Cardiac rhythm abnormalities - An underestimated cardiovascular risk in adult patients with Mucopolysaccharidoses.

Patients with Mucopolysaccharidosis (MPS) have an increased risk of cardiovascular complications, conduction tissue abnormalities and arrhythmia; all rare but underestimated. It has been reported that conduction system defects are progressive in this group of patients and may result in sudden cardiac death. The aim of this study is to review our current practice and suggest best practice guidelines regarding the frequency of cardiac rhythm monitoring in this patient group. Seventy-seven adult MPS patients who attended metabolic clinics between 2013 and 2019 were included in this retrospective observational study. Patients were affected with different MPS types: MPS I (n = 33), MPS II (n = 16), MPS IV (n = 19), VI (n = 8) and VII (n = 1). The assessments included: 12­lead electrocardiogram (ECG), 24-h ECG (Holter monitor), loop recorder/pacemaker interrogation assessment. Data from 12­lead ECG (available from 69 patients) showed a variety of abnormalities: T wave inversion in a single lead III (n = 19), left ventricular hypertrophy (n = 14), early repolarization (n = 14), right axis deviation (RAD, n = 11), partial RBBB (n = 9), right bundle branch block (RBBB) (n = 1) and first degree AV block (n = 1). ECG changes of bundle branch block, RAD (left posterior fascicular block) could represent conduction tissue abnormality and equally could be related to the underlying lung tissue abnormality which is present in most of the patients with MPS. T wave abnormality in a single lead is usually insignificant in healthy individuals; however in MPS patients it could be as a result of chest shape. Among the 34 patients for who 24-hour ECG was available, sinus tachycardia was the most common rhythm noted (n = 9), followed by sinus bradycardia (n = 4), atrial fibrillation (AF) (n = 1) and atrio-ventricular nodal re-entry tachycardia (AVNRT) (n = 1). Permanent pacemaker was inserted in two patients. AF was observed in one patient with MPS II. In conclusion, we postulate that regular cardiac monitoring is required to warrant early detection of underlying conduction tissue abnormalities. In addition, 12­lead ECG is the first line investigation that, if abnormal, should be followed up by 24-hour Holter monitoring. These findings warrant further research studies.

Consensus best practice pathway of the UK Systemic Sclerosis Study group: management of cardiac disease in systemic sclerosis.

Objective: Cardiac disease in SSc can manifest in various ways and is associated with a poor prognosis. There is little evidence on how best to detect and manage cardiac disease in SSc. Our objective was to produce an expert consensus best practice pathway for the management of cardiac disease in SSc. Methods: The UK Systemic Sclerosis Study Group set up several working groups to develop a number of consensus best practice pathways for the management of SSc-specific complications, including cardiac disease. A multidisciplinary task force was convened. The guidelines were partly informed by a comprehensive literature review. Results: A best practice pathway for cardiac disease (with a focus on primary cardiac disease) in SSc is presented, including approaches for early detection and standard pharmacological and device therapies. Due to the benefits, shared care and a multidisciplinary approach are recommended. A future research agenda has been formulated in response to the relative lack of understanding of the natural history of primary cardiac disease that was highlighted by the initiative. Conclusion: The physician should be alert to the possibility of cardiac disease in SSc; it is best managed within a multidisciplinary team including both rheumatologists and cardiologists. This pathway provides a reference for all physicians managing patients with SSc.

Disease-specific therapy for the treatment of the cardiovascular manifestations of Fabry disease: a systematic review.

OBJECTIVE: The cardiovascular manifestations of Fabry disease are common and represent the leading cause of death. Disease-specific therapy, including enzyme replacement therapy (ERT) and chaperone therapy (migalastat), is recommended for patients exhibiting cardiovascular involvement, but its efficacy for modulating cardiovascular disease expression and optimal timing of initiation remains to be fully established. We therefore aimed to systematically review and evaluate the effectiveness of disease-specific therapy compared with placebo, and to no intervention, for the cardiovascular manifestations of Fabry disease. METHODS: Eight databases were searched from inception using a combination of relevant medical subject headings and keywords. Randomised, non-randomised studies with a comparator group and non-randomised studies without a comparator group were included. Studies were screened for eligibility and assessed for bias by two independent authors. The primary outcome comprised clinical cardiovascular events. Secondary outcomes included myocardial histology and measurements of cardiovascular structure, function and tissue characteristics. RESULTS: 72 studies were included, comprising 7 randomised studies of intervention, 16 non-randomised studies of intervention with a comparator group and 49 non-randomised studies of intervention without a comparator group. Randomised studies were not at serious risk of bias, but the others were at serious risk. Studies were highly heterogeneous in their design, outcome measurements and findings, which made assessment of disease-specific therapy effectiveness difficult. CONCLUSION: It remains unclear whether disease-specific therapy sufficiently impacts the cardiovascular manifestations of Fabry disease. Further work, ideally in larger cohorts, with more standardised clinical and phenotypic outcomes, the latter measured using contemporary techniques, are required to fully elucidate the cardiovascular impact of disease-specific therapy. PROSPERO REGISTRATION NUMBER: CRD42022295989.

