Comparing the Benefit of Duplex Ultrasound Surveillance Following Both Infrainguinal Bypass Surgery and Stenting for Femoro-Popliteal Disease.

OBJECTIVE: Duplex ultrasound surveillance (DUS) is commonly used following infrainguinal vein bypass. The role of DUS following endovascular revascularisation is as yet unclear. This study focuses on the role of DUS in a contemporary group of patients undergoing infrainguinal bypass or stent insertion. METHODS: All patients undergoing either an infrainguinal vein graft bypass or stent insertion into the femoro-popliteal segment (November 2014 - January 2017) were identified. Patients were followed up for 2 years. Data on entry into DUS, pre-operative characteristics, adjunctive pharmacotherapy and reintervention were collated. The primary outcomes were major lower limb amputation and mortality at 2 years post revascularisation. RESULTS: One hundred and thirty-five patients underwent infrainguinal vein bypass and 100 patients underwent stent insertion. 107 patients in the bypass cohort and 58 patients in the stent cohort entered DUS. For the bypass cohort, entering DUS was associated with a lower mortality rate (P = .003) but was not associated with an improvement in amputation rates. The odds ratio of major amputation or mortality was greater in the no surveillance group (4.58, 95% CI: 1.855 - 11.364). In the stent cohort, DUS was not associated with a significant improvement in either major amputation or death (odds ratio 2.13 (95% CI 0.903 - 5.051; P = .081). CONCLUSION: DUS was associated with improved survival rates in patients undergoing lower limb bypass but had no benefit in those patients undergoing stent insertion. The role of DUS following stent insertion in the femoropopliteal segment needs to be better defined.

Frailty predicts poor longer-term outcomes in patients following lower limb open surgical revascularization.

BACKGROUND: Frailty in vascular surgery patients is increasingly recognized as a marker of poor outcome. This provides particular challenges for patients with lower limb peripheral arterial disease who require surgical revascularization. This study aimed to assess the impact of frailty on short- and long-term outcome in this specific patient group using a specialty specific frailty score. METHODS: Patients undergoing open surgical revascularization for chronic limb ischemia (January 2015-December 2016) were assessed. Demographics, mode of admission, diagnosis, and site of surgery were recorded alongside a variety of frailty-specific characteristics. We calculated the previously validated Addenbrookes Vascular Frailty Score (AVFS) and Long AVFS (LAVFS). Primary outcome was 3-year mortality. RESULTS: Two hundred and sixty-one patients (75% men, median age 69 years) were studied. The median length of stay was 6 days with a 3-year mortality of 23%. The predictive power of vascular frailty scores showed that for 3-year mortality, area under the receiver operator curve values (AUROC) were specific for both the AVFS score (AUROC: 0.724, 95% CI: 0.654-0.794) and LAVFS Score (AUROC: 0.741, 95%CI: 0.670-0.813). Furthermore, the cumulative AVFS and LAVFS scores both predicted mortality over the follow-up period (P=0.0001) with increased mortality among patients with higher scores. CONCLUSIONS: Incremental worsening of frailty, determined using a specialty specific frailty score, predicts mortality risk in patients undergoing lower limb surgical revascularization.

Patient and Institutional Costs of Failure of Angioplasty of the Superficial Femoral Artery.

BACKGROUND: Debate surrounds the optimal management of superficial femoral artery (SFA) disease. Randomized trial data rarely reflect real world findings, specifically the consequences to the patient of angioplasty failure. We observed the effect of a failed SFA angioplasty on the need for repeated clinic visits, hospital readmissions, imaging requirements, and reinterventions. METHODS: We reviewed a consecutive series of 148 patients (94 men, median age 72 years) undergoing solely SFA angioplasty over a 2-year period. Patient preangioplasty demographics and 2-year post-PTA follow-up data were collated, including hospital attendances (inpatient/outpatient), further imaging (including radiation exposure) and revascularization attempts. We defined "failed angioplasty" as presence of clinical symptoms with radiological evidence of significant restenosis after an initial successful primary SFA angioplasty. RESULTS: Fifty-four patients represented with a failed angioplasty (median time of 4 months after index PTA). In this group, failure of index angioplasty resulted in a further 185 restenosis-related clinic visits and a total of 537 bed days of inpatient stay. This group underwent a further 149 imaging events and required a further 34 endovascular revascularization procedures and 12 infrainguinal bypass procedures. These interventions and investigations corresponded to overall effective radiation dose across all patients of 190.69 mSv. Of the cohort of 99 patients who did not have a "failed angioplasty," they required 100 clinic visits, 21 further scans (total radiation dose 6.42 mSv), and 36 bed days of inpatient admission. CONCLUSIONS: Failed angioplasty results in significant additional consequences for patients and health-care systems. Further work should focus on refining decision-making, providing the right procedure to the right patient at the right time.

