WT (β = 0.07) in the septal and anterior walls, and this regional hypertrophic relationship was progressively stronger among pre-hypertensives (β = 0.10) and hypertensives (β = 0.30).These findings show that the precursors of the hypertensive heart phenotype can be traced to healthy normotensive adults and that an independent and continuous relationship exists between adverse LV remodeling and SBP in a low-risk population. These adaptations show distinct regional variations with concentric hypertrophy of the septum and eccentric hypertrophy of the lateral wall, which challenge conventional classifications of LV remodeling. At least one-quarter of the world’s adult population has hypertension and the increasing burden of disease has prompted efforts to search for earlier interventions and more effective therapeutic targets Our knowledge of the natural history of hypertensive heart disease in human populations has been developed from volume and mass measurements derived using conventional 2-dimensional (2D) echocardiography and cardiac magnetic resonance (CMR). Conventional classifications of hypertrophy and remodeling using LV mass/volume ratio rely on strong geometric assumptions about the anatomic uniformity of phenotypic adaptations In this study, 1,258 adult volunteers  were recruited prospectively via advertisement for the UK Digital Heart Project at Imperial College London. We excluded participants who had known cardiovascular or metabolic disease. Subjects taking prescription medicines were excluded but simple analgesics, antihistamines, and oral contraceptives were acceptable. Female subjects were excluded if they were pregnant or breastfeeding. Standard safety contraindications to magnetic resonance imaging were applied including a weight limit of 120 kg. All subjects provided written informed consent for participation in the study, which was approved by a research ethics committee.Each subject fasted for 4 h prior to the visit. Brachial BP measurement was performed following 5 min rest using a validated oscillometric device . The first of 3 measures was discarded and the second 2 values were averaged.CMR was performed on a 1.5-T Philips Achieva system . To capture the whole-heart phenotype, a high-spatial resolution 3D balanced steady-state free precession cine sequence was used that assessed the left and right ventricles in their entirety in a single breath-hold  Volumetric analysis of 2D LV cine images was performed using CMRtools . Cardiac volumes and mass were indexed to body surface area.Briefly, the heart was segmented from the 3D images using previous knowledge of cardiac anatomy from a set of manually annotated atlases  (14). EaThe definitions of LV geometry used in conventional assessment of chamber size were adapted for 3D datasets Regional end-systolic WS was determined at each point in the LV from the 3D Gaussian radius of curvature (R) and myocardial WT and calculated as follows 2U tests were used. Data from more than 2 groups were analyzed using a Kruskal-Wallis 1-way analysis of variance test followed by a Nemenyi post-hoc test for pairwise multiple comparisons.Data were analyzed using RStudio Server version 0.98  and Matlab . Continuous variables are expressed as mean ± SD and categorical variables as percentages. The associations between phenotypic  parameters and SBP for each point in the 3D datasets were assessed using a regression model adjusted for age, sex, race, and body surface area with correction to control the false discovery rate According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure criteria for SBP The pattern of LV hypertrophy and remodeling observed with respect to each of the phenotypic variables is illustrated in Online Video 1).In normotensives, the 3D regression models revealed a positive relationship between SBP and WT throughout the LV  with the strongest effect observed in the septum and anterior wall. Controlling for ventricular volume, a positive relationship was also found between SBP and RWT that was strongest in the mid-ventricular anterior and septal walls  but was not observed in basal or lateral walls . The greatest hypertrophic response in RWT was observed in the mid-ventricular anterior and septal walls  with negative coefficients elsewhere.In hypertensives, there was a strong and asymmetric association between SBP and both