Systematic review of the incidence and clinical risk predictors of atrial fibrillation and permanent pacemaker implantation for bradycardia in Fabry disease.

INTRODUCTION: Fabry disease (FD) is an X-linked lysosomal storage disorder caused by enzyme deficiency, leading to glycosphingolipid accumulation. Cardiac accumulation triggers local tissue injury, electrical instability and arrhythmia. Bradyarrhythmia and atrial fibrillation (AF) incidence are reported in up to 16% and 13%, respectively. OBJECTIVE: We conducted a systematic review evaluating AF burden and bradycardia requiring permanent pacemaker (PPM) implantation and report any predictive risk factors identified. METHODS: We conducted a literature search on studies in adults with FD published from inception to July 2019. Study outcomes included AF or bradycardia requiring therapy. Databases included Embase, Medline, PubMed, Web of Science, CINAHL and Cochrane. The Risk of Bias Agreement tool for Non-Randomised Studies (RoBANS) was utilised to assess bias across key areas. RESULTS: 11 studies were included, eight providing data on AF incidence or PPM implantation. Weighted estimate of event rates for AF were 12.2% and 10% for PPM. Age was associated with AF (OR 1.05-1.20 per 1-year increase in age) and a risk factor for PPM implantation (composite OR 1.03). Left ventricular hypertrophy (LVH) was associated with AF and PPM implantation. CONCLUSION: Evidence supporting AF and bradycardia requiring pacemaker implantation is limited to single-centre studies. Incidence is variable and choice of diagnostic modality plays a role in detection rate. Predictors for AF (age, LVH and atrial dilatation) and PPM (age, LVH and PR/QRS interval) were identified but strength of association was low. Incidence of AF and PPM implantation in FD are variably reported with arrhythmia burden likely much higher than previously thought. PROSPERO DATABASE: CRD42019132045.

Inflammatory Fabry Cardiomyopathy Demonstrated Using Simultaneous [18F]-FDG PET-CMR.

Using hybridized [18F]-fluorodeoxyglucose positron emission tomography with cardiac magnetic resonance, we identify active myocardial inflammation and demonstrate its relationship with late gadolinium enhancement, in Fabry disease. We demonstrate that late gadolinium enhancement represents, at least in part, active myocardial inflammation and identify an early inflammatory phenotype that may represent a therapeutic window before irreversible tissue injury and adaptation occur. (Level of Difficulty: Intermediate.).

Clinical utilisation of implantable loop recorders in adults with Fabry disease-a multi-centre snapshot study.

Fabry disease (FD) is an X-linked deficiency of alpha-galactosidase-A, leading to lysosomal storage of sphingolipids in multiple organs. Myocardial accumulation contributes to arrhythmia and sudden death, the most common cause of FD mortality. Therefore, there is a need for risk stratification and prediction to target device therapy. Implantable loop recorders (ILRs) allow for continual rhythm monitoring for up to 3 years. Here, we performed a retrospective study to evaluate current ILR utilisation in FD and quantify the burden of arrhythmia that was detected, which resulted in a modification of therapy. This was a snapshot assessment of 915 patients with FD across three specialist centres in England during the period between 1 January 2000 and 1 September 2022. In total, 22 (2.4%) patients underwent clinically indicated ILR implantation. The mean implantation age was 50 years and 13 (59%) patients were female. Following implantation, nine (41%) patients underwent arrhythmia detection, requiring intervention (six on ILR and three post-ILR battery depletion). Three patients experienced sustained atrial high-rate episodes and were started on anticoagulation. Three had non-sustained tachyarrhythmia and were started on beta blockers. Post-ILR battery depletion, one suffered complete heart block and two had sustained ventricular tachycardia, all requiring device therapy. Those with arrhythmia had a shorter PR interval on electrocardiography. This study demonstrates that ILR implantation in FD uncovers a high burden of arrhythmia. ILRs are likely to be underutilised in this pro-arrhythmic cohort, perhaps restricted to those with advanced FD cardiomyopathy. Following battery depletion in three patients as mentioned above, greater vigilance and arrhythmia surveillance are advised for those experiencing major arrhythmic events post-ILR monitoring. Further work is required to establish who would benefit most from implantation.