The Effect of Frailty on Long Term Outcomes in Vascular Surgical Patients.

OBJECTIVE: Frailty is a multidimensional vulnerability due to age associated decline. The impact of frailty on long term outcomes was assessed in a cohort of vascular surgical patients. METHODS: Patients aged over 65 years with a length of stay greater than two days admitted to a tertiary vascular unit over a single calendar year were included. Demographics, mode of admission, and diagnosis were recorded alongside a variety of frailty specific characteristics. Using the previously developed Addenbrookes Vascular Frailty Score (AVFS - 6 point score: anaemia on admission, lack of independent mobility, polypharmacy, Waterlow score > 13, depression, and emergency admission) the effect of frailty on five year mortality and re-admission rates was assessed using multivariable regression techniques. The AVFS was further refined to assess longer term outcomes. RESULTS: In total, 410 patients (median age 77 years) were included and followed up until death or five years from the index admission. One hundred and thirty-four were treated for aortic aneurysm, 75 and 96 for acute and chronic limb ischaemia respectively, 52 for carotid disease, and 53 for other pathologies. The in hospital mortality rate was 3.6%. The one, three, and five year survival rates were 83%, 70% and 59%; and the one, three, and five year re-admission free survival rates were 47%, 29%, and 22% respectively. Independent predictors of five year mortality were age, lack of independent mobility, high Charlson score, polypharmacy, evidence of malnutrition, and emergency admission (p < .010 for all). Patients with AVFS 0 or 1 had restricted mean survival times which were one year longer than those with AVFS 2 or 3 (p < .001), who in turn had restricted mean survival times over one year longer than those with AVFS of 4 or more (p < .001). CONCLUSION: Frailty factors are strong predictors of long term outcomes in vascular surgery. Further prospective studies are warranted to investigate its utility in clinical decision making.

Editor's Choice - Calcification of Thoracic and Abdominal Aneurysms is Associated with Mortality and Morbidity.

INTRODUCTION: Cardiovascular events are common in people with aortic aneurysms. Arterial calcification is a recognised predictor of cardiovascular outcomes in coronary artery disease. Whether calcification within abdominal and thoracic aneurysm walls is correlated with poor cardiovascular outcomes is not known. PATIENTS AND METHODS: Calcium scores were derived from computed tomography (CT) scans of consecutive patients with either infrarenal (AAA) or descending thoracic aneurysms (TAA) using the modified Agatston score. The primary outcome was subsequent all cause mortality during follow-up. Secondary outcomes were cardiovascular mortality and morbidity. RESULTS: A total of 319 patients (123 TAA and 196 AAA; median age 77 [71-84] years, 72% male) were included with a median follow-up of 30 months. The primary outcome occurred in 120 (37.6%) patients. In the abdominal aortic aneurysm group, the calcium score was significantly related to both all cause mortality and cardiac mortality (odds ratios (OR) of 2.246 (95% CI 1.591-9.476; p < 0.001) and 1.321 (1.076-2.762; p = 0.003)) respectively. In the thoracic aneurysm group, calcium score was significantly related to all cause mortality (OR 6.444; 95% CI 2.574-6.137; p < 0.001), cardiac mortality (OR 3.456; 95% CI 1.765-4.654; p = 0.042) and cardiac morbidity (OR 2.128; 95% CI 1.973-4.342; p = 0.002). CONCLUSIONS: Aortic aneurysm calcification, in either the thoracic or the abdominal territory, is significantly associated with both higher overall and cardiovascular mortality. Calcium scoring, rapidly derived from routine CT scans, may help identify high risk patients for treatment to reduce risk.

Variability in Atherosclerotic Disease Progression within the Infrainguinal Arterial Circulation is Dependent on Both Patient and Anatomical Factors.