WT  and RWT  that was observed in the basal septal and anterior walls, with negative coefficients in the lateral wall.Overall, there was an outward increase in the LV epicardial surface, relative to the mean shape, associated with SBP . The majority of the LV endocardial surface also showed an outward expansion in response to SBP . Taken together, these data show a predominantly eccentric hypertrophic pattern in response to SBP. However, in a region from the basal anteroseptal wall to the mid-ventricular anterolateral wall, the increase in WT was associated with an inward shape change of the endocardial surface  at the expense of the LV cavity . ConsideIn normotensives, FWT was positively associated with SBP in the anterior and septal walls and lateral wall , indicating preserved or hyperdynamic radial function across SBP in normotension. In pre-hypertensives, the positive relationship between SBP and FWT was limited to the mid-ventricular lateral and inferior walls  with negative coefficients in the basal septum and anterior walls. In hypertensives, FWT had stronger negative association with SBP, which was localized to the basal and mid-ventricular septum , revealing reduced radial function colocalized to the area of greatest hypertrophic response.Across the full cohort, WS was strongly positively associated with SBP  in the majority of LV, demonstrating an uncompensated increase in WS. However, in the basal anteroseptum and mid-ventricular anterior wall, there was no significant association between WS and SBP. This demonstrates that only in these regions was the increase in BP-dependent WS compensated for by proportionate concentric hypertrophy .Figure 6This study provides new insights into the effects of SBP on LV morphology and function using advanced cardiovascular phenotyping and computational modeling. Accurate representations of cardiac morphology can be obtained using atlas-based methods, and this approach provides new opportunities for understanding the regulation of LV hypertrophy in humans and can be applied to large population-level datasets for mechanistic or interventional studies A central dogma of experimental studies is that pressure overload causes elevated WS, which stimulates a concentric pattern of compensatory hypertrophy We observed that rising SBP is associated with a normalization of Laplacian WS in the septum where concentric hypertrophy is predominant. However, in the majority of the LV, the increase in WS with rising SBP was not balanced by a proportionate increase in RWT. High WS without signs of decompensation has been reported in uncomplicated hypertension due to an increase myocardial contractility in the early stages of disease Prognostically adverse cardiovascular features, including LV hypertrophy and increased vascular stiffness, have been observed in pre-hypertensives with a high prevalence of obesity and diabetes A cross-sectional study cannot determine the causal relationships between increased SBP and LV geometry. We categorized subjects according to the thresholds in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, as more recent guidelines have not addressed the definitions of hypertension or pre-hypertension PerspectivesCOMPETENCY IN MEDICAL KNOWLEDGE: The precursors of the hypertensive cardiac phenotype are apparent in healthy normotensive adults. In contrast to current classifications of remodeling, the LV makes strong and distinct regional adaptations to rising SBP, which encompass both concentric and eccentric patterns of hypertrophy.TRANSLATIONAL OUTLOOK: High-resolution 3D imaging with computational analysis provides an automated and objective means to assess the environmental and genetic determinants of whole-heart structure and function. Future epidemiological research should apply these methods in prospective studies to determine how cumulative exposure to elevated SBP leads to hypertrophy in susceptible individuals.The precursors of the hypertensive heart phenotype can be traced to healthy normotensive adults and a continuous relationship exists between adverse LV remodeling and SBP in a low-risk population. Rising SBP is associated with concentric hypertrophy of the septum and eccentric hypertrophy of the lateral wall. These findings challenge the conventional understanding of compensated cardiac hypertrophy in pressure overload.