Enzyme replacement therapy improves cardiac features and severity of Fabry disease.

BACKGROUND: Although left ventricular hypertrophy (LVH) in Fabry disease (FD) can improve with enzyme-replacement therapy (ERT), the response is difficult to predict. Furthermore, the response of other cardiac features such as aortic dilatation and ECG changes are poorly understood. METHODS: A local registry of 66 patients with FD was studied. ECG, echocardiogram and Fabry Outcome Survey-Mainz Severity Score Index (FOS-MSSI) data were compared between baseline and after long-term ERT (median 36 months). RESULTS: In patients with LVH (n=42), left ventricular mass index (LVMI), maximal wall thickness (MWT), left ventricular end-diastolic diameter (LVEDD) and ejection fraction (EF) were all seen to improve after ERT (LVMI: 135±13 vs. 133±13 g/m(2), MWT: 17±6 vs. 16±5 mm, LVEDD: 55±6 vs. 54±6 mm; EF: 62±5 vs. 64±3%; p<0.05). In the entire patient group, PQ interval and P wave duration significantly increased with ERT (PQ: 131±13 vs. 144±13 ms, P: 76±5 vs. 90±6 ms; p values<0.001); QT(c) interval significantly decreased (418±18 vs. 410±15 ms; p<0.001); and median FOS-MSSI score fell from 16 to 14 (p<0.001). On logistic-regression analysis, none of the recorded baseline features (age, gender, LVMI, MWT, LVEDD, aortic diameter, EF, PQ interval, P wave duration, QRS duration, QT interval, Romhilt-Estes score or FOS-MSSI) predicted improvements in LVH or FOS-MSSI with ERT (p>0.05). CONCLUSIONS: ERT improved LV morphology and function in patients with LVH - but there was no relationship between age, gender, FOS-MSSI or baseline ECG/TTE features and the response. ERT also normalised long QTc intervals, short PQ intervals and short P waves; and reduced disease burden (FOS-MSSI).

Ventricular fibrillation following successful DC cardioversion for atrial fibrillation.

Cardioversion remains an important therapy in the management of atrial fibrillation. Here, we report a case where direct current cardioversion resulted in a sudden dramatic change of heart rate that was associated with multiple ventricular fibrillation arrests in a manner akin to that previously observed post-atrioventricular node ablation.

Platypnoea-orthodeoxia in an elderly man with patent foramen ovale and dilated ascending aorta.

We report the case of an 85-year-old male with platypnoea-orthodeoxia associated with patent foramen ovale (PFO) and ectatic ascending aorta, in the absence of any significant pulmonary pathology.

Pre-operative Considerations in Adult Mucopolysaccharidosis Patients Planned for Cardiac Intervention.

Mucopolysaccharidoses (MPS) are rare lysosomal storage diseases characterized by multiorgan involvement and shortened longevity. Due to advances in therapies such as enzyme replacement therapy and haematopoietic stem cell therapy, life expectancy has increased posing newer challenges to patients and health professionals. One such challenge is cardiovascular manifestations of MPS, which can be life limiting and cause reduction in quality of life. Any cardiovascular intervention mandates comprehensive, multi-systemic work-up by specialist teams to optimize outcome. We highlight the importance of multidisciplinary evaluation of adult MPS patients requiring cardiovascular intervention. Clinical assessments and investigations are discussed, with a focus on the cardiac, anesthetic, airway, respiratory, radiological and psychosocial factors.

Validated Model for Prediction of Adverse Cardiac Outcome in Patients With Fabry Disease.