BACKGROUND: Studies suggest 25% of patients with symptomatic peripheral arterial disease develop symptom progression over time, yet there is minimal data related to actual atherosclerotic progression. METHODS: Patients who underwent consecutive duplex imaging of the lower limb arteries, at least 6 months apart with no intervening arterial intervention, were identified. Atherosclerotic burden was determined for both femoropopliteal (FP) and crural (CR) arterial segments utilizing the Bollinger score (BoS). Overall change in BoS over time was determined, and patients were divided into group 1: disease progression and group 2: no change/disease regression. Patient demographics, comorbidities, and long-term outcomes were collated. RESULTS: A total of 215 FP segments (155 men; median age 74 years) were assessed with 82 limbs showing atherosclerotic disease progression. FP atherosclerotic progression was associated with increased age, a diagnosis of ischemic heart disease and hypertension, and a lack of prescription of both an antiplatelet therapy and an angiotensin-converting enzyme inhibitor (all P < 0.05). FP atherosclerotic progression was also associated with an increased longer term mortality rate. A total of 272 CR arterial segments (190 men; median age 74 years) were assessed with 86 limbs showing atherosclerotic disease progression. CR atherosclerotic disease progression was associated with a diagnosis of diabetes mellitus at baseline (P = 0.019). CONCLUSIONS: A number of variable factors predict atherosclerotic progression. Differences exist between factors and the arterial segments affected (FP/CR). This suggests that underlying atherosclerotic processes may vary depending on arterial segment, warranting further investigation.

Metabolic flexibility of mitochondrial respiratory chain disorders predicted by computer modelling.

Mitochondrial respiratory chain dysfunction causes a variety of life-threatening diseases affecting about 1 in 4300 adults. These diseases are genetically heterogeneous, but have the same outcome; reduced activity of mitochondrial respiratory chain complexes causing decreased ATP production and potentially toxic accumulation of metabolites. Severity and tissue specificity of these effects varies between patients by unknown mechanisms and treatment options are limited. So far most research has focused on the complexes themselves, and the impact on overall cellular metabolism is largely unclear. To illustrate how computer modelling can be used to better understand the potential impact of these disorders and inspire new research directions and treatments, we simulated them using a computer model of human cardiomyocyte mitochondrial metabolism containing over 300 characterised reactions and transport steps with experimental parameters taken from the literature. Overall, simulations were consistent with patient symptoms, supporting their biological and medical significance. These simulations predicted: complex I deficiencies could be compensated using multiple pathways; complex II deficiencies had less metabolic flexibility due to impacting both the TCA cycle and the respiratory chain; and complex III and IV deficiencies caused greatest decreases in ATP production with metabolic consequences that parallel hypoxia. Our study demonstrates how results from computer models can be compared to a clinical phenotype and used as a tool for hypothesis generation for subsequent experimental testing. These simulations can enhance understanding of dysfunctional mitochondrial metabolism and suggest new avenues for research into treatment of mitochondrial disease and other areas of mitochondrial dysfunction.

Chemometrics as a tool of origin determination of Polish monofloral and multifloral honeys.

The aim of this study was to evaluate the application of chemometrics studies to determine the botanical origin of Polish monofloral honeys using NMR spectroscopy. Aqueous extracts of six kinds of honeys, namely, heather (Calluna vulgaris L.), buckwheat (Fagopyrum esculentum L), lime (Tilia L), rape (Brassica napus L. var. napus), acacia (Acacia Mill.), and multifloral ones, were analyzed. Multivariate chemometric data analysis was performed using principal component analysis (PCA) and orthogonal partial least-squares discriminant analysis (OPLS-DA). Chemometric analysis supported by pollen analysis revealed the incorrect classification of acacia honeys by the producers. Characteristic motives for each honey were identified, which allowed chemical profiles of tested honeys to be built. Thus, phenylacetic acid and dehydrovomifoliol (4-hydroxy-4-[3-oxo-1-butenyl]-3,5,5-trimethylcyclohex-2-en-1-one) were proposed to be markers of Polish heather honey. Formic acid and tyrosine were found to be the most characteristic compounds of buckwheat honey, whereas 4-(1-hydroxy-1-methylethyl)cyclohexane-1,3-dienecarboxylic acid was confirmed as a marker of lime honey.

Evaluation of the relations between the presence of the metabolic syndrome and the degree of visceral obesity and the severity of coronary artery disease by coronary angiography.