Type 2 diabetes has been associated with a higher prevalence of diastolic dysfunction and congestive heart failure. A hypothesized contributor is the accelerated accumulation of diffuse myocardial fibrosis. In a cohort of type 2 diabetic patients without overt cardiovascular disease, we sought to explore the capacity of quantitative T1 mapping and feature-tracking based strain analysis. These protocols were utilized to identify the presence of diffuse myocardial fibrosis and related pre-clinical systolic dysfunction. Quantitative analyses were compared to healthy age-matched controls.Nineteen Type 2 diabetes patients with no cardiovascular symptoms and no prior cardiac disease were recruited in addition to 13 age-matched healthy volunteers. A standardized imaging protocol was performed using a 1.5T MRI Scanner  using cine imaging, native and post-contrast T1 mapping, and late gadolinium enhancement. T1 mapping was performed using a saturation recovery single shot acquisition (SASHA) pulse sequence in basal and mid short axis views. Sequential short axis and long-axis cine images were analyzed using a prototype feature tracking strain analysis tool  to determine peak global circumferential and longitudinal systolic strain, and peak longitudinal diastolic strain rate. Segmental T1 values were determined from basal and mid slices using custom software (MATLAB), these averaged to provide a global mean T1 value for each subject. Manual exclusion of segments with visible imaging artifact was performed.A1c range 7.5-9.9%. The mean age of healthy volunteers was 52±12 years, 2 (15%) being female. The left ventricular ejection fraction was normal among all diabetic and healthy controls . Strain analysis was successful in all subjects and showed trends towards reduction among diabetics in peak longitudinal systolic strain . Late gadolinium enhancement imaging was visually normal in all subjects with no evidence of focal injury. There was a significant increase in native myocardial T1 values in diabetics compared to age-matched controls  and decrease in post-contrast T1 values , both of which are consistent with the presence of diffuse myocardial fibrosis.Among diabetic subjects, the mean age was 57±9 years, 7 (39%) being female, and HbQuantitative T1 mapping in asymptomatic type 2 diabetic patients showed changes consistent with increased myocardial fibrosis, as compared to controls. A trend towards reduced systolic strain indices was also seen, despite preservation of global ejection fraction. These imaging markers show promise for the detection of pre-clinical cardiomyopathy in patients with type 2 diabetes.Ms. Schmidt receives MD-PhD support from Alberta Innovates-Health Solutions. Funding was additionally provided, in part, by an AI-HS Interdisciplinary Team Grant via Alberta HEART. Dr White is supported a Heart and Stroke Foundation of Alberta Early Investigator Award.


There was no difference in disease duration, disease types, or prevalence of positive autoimmune antibodies or high serum NT-proBNP level (>125 pg/ml). When cardiac involvement of SSc was defined as low LVEF, ECG abnormalities or high NT-proBNP, the sensitivity, specificity positive and negative predictive values of LGE were 36, 92, 71 and 72 %, respectively. We could clarify the prevalence and distribution of LGE in Japanese patients with SSc. The presence of LGE was associated with cardiac symptom, conduction disturbance and impaired LV/RV contraction.Cardiac involvement in systemic sclerosis (SSc) is considerably frequent in autopsy, but the early identification is clinically difficult. Recent advantages in cardiac magnetic resonance (CMR) enabled to detect myocardial fibrotic scar as late gadolinium enhancement (LGE). We aimed to examine the prevalence and distribution of LGE in patients with SSc, and associate them with clinical features, electrocardiographic abnormalities and cardiac function. Forty patients with SSc  underwent serological tests, 12-lead electrocardiogram (ECG) and CMR. Seven patients (17.5 %) showed LGE in 26 segments of left ventricle (LV). LGE distributed mainly in the basal to mid inter-ventricular septum and the right ventricular (RV) insertion points, but involved all the myocardial regions. More patients with LGE showed NYHA functional class II and more (71 vs. 21 %,  Systemic sclerosis (SSc) is characterized by vascular changes and fibrosis of the skin and internal organs. The prevalence of cardiac involvement in SSc was considered clinically to be 1.4–5.4 % for impaired left ventricular ejection fraction (LVEF), or 18–30 % for diastolic dysfunction –8. PatieUnfortunately, especially in the early phase, most patients with cardiac involvement are asymptomatic and difficult to be detected in subclinical stage. Previous studies have suggested that tissue Doppler echocardiography is useful for detection of the depressed contractility , and serThis study aimed to assess the prevalence and distribution of LGE in patients with SSc, and to associate them with clinical features, electrocardiographical abnormalities and cardiac function.2, (3) implanted pacemaker, or (4) no informed consent. Finally, a total of 40 patients were enrolled in this study.This was a single center trans-sectional study. We selected a total of 47 consecutive patients with SSc (17–77 years old) attending the division of immunology and rheumatology at Hamamatsu University Hospital between January 2012 and March 2013. The diagnosis of SSc was based on the guideline of Japanese Ministry of Health and Welfare , and theAll patients underwent CMR, serological test and 12-lead electrocardiogram (ECG) within 1 month. The serological test included cardiac biomarkers such as NT-proBNP and troponin I, and autoimmune antibodies such as anti-Scl-70, anti-centromere and anti-U1-RNP. This study protocol was conducted in accordance with the Declaration of Helsinki and was approved by an institutional review board. All patients gave their informed consent.CMR imaging was performed on a 1.5 tesla (T) MR system  with a gradient system performance of maximum amplitude of 40 mT/m and slew time of 150 T/m/s . An 8-elLate gadolinium enhancement images were acquired from 15 min after an injection of 0.2 mmol/kg of contrast material . LGE imaging was based on the inversion recovery prepared fast gradient echo (IR-FGRE) sequence. The imaging parameters were as follows; matrix of 256 × 160, field of view of 34 cm, flip angle of 20º, readout bandwidth of 31.25 kHz. The IR-FGRE technique repeated during every R-to-R interval and the trigger delay was 300 ms. The readout data line was 160 each, where 24 data lines were acquired per segment. The inversion time (200–240 ms) was individually determined right before the LGE imaging on basis to optimize nulling of the normal myocardium signal. The process to identify optimum contrast was concluded within 3 min.Two experienced cardiovascular radiologists (M.S. and H.S.) interpreted all the CMR images without any knowledge of clinical findings. The 17-segments model was used for segmental analyses for morphology, function and LGE. LV/RV end-diastolic volume (LVEDV/RVEDV), end-systolic volume (LVESV/RVESV) and LV/RVEF were acquired from 2D FIESTA cine images in the short axis view. For LV/RV volume analysis, both the endocardial and epicardial contours for LV and only the endocardial contour for RV were manually traced in both end-diastole and end-systole phase, using analysis software . All the aortic, pulmonary and tricuspid valve rings were excluded from the volume. The LV and RV volume indices (LVEDVI/LVESVI and RVEDVI/RVESVI), and LV mass index (LVMI) were calculated by dividing them with body surface area. Asynergy in LV wall was also determined when several contiguous segments showed reduced contractility compared with other segments. LGE was defined as an area with a signal intensity which was higher than a signal intensity value >2SD above the normal myocardium, and was present in the same myocardial segment in at least two different planes. The presence, location, and pattern of myocardial LGE were determined by the consensus of the two observers. To assess LGE quantitatively, all the short-axis slices from base to apex were inspected visually, and in each image, the boundaries of LGE area were manually traced. The summed LGE area was rendered to LGE volume and the percentage against total muscle volume (%LGE volume) was calculated .The pericardial involvement was also examined using cine- and LGE-CMR images. We evaluated the presence of pericardial effusion, and the grade of pericardial LGE as shown in constrictive pericarditis . The pren) or percentages, as appropriate. Categorical variables were compared between the patient groups by Chi-square or Fisher exact tests. Continuous variables between groups were examined by unpaired t test. Correlations between numerical parameters were evaluated by Pearson’s correlation. The differences were considered to be significant when p < 0.05. All the statistical analyses were performed using the software IBM SPSS (Ver.21).All the data were expressed as the mean ± standard deviation (SD) of the indicated numbers . There was no significant correlation between %LGE volume and LVEF, RVEF, LVEDVI or RVEDVI (data not shown). No LGE was found in RV or atrial wall.We found 26 segments with LGE at the LV myocardium in 7 17.5 %) patients with SSc. The representative three cases with myocardial LGE are shown in Figs. 7.5 % patTable p < 0.05). Four patients with LGE showed high serum levels of NT-proBNP (>125 pg/ml), but seven without LGE also had, and the difference did not reach significant . In 12-lead ECG, 4 patients (57 %) with LGE showed bundle branch blocks . Only one patient with LGE showed paroxysmal atrial fibrillation (Case 7). Three patients with LGE had normal ECG  and three of them had asynergic wall motion in segments with LGE (p = ns.).The pericardial effusion was observed in three patients (43 %) with LGE and four (12 %) without LGE. Mild to severe pericardial LGE was seen in four patients (57 %) with LGE and 23 (70 %) without LGE. No patient demonstrated pericardial thickness over 4 mm. The prevalence of pericardial effusion or LGE did not differ between patients with and without LGE , the sensitivity and specificity of LGE were 36 and 92 %, and positive and negative predictive values were 71 and 72 %, respectively.When cardiac involvement of SSc was defined as low LVEF, ECG abnormalities or high NT-proBNP (except patients with eGFR <60 ml/min/1.73 mThis study examined CMR in patients with SSc and showed that (1) LGE in myocardium was considerably frequent, (2) LGE distributed mainly in the basal to mid IVS and the RV insertion points, but involved all myocardial regions, and (3) more patients with LGE were symptomatic and had ECG abnormalities, low LV/RV EF and asynergy. We could clarify, for the first time, the prevalence and distribution of LGE, and the association with ECG abnormalities and impaired cardiac function in patients with SSc.In autopsy, myocardial fibrosis in SSc was identified in 50–80 % , 5. BulkThis study showed that LGE has been distributed in 7 (17.5 %) of 40 Japanese patients with SSc. In previous reports from Western countries, LGE was observed in 21–66 % –15. The In pathological studies, myocardial fibrosis in SSc was assumed to be derived from impairment of microcirculation due to micro-vascular abnormalities or primary myocardial fibrosis, and from ischemic damage due to coronary atherosclerosis –8. In adHowever, although LGE-CMR can differentiate the myocardial fibrotic scar from normal myocardium , diffuseAdditionally, several studies have shown that patients with pulmonary arterial hypertension have LGE in the RV insertion points and in IVS , and thaMany studies have associated LGE with clinical and ECG features and long-term cardiac events in patients with ischemic and non-ischemic cardiomyopathies , 31–36]–3631–36]The presence of LGE was not associated with disease duration, disease types, or autoimmune antibodies. However, Tzelepis et al.  showed aIn 12-lead ECG, more patients with LGE had bundle branch blocks. Follansbee et al.  reportedIn cardiac function, previous reports showed that even asymptomatic patients with SSc had systolic and diastolic dysfunction in echocardiography –42. In tFinally, the pericardial involvement was frequent in our patients with SSc, although the prevalence did not differ between patients with and without myocardial LGE. Previous necropsy studies showed pericardial diseases in 33–77 % of the cases, whereas any symptoms occurred in only 7–20 %. The pericardial involvement included fibrinous pericarditis, chronic fibrous pericarditis, pericardial adhesions, and pericardial effusions , 43. We First, as mentioned above, LGE-CMR cannot visualize diffuse fibrosis, because myocardium with diffuse fibrosis is regarded as normal by the nulling method. Actually, the sensitivity of LGE was low for cardiac involvement of SSc defined with other diagnostic modalities. However, previous studies and our data suggest the analysis of fibrotic scar with LGE-CMR still has clinical relevance , 33, 34.This study could clarify the prevalence and distribution of LGE in patients with SSc. The presence of LGE was associated with cardiac symptom, conduction disturbance and impaired LV and RV contraction. Further studies are necessary to elucidate the relevance of LGE for early detection of cardiac involvement and for prediction of long term outcomes in patients with SSc.


The following review aims to examine the available evidence to guide best practice in preventing ovarian hyperstimulation syndrome (OHSS). As it stands, there is no single method to completely prevent OHSS. There seems to be a benefit, however, in categorizing women based on their risk of OHSS and individualizing treatments to curtail their chances of developing the syndrome. At present, both Anti-Müllerian Hormone and the antral follicle count seem to be promising in this regard. Both available and upcoming therapies are also reviewed to give a broad perspective to clinicians with regard to management options. At present, we recommend the use of a “step-up” regimen for ovulation induction, adjunct metformin utilization, utilizing a GnRH agonist as an ovulation trigger, and cabergoline usage. A summary of recommendations is also made available for ease of clinical application. In addition, areas for potential research are also identified where relevant. Ovarian hyperstimulation syndrome (OHSS) is encountered in practice as an iatrogenic complication of controlled ovarian stimulation (COS). COS is aimed at producing multiple ovarian follicles during assisted conception cycles in hope of increasing the number of oocytes available for collection. OHSS, however, is characterised by an exaggerated response to this process , 2.The incidence of moderate to severe OHSS is between 3.1 and 8% of in vitro fertilization (IVF) cycles but can be as high as 20% in high risk women . TypicalA literature search was carried out on the following electronic databases (until December 2014): MEDLINE, EMBASE, and The Cochrane Central Register of Controlled Trials. Only articles in English were taken into consideration and abstracts were excluded. A combination of text words or Medical Subject Headings (MeSH) terms were subsequently utilized to generate a list of citations: (“OHSS” OR “ovarian hyperstimulation syndrome”) AND (“prevention”). Articles and their references were then examined in order to identify other potential studies which could provide perspective for the following review.Systematic reviews, meta-analyses, and randomized controlled trials (RCTs) were then preferentially selected over other forms of data where feasible in order to formulate the following review and recommendations.OHSS is theorized to manifest systemically as a result of vasoactive mediators being released from hyperstimulated ovaries. As a result, capillary permeability is increased which causes the extravasation of fluid from the intravascular compartment into the third space. The haemoconcentration which ensues results in complications such as hypercoagulability and reduced end organ perfusion , 7.There is currently no consensus on the exact cause of OHSS. Human Chorionic Gonadotrophin (hCG) exposure, however, is thought to be a critical mediator of the syndrome. This is based on the findings that OHSS does not develop when hCG is withheld as an ovulatory trigger during COS and also that increased hCG exposure is associated with an increased risk of OHSS , 9.The role of hCG can be further elucidated via the two distinct clinical presentations observed in OHSS: the “early” and “late” forms. “Early” OHSS occurs within 9 days of hCG being administered as an ovulatory trigger and reflects the effect of exogenous hCG on ovaries that have already been hyperstimulated by gonadotrophins. “Late” OHSS, on the other hand, occurs more than 10 days after the use of hCG as an ovulatory trigger  and demonstrates the ovarian response to endogenous hCG produced by the trophoblast  can identify normal responders (≥4 oocytes retrieved) to COS with a success rate of 98% . This pr2) concentrations, however, have performed poorly in identifying women at risk of developing OHSS. This can mostly be attested to the marked heterogeneity in studies with regard to the threshold E2 levels used to define high risk women [Absolute serum oestradiol , are also another facet worthy of mention in the prediction of OHSS. Available evidence suggests that the AFC is equally predictive of excessive response to COS and OHSS as the basal serum AMH –25. Jaya(B) Secondary Risk Factors. Secondary risk factors examine ovarian response parameters related to COS in the hope of predicting OHSS. During COS, ultrasound and serum E2 monitoring are considered to be vital components of surveillance for OHSS. Based on this, parameters such as a rapidly rising E2 level, a large number of developing follicles on the day of hCG administration (>14 follicles with a diameter of 11 mm), and a large number of oocytes retrieved have been proposed as risk factors for developing OHSS [ing OHSS , 28. Noning OHSS , 29.2 ≥ 5000 ng/L on the day of hCG trigger to be more useful  than E2 concentrations alone in the prediction of severe OHSS [In combination, however, Papanikolaou et al. in their prospective cohort of 2524 GnRH antagonist cycles have identified the combination of ≥18 follicles on ultrasound (diameter ≥ 11 mm) and Eere OHSS .It also should be noted, however, that women without any risk factors can develop OHSS as there is some degree of hyperstimulation in all stimulation protocols. The possibility of OHSS therefore should always remain at the back of the clinicians mind in any woman undergoing COS .Prevention strategies for OHSS are broadly classified as both primary and secondary in nature. Primary prevention classifies a person based on their risk factors into high, normal, or low risk for OHSS, then individualizing treatment regimens to them on that basis. Secondary prevention, on the other hand, focuses on methods used in patients who have displayed an excessive response to ovarian stimulation during a cycle and aims to prevent progression to OHSS .In women who are identified as being at a high risk of OHSS, treatment regimens need to be modified in view of curtailing an overexcessive ovarian response.(A) Targeting Unifollicular Ovulation. As previously highlighted, women with PCOS are at an increased risk for OHSS. Since 4–8% of women worldwide have the syndrome, this is a major subpopulation towards whom primary prevention should be directed. The goal of therapy therefore in this subgroup of women is to induce unifollicular ovulation through ovulation induction (OI) and thereby prevent progression to OHSS [ to OHSS . With th(i) Reducing the Gonadotrophin Dose. The best evidence suggests that the minimum gonadotrophin dose should be used for OI given its lower risk of OHSS. This favours a “step-up” regimen over a “step-down” regimen. In the “step-up” regimen, ovarian stimulation is initiated with a low dose of FSH , which is subsequently increased every 7 days  until an ovarian response is noted (follicle > 10 mm). This dose is then continued until the criteria for an ovulatory trigger are met [ are met , 18. Thi are met , 32.(ii) Avoiding Adjunct GnRH Agonist (GnRHa) Utilization. During OI in women with PCOS, GnRHa is concomitantly administered with gonadotrophins to downregulate the endogenous pituitary secretion of LH in hope of preventing premature luteinisation. This process, however, seems to increase the dose of exogenous gonadotrophins required [required . In theirequired .(iii) Reducing the Gonadotrophin Duration. There is consensus on the fact that reducing the duration of gonadotrophin exposure reduces the risk of OHSS. One way this is achieved is through “mild” stimulation protocols which delay the administration of FSH till the mid or late follicular phase [ar phase , 34. Prear phase –38.(iv) Utilising Adjuvant Metformin Therapy. Metformin is theorized to exert its influence in preventing OHSS by inhibiting the secretion of vasoactive molecules, such as VEGF, during OI and thereby modulates vascular permeability [eability . In the eability  without Based on the studies, a daily dose between 1000 and 2000 mg at least 2 months prior to COS is recommended for the purpose of preventing OHSS –43.(v) Utilising Aromatase Inhibitors (AIs) for Ovulation Induction. AIs, such as letrozole, function by downregulating oestrogen production through inhibition of cytochrome P450 enzymes. This causes an increase in pituitary secretion of FSH which promotes folliculogenesis. In addition, the central negative feedback mechanisms still remain intact, which leads to the theory that it may reduce the incidence of OHSS during OI [uring OI . A recenAs such, AIs are not routinely recommended.(B) Individualizing IVF Treatment Regimens. There is increasing evidence to suggest that individualised COS (iCOS) can reduce OHSS and associated cycle cancellations [llations , 47. iCOllations , 48. Thellations . The CONllations . Findingllations .As it stands, however, iCOS shows a lot of promise in curtailing OHSS through tailored COS regimens and seems to be the initial steps towards an ART of the near future.(C) Avoiding hCG for Luteal Phase Support (LPS). During COS, endogenous LH concentrations are markedly lower due to the negative feedback caused by the supraphysiological progesterone (P4) concentrations maintained by the multiple corpora lutea. This results in a shortened luteal phase and poor endometrial receptivity resulting in reduced implantation and pregnancy rates. As such luteal phase support is imperative to improve these parameters [rameters –54. hCG,rameters .On the basis of these findings, the routine use of progesterone over hCG is recommended for LPS.(D) Considering Alternatives for Triggering Ovulation. The agent of choice for triggering ovulation should be picked based on the risk of the woman for developing OHSS. No agent, however, completely eliminates the risk of OHSS.Exogenous hCG has long been used to mimic the ovulatory LH surge. Its long half-life (2.32 days) however causes prolonged luteotrophic effects, multiple corpora lutea development, and higher luteal phase P4 and E2 concentrations. Hence, given its higher risk of potentiating OHSS it should be either used at the lowest possible dose  or altogether avoided in high risk women [sk women , 56. It sk women , 58.GnRH agonists (GnRHa) produce a more tempered and shorter midcycle gonadotrophin surge (24–36 hours) in contrast to hCG by stimulating pituitary LH secretion. Theoretically, this LH surge should just be sufficient to induce ovulation without being prolonged enough to induce hyperstimulation. The available data supports this notion by demonstrating that OHSS is virtually eliminated with GnRHa utilization  which mandates its consideration in the high risk woman [sk woman –61. Thissk woman –64.Recombinant LH (rhLH) use is also another possible prevention strategy in the high risk woman by attempting to mimic the endogenous LH surge. With a half-life of 10 hours, and a shorter and/or lower LH peak, it is expected that there should be minimal risk of causing OHSS. A Cochrane Review by Youssef et al. however did not show any difference in the risk for severe OHSS between rhLH and urinary hCG. Furthermore, it has also been associated with a lower pregnancy rate and a poor cost benefit ratio. Its routine use therefore cannot be recommended [ommended , 66.Secondary prevention is extended to women who have undergone COS and subsequently mounted an exaggerated response. The aim of interventions in these circumstances is to prevent progression to OHSS.(A) Coasting. Coasting is a preventative strategy by which gonadotrophins are withdrawn when a certain E2 concentration and/or a critical number of follicles are reached. hCG trigger is subsequently delayed until E2 levels significantly decrease or plateau. Once the E2 reaches a “safe” level, hCG is administered followed by oocyte retrieval and embryo transfer or freezing depending on the E2 concentration. It is generally employed for a period less than 3 days [n 3 days , 67.Coasting is a commonly used first line secondary prevention strategy by clinicians . QuestioAs it stands, there is not much strong evidence to back its routine use and no specific criteria about commencing and discontinuing coasting given the wide heterogeneity in study protocols, control groups, and definition of OHSS classes as well , 67.(B) Cryopreservation of Embryos. During cryopreservation, COS and subsequent oocyte retrieval is performed followed by the cryopreservation of embryos. These are then transferred in a subsequent unstimulated IVF cycle where the woman's ovarian response to hCG has normalized [rmalized . A Cochrrmalized . Recent rmalized .Another dogma which previously surrounded cryopreserved embryos was the lower pregnancy rates in contrast to fresh embryo transfers related to older slow freezing methods . With thBased on these findings, we recommend the use of a GnRHa trigger followed by cryopreservation for averting OHSS.(C) Cycle Cancellation. Cycle cancellation and withholding of hCG are the only definite methods of preventing OHSS [ing OHSS , 79. Howing OHSS , 29.(A) Colloid Infusion. Colloid infusions are administered around the time of oocyte retrieval as they are theorized to prevent OHSS by binding to and deactivating the vasoactive mediators of OHSS.(i) Albumin. A Cochrane Review by Youssef et al. noted that there was borderline statistically lower incidence of severe OHSS with albumin utilization but there was marked heterogeneity in the studies . A subsequent sensitivity analysis performed after excluding 2 unpublished studies, however, showed no significant alteration in the results  [47–1.21) . Another47–1.21) . The lac47–1.21) .On the basis of these factors, the routine use of IV albumin to prevent OHSS cannot be recommended.(ii) Hydroxyethyl Starch (HES). HES is a plasma expander that has been mooted as an alternative to albumin as it is nonbiological and therefore negates the above-mentioned risks associated with albumin use. The evidence behind its benefit is certainly more robust as well. The Cochrane Review by Youssef et al. noted that there was a statistically significant decrease in severe OHSS  with HES use without any effect on pregnancy rates  [49–2.95) .It must be borne in mind that these findings were based on only 3 RCTs and more compelling evidence should be sought prior to recommending its routine use.(iii) Cabergoline. Cabergoline is a dopamine antagonist which prevents the excessive increase in VEGF mediated vascular permeability encountered with OHSS through its antiangiogenic properties [operties . Tang etoperties . A recenoperties .Therefore, the use of cabergoline is recommended and it is suggested that treatment be commenced on the day of hCG trigger at a dose of 0.5 mg for 8 days .(C) Vasopressin Induced VEGF Secretion Blockade. Amongst the novel therapies being investigated for the prevention of OHSS, the vasopressin V1a receptor antagonist, relcovaptan, has been studied for its ability to inhibit VEGF by modulating vasoconstriction and vascular smooth muscle proliferation. Relcovaptan, in the hyperstimulated rat model, has shown lower concentrations of VEGF-A in the peritoneal fluid and lesser ovarian weight gain significant decreases in the number of corpora lutea in contrast to control groups. Further research in this area remains rather promising and may broaden the management protocols which clinicians have for OHSS in the near future [r future .OHSS is a complication associated with COS which clinicians have no complete way of preventing at present. Through the various prevention strategies reviewed in this paper (summarized in