BACKGROUND: The cardiac manifestations of Fabry disease are the leading cause of death, but risk stratification remains inadequate. Identifying patients who are at risk of adverse cardiac outcome may facilitate more evidence-based treatment guidance. Contemporary cardiovascular cardiac magnetic resonance biomarkers have become widely adopted, but their prognostic value remains unclear. OBJECTIVES: The objective of this study was to develop, internally validate, and evaluate the performance of, a prognostic model, including contemporary deep phenotyping, which can be used to generate individual risk estimates for adverse cardiac outcome in patients with Fabry disease. METHODS: This longitudinal prospective cohort study consisted of 200 consecutive patients with Fabry disease undergoing clinical cardiac magnetic resonance. Median follow-up was 4.5 years (IQR: 2.7-6.3 years). Prognostic models were developed using Cox proportional hazards modeling. Outcome was a composite of adverse cardiac events. Model performance was evaluated. A risk calculator, which provides 5-year estimated risk of adverse cardiac outcome for individual patients, including men and women, was generated. RESULTS: The highest performing, internally validated, parsimonious multivariable model included age, native myocardial T1 dispersion (SD of per voxel myocardial T1 relaxation times), and indexed left ventricular mass. Median optimism-adjusted c-statistic across 5 imputed model development data sets was 0.77 (95% CI: 0.70-0.84). Model calibration was excellent across the full risk profile. CONCLUSIONS: This study developed and internally validated a risk prediction model that accurately predicts 5-year risk of adverse cardiac outcome for individual patients with Fabry disease, including men and women, which could easily be integrated into clinical care. External validation is warranted.

Cardiac device implantation and device usage in Fabry and hypertrophic cardiomyopathy.

BACKGROUND: Fabry disease (FD) is a treatable X-linked condition leading to progressive cardiac disease, arrhythmia and premature death. We aimed to increase awareness of the arrhythmogenicity of Fabry cardiomyopathy, by comparing device usage in patients with Fabry cardiomyopathy and sarcomeric HCM. All Fabry patients with an implantable cardioverter defibrillator (ICD) implanted in the UK over a 17 year period were included. A comparator group of HCM patients, with primary prevention ICD implantation, were captured from a regional registry database. RESULTS: Indications for ICD in FD varied with 72% implanted for primary prevention based on multiple potential risk factors. In FD and HCM primary prevention devices, arrhythmia occurred more frequently in FD over shorter follow-up (HR 4.2, p < 0.001). VT requiring therapy was more common in FD (HR 4.5, p = 0.002). Immediate shock therapy for sustained VT was also more common (HR 2.5, p < 0.001). There was a greater burden of AF needing anticoagulation and NSVT in FD (AF: HR 6.2, p = 0.004, NSVT: HR 3.1, p < 0.001). CONCLUSION: This study demonstrates arrhythmia burden and ICD usage in FD is high, suggesting that Fabry cardiomyopathy may be more 'arrhythmogenic' than previously thought. Existing risk models cannot be mutually applicable and further research is needed to provide clarity in managing Fabry patients with cardiac involvement.

Infective Endocarditis in Patients With Intestinal Failure: Experience From a National Referral Center.

BACKGROUND: Infective endocarditis (IE) is a recognized complication of central line-associated bloodstream infection (CLABSI). Central venous access devices (CVADs) are essential for the delivery of long-term parenteral nutrition (PN), yet there are no published data as to the prevalence, characteristics and outcomes of IE in this population. METHODS: A prospectively maintained database of patients with intestinal failure (IF) types 2 and 3, managed by a national intestinal failure center between January 2010 and December 2018, was analyzed retrospectively and relevant factors extracted from case records. RESULTS: A total of 745 patients with IF and CVADs in situ on admission, or placed during their stay, were admitted over the duration of this study, 640 with type 2 IF and 105 with type 3 IF. Two hundred eighty-two echocardiograms were performed to investigate potential IE associated with a CLABSI event. Four cases of IE were identified in the entire cohort of 782,666 catheter days (IE incidence rate: 0.005 per 1000 catheter days and 187 per 100,000 person-years for the entire cohort; 0.048 per 1000 inpatient catheter days for acute type 2 IF, 0.0026 per 1000 outpatient catheter days [ie, 99 per 100,000 person-years for outpatients with type 3 IF]). CONCLUSION: IE is rare in the type 3 IF population and a rare consequence of CLABSI in inpatient acute type 2 IF. However, mortality and morbidity are high. Routine echocardiography may not be warranted for investigation of CLABSI unless there is a high risk of IE or a virulent organism is involved.

A randomised controlled trial evaluating arrhythmia burden, risk of sudden cardiac death and stroke in patients with Fabry disease: the role of implantable loop recorders (RaILRoAD) compared with current standard practice.

BACKGROUND: Fabry disease (FD) is a genetic disorder caused by a deficiency in the enzyme alpha-galactosidase A, leading to an accumulation of glycosphingolipids in tissues across the body. Cardiac disease is the leading cause of morbidity and mortality. Advanced disease, characterised by extensive left ventricular hypertrophy, ventricular dysfunction and fibrosis, is known to be associated with an increase in arrhythmia. Data identifying risk factors for arrhythmia are limited, and no Fabry-specific risk stratification tool is available to select those who may benefit from initiation of medical or device therapy (implantable cardiac defibrillators). Current monitoring strategies have a limited diagnostic yield, and implantable loop recorders (ILRs) have the potential to change treatment and clinical outcomes. AIM: The aim of this study is to determine whether ILRs can (1) improve arrhythmia detection in FD and (2) identify risk predictors of arrhythmia. METHODS: A prospective, 5-year, open-label, international, multi-centre randomised controlled trial of a minimum of 164 participants with genetically or enzymatically confirmed FD (or both) who have evidence of cardiac disease will be recruited from five centres: Queen Elizabeth Hospital, Birmingham, UK; Salford Royal Hospital, Salford, UK; Royal Free Hospital, London, UK; Addenbrookes Hospital, Cambridge, UK; and Westmead Hospital, Sydney, Australia. Participants will be block-randomised (1:1) to two study arms for cardiac monitoring (i) control arm: standard of care with annual 24 h or 5-day Holter monitor or (ii) treatment arm: continuous cardiac monitoring with ILR implantation plus standard of care. Participants will undergo multiple investigations-blood/urine biomarkers, 12-lead and advanced electrocardiogram (ECG) recording, echocardiography and cardiovascular magnetic resonance (CMR) imaging-at baseline and 6-12 monthly follow-up visits. The primary endpoint is identification of arrhythmia requiring initiation or alteration in therapy. Secondary outcome measures include characterising the risk factors associated with arrhythmia and outcome data in the form of imaging, ECG and blood biomarkers. DISCUSSION: This is the first study evaluating arrhythmia burden and the use of ILR across the spectrum of risk profiles in Fabry cardiomyopathy. This will enable detailed characterisation of arrhythmic risk predictors in FD and ultimately support formulation of Fabry-specific guidance in this high-risk population. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03305250 ). Registered on 9 October 2017.

Study of indications for cardiac device implantation and utilisation in Fabry cardiomyopathy.

BACKGROUND: Fabry disease is a treatable X-linked condition leading to progressive cardiomyopathy, arrhythmia and premature death. Atrial and ventricular arrhythmias contribute significantly to adverse prognosis; however, guidance to determine which patients require cardiovascular implantable electronic devices (CIEDs) is sparse. We aimed to evaluate indications for implantation practice in the UK and quantify device utilisation. METHODS: In this retrospective study, we included demographic, clinical and imaging data from patients in four of the largest UK Fabry centres. Ninety patients with Fabry disease were identified with CIEDs implanted between June 2001 and February 2018 (FD-CIED group). To investigate differences in clinical and imaging markers between those with and without devices, these patients were compared with 276 patients without a CIED (FD-control). RESULTS: In the FD-CIED group, 92% of patients with permanent pacemakers but only 28% with implantable cardioverter-defibrillators had a class 1 indication for implantation. A further 44% of patients had defibrillators inserted for primary prevention outside of current guidance. The burden of arrhythmia requiring treatment in the FD-CIED group was high (asymptomatic atrial fibrillation:29%; non-sustained ventricular tachycardia requiring medical therapy alone: 26%; sustained ventricular tachycardia needing anti-tachycardia pacing/defibrillation: 28%). Those with devices were older, had greater LV mass, more scar tissue and larger atrial size. CONCLUSIONS: Arrhythmias are common in Fabry patients. Those with cardiac devices had high rates of atrial fibrillation requiring anticoagulation and ventricular arrhythmia needing device treatment. These are as high as those in hypertrophic cardiomyopathy, supporting the need for Fabry-specific indications for device implantation.

Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document.

INTRODUCTION: Fabry disease (FD) is a lysosomal storage disorder resulting in progressive nervous system, kidney and heart disease. Enzyme replacement therapy (ERT) may halt or attenuate disease progression. Since administration is burdensome and expensive, appropriate use is mandatory. We aimed to define European consensus recommendations for the initiation and cessation of ERT in patients with FD. METHODS: A Delphi procedure was conducted with an online survey (n = 28) and a meeting (n = 15). Patient organization representatives were present at the meeting to give their views. Recommendations were accepted with ≥75% agreement and no disagreement. RESULTS: For classically affected males, consensus was achieved that ERT is recommended as soon as there are early clinical signs of kidney, heart or brain involvement, but may be considered in patients of ≥16 years in the absence of clinical signs or symptoms of organ involvement. Classically affected females and males with non-classical FD should be treated as soon as there are early clinical signs of kidney, heart or brain involvement, while treatment may be considered in females with non-classical FD with early clinical signs that are considered to be due to FD. Consensus was achieved that treatment should not be withheld from patients with severe renal insufficiency (GFR < 45 ml/min/1.73 m(2)) and from those on dialysis or with cognitive decline, but carefully considered on an individual basis. Stopping ERT may be considered in patients with end stage FD or other co-morbidities, leading to a life expectancy of <1 year. In those with cognitive decline of any cause, or lack of response for 1 year when the sole indication for ERT is neuropathic pain, stopping ERT may be considered. Also, in patients with end stage renal disease, without an option for renal transplantation, in combination with advanced heart failure (NYHA class IV), cessation of ERT should be considered. ERT in patients who are non-compliant or fail to attend regularly at visits should be stopped. CONCLUSION: The recommendations can be used as a benchmark for initiation and cessation of ERT, although final decisions should be made on an individual basis. Future collaborative efforts are needed for optimization of these recommendations.

Plethysmography without venous occlusion for measuring forearm blood flow: comparison with venous occlusive method.

Limb blood flow is widely used as an indicator of the human vascular properties. There are only few non-invasive methods for its measurement such as venous occlusion plethysmography. However, several authors have questioned its validity. The problems appear to be related to the process of venous occlusion. We developed two methods to measure forearm blood flow by plethysmography without venous occlusion in combination with Doppler velocimetry (without imaging). Method 1: the gradient of a tangent drawn on the latter part of the down stroke of the plethysmographic volume pulse is an approximation of venous blood flow in the absence of diastolic blood flow. At equilibrium, it equals the average arterial flow in a cardiac cycle. The Doppler velocity waveform recorded simultaneously allows improvement of this approximation when there is diastolic blood flow. Method 2: the volume pulse detected by a plethysmograph calibrated in absolute volume is used to calibrate the velocity waveform recorded simultaneously to produce an approximation of arterial volumetric flow waveform. Bland-Altman analysis shows both methods have good correlation and agreement with venous occlusion plethysmography at rest. Method 1: mean difference (blood flow measured by venous occlusion minus calculated flow) = 0.10 ml/pulse (+/-0.18), limits of agreement = -0.41 and 0.61 ml/pulse. Method 2: mean difference = -0.041 ml/pulse (+/-0.15), limits of agreement = -0.45 and 0.37 ml/pulse. During hyperaemia, venous occlusion plethysmography grossly underestimated relative to the new methods. The new methods are not dependent on venous occlusion and produce consistent results with or without hyperaemia.

Plethysmographic curve analysis and response to exercise in normal subjects, hypertension, and cardiac failure.

Occlusion plethysmographic recordings were obtained on 26 subjects prior to and immediately following repeated venous occlusions. A simple method of approximating the curve shape by 2 straight lines is described. The results indicate that, following an initial occlusion, the height of subsequent curves is reduced and the angulation between the 2 lines approximating the curves changes in a way that indicates that the principal mechanism is venous shunting. The degree of shunting was quantified by taking the relative percentage change in shape of the 2 lines approximating the curve, i.e., the percentage shunt. Venous shunting is shown to be much more marked after hand exercise than at rest in normal subjects and in those with heart failure or hypertension.

Blood flow measurement from plethysmographic pulse waves without venous occlusion.

An air plethysmograph with a sensitive phototransducer was constructed so that plethysmographic volume-change pulsations could be displayed in detail without using venous occlusion. Software was developed to allow analysis of the pulses using a modification of the backward extrapolation technique. This allowed calculation of the forward arterial blood flow and noninvasive derivation of the resting arterial flow waveform. There is good reproducibility of the technique, with 8% variability between pairs of measurements at rest and 4% variability after hand exercise. Direct comparison made with blood flows measured by venous occlusion plethysmography showed good average agreement. The mean blood flow for venous occlusion (rest and exercise) was 0.76 +/- 0.07 mL/beat (mean +/- SEM), and the mean blood flow for backward extrapolation (rest and exercise) was 0.74 +/- 0.09 mL/beat (mean +/- SEM). This corresponds to 3.86 +/- 0.36 mL/min/100 mL and 3.76 +/- 0.46 mL/min/100 mL, respectively. Important assumptions when using this method are that venous return is constant and that forward arterial flow is over before the end of the cardiac cycle.