BACKGROUND: The prevalence of the metabolic syndrome (MetSy) steadily increases worldwide. AIM: To evaluate the relation between the presence of MetSy and visceral obesity and the presence of coronary lesions, and to assess correlations between waist circumference and body mass index (BMI) and coronary lesions. METHODS: We studied 105 patients who underwent elective coronary angiography. The study population was divided into four groups depending on the presence of MetSy and visceral obesity. Coronary angiographic evaluation was performed by an invasive cardiologist. For ultimate objective evaluation of the degree of coronary stenoses, quantitative coronary angiography was performed. Based upon coronary angiography results, patients were divided into four groups depending on the severity of coronary artery disease (CAD): with no coronary lesions, with haemodynamically insignificant lesions (1-69% stenosis), with haemodynamically significant lesions (> 70%) in 1 or 2 vessels, and with multivessel disease (> 70% stenoses in 3 vessels or a > 50% stenosis in the left main coronary artery). RESULTS: Normal coronary arteries were significantly more commonly found in patients without obesity and MetSy (50% of patients). Haemodynamically significant lesions were most frequently found among obese patients with MetSy (40% of patients) and among obese patients without MetSy (38.1% of patients). Concomitant presence of obesity among patients with MetSy (i.e., MetSy with obesity as compared to MetSy without obesity) was not found to be significantly related to the severity of CAD. In addition, advanced CAD was significantly more frequent in obese patients with MetSy compared to the other groups. Isolated visceral obesity in patients without MetSy (i.e., obese patients without MetSy as compared to non-obese patients without MetSy) was found to correlate with haemodynamically significant coronary lesions. When we evaluated nonparametric correlations between waist circumference, BMI; and the severity of CAD, BMI did not correlate with coronary lesions (r = 0.08, p = 0.37). In contrast, a significant correlation was found between waist circumference and the severity of CAD (r = 0.55, p < 0.001). Haemodynamically significant lesions were more significantly more frequent in patients with MetSy compared to patients without MetSy (76% vs. 24%, p < 0.001). Haemodynamically significant lesions were found in 67.7% of patients with isolated visceral obesity compared to 23.2% of non-obese patients without MetSy. In multivariate analysis, CAD was significantly more likely among patients with MetSy regardless of the analysed model (OR 5.3, 95% CI 1.1-25.8, p < 0.05). CONCLUSIONS: 1. The presence of MetSy significantly correlates with haemodynamically significant coronary lesions. 2. The degree of visceral obesity significantly correlates with the severity of CAD. 3. BMI does not correlate with the severity of CAD. 4. Isolated visceral obesity is a weaker determinant of haemodynamically significant coronary lesions compared to MetSy with associated obesity. 5. MetSy is associated with significantly more advanced coronary lesions, i.e. multivessel disease.

Polyplex-microbubble hybrids for ultrasound-guided plasmid DNA delivery to solid tumors.

Microbubble ultrasound contrast agents are being developed as image-guided gene carriers for targeted delivery in vivo. In this study, novel polyplex-microbubbles were synthesized, characterized and evaluated for systemic circulation and tumor transfection. Branched polyethylenimine (PEI; 25 kDa) was modified with polyethylene glycol (PEG; 5 kDa), thiolated and covalently attached to maleimide groups on lipid-coated microbubbles. The PEI-microbubbles demonstrated increasingly positive surface charge and DNA loading capacity with increasing maleimide content. The in vivo ultrasound contrast persistence of PEI-microbubbles was measured in the healthy mouse kidney, and a two-compartment pharmacokinetic model accounting for free and adherent microbubbles was developed to describe the anomalous time-intensity curves. The model suggested that PEI loading dramatically reduced free circulation and increased nonspecific adhesion to the vasculature. However, DNA loading to form polyplex-microbubbles increased circulation in the bloodstream and decreased nonspecific adhesion. PEI-microbubbles coupled to a luciferase bioluminescence reporter plasmid DNA were shown to transfect tumors implanted in the mouse kidney. Site-specific delivery was achieved using ultrasound applied over the tumor area following bolus injection of the DNA/PEI-microbubbles. In vivo imaging showed over 10-fold higher bioluminescence from the tumor region compared to untreated tissue. Ex vivo analysis of excised tumors showed greater than 40-fold higher expression in tumor tissue than non-sonicated control (heart) tissue. These results suggest that the polyplex-microbubble platform offers improved control of DNA loading and packaging suitable for ultrasound-guided tissue transfection.

Probing asphaltene aggregation in native crude oils with low-field NMR.

We show that low-field proton nuclear magnetic resonance (NMR) relaxation and diffusion experiments can be used to study asphaltene aggregation directly in crude oils. Relaxation was found to be multiexponential, reflecting the composition of a complex fluid. Remarkably, the relaxation data for samples with different asphaltene concentrations can be collapsed onto each other by a simple rescaling of the time dimension with a concentration-dependent factor xi, whereas the observed diffusion behavior is unaffected by asphaltene concentration. We interpret this finding in terms of a theoretical model that explains the enhanced relaxation by the transitory entanglement of solvent hydrocarbons within asphaltene clusters and their subsequent slowed motion and diffusion within the cluster. We relate the measured scaling parameters xi to cluster sizes, which we find to be on the order of 2.2-4.4 nm for an effective sphere diameter. These sizes are in agreement with the typical values reported in the literature as well as with the small-angle X-ray scattering (SAXS) experiments performed on our samples.

Two-dimensional NMR of diffusion systems.

We consider diffusion in porous media with well-connected pore space for which isolated-pore models are insufficient. Explicit pore-to-pore exchange parameters were introduced in recent 2D NMR experiments. However, such parameters capture only certain aspects of the interpore spin dynamic which, for single-fluid saturated media, are wholly determined by diffusion. Here, we develop a theoretical approach suitable for a quantitative description of such 2D NMR taking a full account of the underlying diffusion modes. We use simple models of one pore and two coupled pores to demonstrate the rich behavior of 2D NMR.

[The thrombin generation is associated with the PIA1/A2 beta3, integrin polymorphism in aspirin-treated patients with coronary artery disease: a role of statins]. / Allel PIA1/A2 beta3 integryny wiaze sie ze zwiekszona generacja trombiny u pacjentów z choroba wiencowa leczonych kwasem acetylosalicylowym: wplyw leczenia statynami.

INTRODUCTION: The PIA2 allele is present in about 20-30% of European population. This allele has been associated with resistance to the antithrombotic action of aspirin in healthy PIA2 carriers. OBJECTIVES: To evaluate the functional association of the PIA1/A2 polymorphism of beta3 intergrins with increased thrombin generation and platelet activation in patients with coronary artery disease (CAD), treated with low-dose aspirin and whether the effect of this polymorphism is modulated by statin administration. PATIENTS AND METHODS: In 31 patients (25 M, 6 F) with CAD, aged 47 to 76 years, the thrombin-antithrombin complex generation (TAT) and the soluble form of CD40 ligand level (sCD40L) in blood collected every 60 seconds at sites of standardized microvascular injury were determined. RESULTS: Coronary angiography revealed > or = 1 major epicardial artery stenosis (> or = 50%) in all patients. Genotyping determined 18 subjects homozygous for PIA1 and 13 PIA2 heterozygous carriers. Homozygous PIA1 subjects exhibited increased fibrinogen levels compared with PIA2 carriers (4.2 [IQ 2.39] g/l vs. 2.5 [0.73] g/l, p <0.05). Maximal TAT level observed 6 min after microvascular injury was higher in PIA2 carriers (p = 0.01). Maximal sCD40L did not differ between PIA1/A1 subjects and PIA2 carriers. The PIA2 allele did not alter the velocity of TAT production and sCD40L release. The analysis of the area under the concentration vs. time curve for TAT revealed that PIA2 carriers exhibited increased thrombin generation compared with PIA1A1 subjects (by 17.5%, p <0.05). Subjects treated with statins (n = 12) had lower TAT generation and sCD40L release than non-treated (by 20%, p <0.005 and 23%, p <0.005, respectively). This effect was not altered by the PIA2 presence. CONCLUSIONS: In a model of microvascular injury the PIA1/A2 polymorphism influenced thrombin formation but not platelet activation in CAD patients treated with low-dose aspirin. The PIA2 allele did not alter the beneficial effect of statins on blood coagulation.

Probing short length scales with restricted diffusion in a static gradient using the CPMG sequence.

We experimentally verify a new method of extracting the surface-to-volume ratio (S/V) of porous media with diffusion NMR. In contrast to the widely used pulsed field gradient (PFG) technique, which employs the stimulated echo coherence pathway, we use here the direct Carr-Purcell-Meiboom-Gill (CPMG) path. Even for high echoes, which exhibit ample attenuation due to diffusion in the field gradient, the relevant ruler length for the direct pathway is fixed by the diffusion length during a single inter-pulse spacing. The direct path, therefore, is well suited for probing shorter length scales than is possible with the conventional approach. In our experiments in a low-field static-gradient system, the direct CPMG pathway was found to be sensitive to structure an order of magnitude smaller than accessible with the stimulated-echo pathway.

Short-time restricted diffusion in a static gradient and the attenuation of individual coherence pathways.

We experimentally explore some of the implications of a recent theoretical study [J. Magn. Reson. 64 (2003) 145] for the measurement of restricted diffusion in connected porous media in a static gradient. In particular, we examine how restriction affects the short-time attenuation of different coherence pathways, all excited with the same sequence of slice-selective radiofrequency (RF) pulses, and how the various pathways make the transition to the long-time or tortuosity regime. We confirm that every pathway contains equivalent diffusional information and, for short times, yields the surface-to-volume ratio (S/V) of the confining space. We find also, in agreement with the theoretical predictions, that different pathways are controlled by different time scales and, thus, exhibit different sensitivity to restriction. This property might be exploited when designing optimal sequences to study restricted motion.

Effect of internal gradients in the nuclear magnetic resonance measurement of the surface-to-volume ratio.

We consider a system of spins diffusing in a static inhomogeneous (nonuniform-gradient) magnetic field B in a restricted geometry and in the presence of surface relaxation. We show that the short-time diffusional decay of nuclear magnetization is controlled by the field scattering kernel F(t) identical with [B(t)-B(0)](2), which is a measure of the average field inhomogeneity sampled by the spins in time t and does not depend on the particular sequence of radio-frequency pulses used. Magnetization in arbitrary sequences can be straightforwardly computed by evaluating elementary integrals of F(t). Diffusion takes place while the field is on, so that the spins precess as they diffuse, in contrast to the simpler problem of purely classical diffusion considered in [P. P. Mitra, P. N. Sen, and L. M. Schwartz, Phys. Rev. B 47, 8565 (1993)] which is applicable only to the ideal pulsed-field gradient experiment. We compute the short-time asymptotic form of F(t) and find that it depends on the surface-to-volume ratio (S/V) of the pore space as well as on the average of the gradients over the bounding surface. In a system with nonuniform gradients that vary faster near the surface than in the bulk, as for internal susceptibility fields, this gradient surface average may be much larger than the gradients in the bulk, significantly enhancing the apparent S/V. We discuss the application of our results to the widely used Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence as well as proposing a modification of it, which we term "padded" CPMG, that may be preferable in systems with significant surface relaxation. We indicate how each sequence can be used to probe the internal fields.

Effects of finite-width pulses in the pulsed-field gradient measurement of the diffusion coefficient in connected porous media.

We analytically compute the apparent diffusion coefficient D(app) for an open restricted geometry, such as an extended porous medium, for the case of a pulsed-field gradient (PFG) experiment with finite-width pulses. In the short- and long-time limits, we give explicit, model-independent expressions that correct for the finite duration of the pulses and can be used to extract the pore surface-to-volume (S/V) ratio as well as the tortuosity. For all times, we compute D(app) using a well-established model form of the actual time-dependent diffusion coefficient D(t) that can be obtained from an ideal narrow-pulse PFG. We compare D(app) and D(t) and find that, regardless of pulse widths and geometry-dependent parameters, the two quantities deviate by less than 20%. These results are in sharp contrast with the studies on closed geometries [J. Magn. Reson. A 117 (1995) 209], where the effects of finite gradient-pulse widths are large. The analytical results presented here can be easily adapted for different pulse protocols and time sequences.

Restricted diffusion in grossly inhomogeneous fields.

We analyze the effects of geometrical restriction on the nuclear magnetization of spins diffusing in grossly inhomogeneous fields where radio-frequency (RF) pulses are weak relative to the total field inhomogeneity, making the rotation angle space-dependent and thus exciting multiple coherence pathways. We show how to separate the effects of restricted diffusion from the effects of the pulses in the case when the change in the field experienced by a diffusing spin in the course of the experiment is small compared to the RF magnitude. We then derive explicit formulas for the contribution of individual coherence pathways to the total magnetization in arbitrary pulse sequences. We find that, for long diffusion times, restriction can dramatically alter the spectrum and the shape of a particular echo, while for short times, the correction will be proportional to the pore space surface-to-volume ratio. We demonstrate these results on the example of the early echoes of the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence.