At approximately the same time,  Cordis  (a division of  Johnson & Johnson ) was developing the  Cypher stent , a stent that would release  sirolimus  (a chemotherapeutic agent) over time.  The first study of these individuals revealed an incredible lack of restenosis (zero percent restenosis) at six months. [ 34 ]   This led to the approval for the stent to be used in Europe in April 2002. [ 35 ]   Further trials with the Cypher stent revealed that restenosis did occur in some individuals with high risk features (such as long areas of stenosis or a history of  diabetes mellitus ), but that the restenosis rate was significantly lower than with bare metal stents (3.2 percent compared to 35.4 percent). [ 36 ]   About a year after approval in Europe, the United States  FDA  approved the use of the Cypher stent as the first  drug-eluting stent  for use in the general population in the United States. [ 37 ]


Concurrent with the development of the Cypher stent,  Boston Scientific  started development of the  Taxus stent .  The Taxus stent was the Express2 metal stent, which was in general use for a number of years, [ 38 ]  with a  copolymer  coating of  paclitaxel  that inhibited cell replication.  As with the Cypher stent before it, the first trials of the Taxus stent revealed no evidence of in-stent restenosis at six months after the procedure, [ 39 ]  while later studies showed some restenosis, at a rate much lower than the bare metal counterpart. [ 40 ]  With further study, [ 41 ]  the FDA approved the use of the Taxus stent in the United States in March 2004. [ 42 ]


By the end of 2004, drug-eluting stents were used in nearly 80 percent of all percutaneous coronary interventions. [ 43 ]


Another source of controversy in the field of interventional cardiology has been the overlapping roles of PCI and coronary artery bypass surgery for individuals with coronary artery disease compared to the role of intense pharmacologic therapy.  This area has been studied in a number of trials since the early 1990s. [ 44 ] [ 45 ] [ 46 ]  With rapid changes in techniques occurring in both bypass surgery as well as PCI, multiple studies have been conducted with the hope of identifying which individuals do better with PCI and which do better with  coronary artery bypass graft  (CABG) surgery. [ 47 ]


Several of these studies evaluate the effectiveness of newer techniques, such as  fractional flow reserve  (FFR), and suggest PCI can frequently improve outcomes for patients with clinically significant coronary atherosclerosis. [ 48 ]  The  FAME study  found that the primary endpoint of death, nonfatal myocardial infarction, and repeat revascularization were 5.1% lower after one year in patients whose care was guided by FFR. [ 49 ]  Benefits from PCI have also been shown for those having a heart attack ( ST elevation myocardial infarction , or STEMI), those having a heart attack without EKG changes ( non-ST elevation myocardial infarction , or NSTEMI), and those with angina that is not being controlled with medication. [ 50 ]  In general, each case is individualized to the patient and the relative comfort level of their interventional cardiologist and cardiothoracic surgeon.


At the 2007 meeting of the  American College of Cardiology  (ACC), data from the COURAGE trial was presented, suggested that the combination of PCI and intensive (optimal) medical therapy did not reduce the incidence of death, heart attacks, or stroke compared to intensive medical therapy alone. [ 51 ]


Research conducted since 2007 has documented ways in which PCI can be an effective treatment in specific instances. Data analysis of COURAGE trial results showed an incremental benefit for patients during the first 12-24 months following treatment using PCI, specifically regarding frequency of angina, physical limitations, and quality-of-life factors. [ 52 ]  Results from a 2019 trial did not show evidence that an initial invasive strategy reduced the risk of ischemic cardiovascular events or death from any cause. However, they did show that for patients with angina, an initial invasive strategy led to more effective relief of angina symptoms, [ 53 ]  and that PCI reduced the risk of spontaneous myocardial infarction when compared with initial conservative management. [ 54 ]


When results from the first trials of drug-eluting stents were published, there was a general feeling in the interventional cardiology community that these devices would be part of the perfect revascularization regimen for coronary artery disease. With the very low restenosis rates of the RAVEL [ 34 ]  and SIRIUS [ 36 ]  trials, interventions were performed on more complex blockages in the coronary arteries under the assumption that real-life results would mimic the results from the trials. Based on early trials, the advised antiplatelet regimen for drug-eluting stents was a combination of  aspirin  and  clopidogrel  for 3 months when Cypher stents were used, [ 36 ]  and 9 months when Taxus stents were used, [ 55 ]  followed by aspirin indefinitely.


Soon, case reports started being published regarding late stent thrombosis. [ 56 ]   At the 2006 ACC annual meeting, preliminary results from the BASKET-LATE trial were presented, which showed a slight increase in late thrombosis associated with drug-eluting stents over bare metal stents. [ 57 ]   However, this increase was not statistically significant, and further data would have to be collected.  Additional data published over the following year had conflicting results, [ 58 ]  making it unclear whether stent thrombosis was truly higher when compared to bare metal stents.  During this time of uncertainty, many cardiologists started extending the dual antiplatelet regimen of aspirin and clopidogrel in individuals with drug-eluting stents, as some data suggested it may prevent late thrombosis. [ 59 ]


The  FDA Center for Devices and Radiological Health  held a Circulatory System Devices Panel in December 2006 to review data presented by Cordis and Boston Scientific to determine if drug-eluting stents should be considered less safe than bare metal stents. [ 60 ]   It became evident at the meeting that with all the data published, there were varied definitions of late thrombosis and key differences in the types of lesions in different studies, hampering analysis of the data. [ 43 ]   It was also noted that with the advent of drug-eluting stents, interventional cardiologists had started performing procedures on more complex lesions, subsequently using the stents in "off label" coronary artery lesions that would otherwise go untreated, or for  bypass surgery . [ 43 ]   The FDA advisory board reiterated the ACC guidelines that clopidogrel should be continued for 12 months after drug-eluting stent placement in individuals who are at low risk for bleeding. [ 61 ] [ 62 ]


Since 2006, technology advancements for drug-eluting stents have led to safety improvements. More recent analysis of clinical data note drug-eluting stents can be safely used and can lead to more effective reduction in stent thrombosis than bare metal stents. [ 63 ]  According to a 2018 data analysis, using drug-eluting stents in coronary intervention lowered risk of myocardial infarction, ischemia-driven target lesion revascularization, target vessel revascularization, and stent thrombosis in the first month following stenting. [ 64 ]  Newer generations of drug-eluting stents have been found to reduce the risk of restenosis, myocardial infarction, and death when compared with bare-metal stents. [ 65 ]  Advancements in stent design that include reducing strut thickness have shown further improvements for patients compared to previous generations. [ 65 ]


A 2021 study noting a lack of age-specific recommendations for elderly patients with ischemic heart disease found a statistically significant decrease in major cardiovascular events when elderly patients were treated using drug-eluting stents. [ 66 ]  The findings led the study's authors to recommend drug-eluting stents over bare metal stents when treating the elderly. [ 66 ]


HL7 aECG  (the  HL7  Annotated  Electrocardiogram ) is a standard medical record data format for storing and retrieving electrocardiogram data for a patient.  Like other HL7 formats, it is XML based.


The HL7 aECG standard was created in response to the  Food and Drug Administration ’s digital electrocardiogram initiative which was introduced November, 2001. [ 1 ]   The FDA initiative required ECG waveforms and annotations submitted to the FDA to have a standard format for the data. At the time, no current ECG waveform standards met all the FDA's needs. As a result, the FDA, sponsors, core laboratories, and device manufactures worked together within HL7 to create a standard to meet the FDA requirements.


The aECG standard was created by HL7's Regulated Clinical Research Information Management ( RCRIM ). It passed final balloting in January, 2004, and was accepted by ANSI May, 2004.
 [ 2 ]


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Hurst's The Heart  is a  medical   textbook  published by  McGraw-Hill Education . First released in 1966, it is currently in its 15th edition. It covers the field of  cardiology  and is one of the most widely used medical textbooks in the world. [ 1 ]


The first edition of the book, titled  The Heart , was written in 1966 by  John Willis Hurst , who had served as the  cardiologist  of former U.S. President  Lyndon B. Johnson . In 1986, the book was renamed  Hurst's The Heart . [ 1 ]  It is currently in its 15th edition published as Fuster and Hurst's The Heart in June 2022.


Hurst's the Heart: Manual of Cardiology  provides a summary of the clinical content of its larger companion textbook. It features a streamlined, quick-access presentation designed for use in emergencies and urgent clinical situations. It is edited by Robert A O'Rourke. [ 2 ]


The book has been described as a "widely read textbook of cardiology", [ 3 ]  and a "standard reference" work. [ 4 ]  According to  The New York Times ,  Hurst's The Heart  has become one of the most widely used medical textbooks in the world. [ 1 ]


A  hybrid cardiac surgical procedure  in a narrow sense is defined as a procedure that combines a conventional, more invasive surgical part (including a skin incision) with an interventional part, using some sort of  catheter -based procedure guided by  fluoroscopy  (or other, e.g.,  CT  or  MRI ) imaging in a  hybrid operating room (OR)  without interruption. [ 1 ]  The hybrid technique has a reduced risk of surgical complications and has shown decreased recovery time. It can be used to treat numerous heart diseases and conditions and with the increasing complexity of each case, the hybrid surgical technique is becoming more common.


A hybrid cardiac surgery can be either a one-stage or two-stage procedure. The difference between the two is the extent of time elapsed between the two components of a hybrid surgery. A one-stage procedure is done in hybrid suite and requires a specialized operating room. In the two-stage procedure, there is a time gap between the catheter intervention and the surgical operation. The time between can vary by minutes or hours, and although unlikely, up to days and weeks. The two-stage procedure is typically done in different locations, beginning in a  catheterization laboratory  followed by a surgical operating room.


The first uses of the technical hybrid cardiac surgical procedures were done in the 1990's. However, there have been descriptions of such procedures earlier in the 1970's. [ 2 ]


There are no absolute contraindications to a hybrid cardiac surgery, and the precise circumstances which indicate a hybrid surgery would be most beneficial are uncertain. [ 3 ]   However, several factors should be considered when devising a care plan.


Regarding most cardiovascular diseases, high-risk and re-operative patients are ideal candidates for a hybrid surgery. [ 3 ]   Crucial factors to acknowledge are the complexity of the disease and the possible  comorbidities , such as advanced age,  obesity  and decreased pulmonary function. Cardiologists often use the  SYNTAX score  grading system to determine the complexity of the coronary artery disease and the possible surgical outcomes. Other deciding factors may include the patient's suitable vessels for grafting, body mass index,  radiographic contrast  allergies, and response to  antiplatelet therapies . [ 3 ]


Both components of a hybrid surgery have multiple uses and can be used independently to restore cardiac functions. Each component also has risks and complications associated.


Cardiac catheterization  is the insertion of a  catheter  into the heart through a blood vessel. The cardiac catheter can then be used to run tests and perform other procedures. Such procedures are  stent placement ,  angioplasty ,  fractional flow reserve ,  intravascular ultrasound (IVUS)  and  cardiac biopsy . [ 4 ]  Conditions indicating the need for a cardiac catheter include the following:  atherosclerosis ,  cardiomyopathy ,  congenital heart disease ,  heart failure , and  heart valve disease . [ 4 ]  The risks associated with cardiac catheterization are bleeding, bruising, pain, blood clot, blood vessel damage, or infection where the catheter was inserted,  heart arrhythmia ,  ischemia , sudden blockage of a  coronary artery , a tear in the lining of an  artery ,  kidney damage  or  stroke .  [ 4 ]  Many of the risks associated with catheterization are also risks when more invasive cardiac procedures are done. Hybrid surgeries involve many of the same risks applied and there is often concern about the success of antiplatelet therapy and bleeding postoperative.


Surgical  bypass grafting  and percutaneous coronary artery  revascularization  are traditionally considered isolated options. A simultaneous hybrid approach may allow an opportunity to match the best strategy for a particular anatomic  lesion . Thus  hybrid coronary revascularization  and MIDCAB ( minimally invasive direct coronary artery bypass surgery ) have been developed.  Revascularization  of the  left anterior descending artery  with the  left internal mammary artery  is by far the best treatment option in terms of long-term results. Integrating this therapy with percutaneous coronary  angioplasty  (hybrid procedure) offers multi-vessel revascularization through a  mini-thoracotomy . Particularly in high risk patients,  morbidity  and  mortality  decreases in comparison to conventional  surgery . [ medical citation needed ]


For people who undergo  coronary artery bypass grafting , coronary imaging (completion  angiography ) for the routine evaluation of the  bypass grafts  may be reasonable. During the hybrid procedure  angiographs  may be used to monitor and confirm  anastomosis . [ 3 ]


For  congenital  cardiac malformations, even though surgery remains the treatment of choice,  interventional cardiology  approaches are increasingly being used. However, such percutaneous approaches can be challenging or even impossible because of difficult and complex anatomies (such as double-outlet right ventricle, or transposition of the great arteries, acute turns or kinks in the pulmonary arteries of  tetralogy of Fallot  patients) and patient characteristics/ complications (low weight, poor vascular access, induced rhythm disturbances, hemodynamic compromise). [ 5 ] [ 6 ]  Nevertheless, surgery has its limitations, so that combining interventions and surgery into a single therapeutic procedure potentially leads to reduction of complexity,  cardiopulmonary bypass  time, risk, and to improved outcomes.
Another important concept in hybrid procedures is completion  angiography , as described above, which in the case of  congenital heart disease  surgery may detect residual structural lesions, thus reduce postoperative complications. Again, 3D imaging using  rotational angiography  should be the concept of choice. [ 7 ]  Completion angiography in a hybrid OR may even induce a reduction of  contrast media  and  ionizing radiation  dose applied to the patient, as it reduces the need for post-operative examination. [ 8 ]  Further dose reduction can be achieved with a combination of intraoperative  rotational angiography  and intraoperative  MRI , when both a fixed C-arm and an MRI system are available in the surgical theatre, and MRI adds functional information. [ 9 ]


The conventional approach for treatment of  aortic valve stenosis  is surgical replacement of the  aortic valve . This procedure has excellent outcomes particularly in younger patients at relatively low-risk and will remain the gold standard for aortic valve replacement in the upcoming years. However,  TAVI  (transcatheter aortic valve implantation) has emerged as a valid alternative for patients in whom conventional surgical techniques are considered too invasive and risky. To put this approach into practice, a hybrid operating room is strongly recommended by a number of professional associations, including the  European Society of Cardiology , the European Association of Cardio-thoracic Surgery, [ 10 ]  the German Society of Cardiology, and the German Society of Cardiac, Thoracic and Vascular Surgery.


The repair of a defected mitral valve is a potential future hybrid procedure, that is still dependent on approval of the necessary devices by the U.S.  Food and Drug Administration . Some of these devices also will most likely be used for procedures performed in regular  cath labs . Further prostheses for mitral und  tricuspid valve  replacement are under development and certainly will be available within the next years. Complex hybrid procedures may arise where the various parts of the mitral valve apparatus (e.g.  chordae ,  leaflet  and  ring ) are repaired on a beating heart in combination with purely interventional techniques (e.g. MitralClip). From an imaging modality perspective, fluoroscopy will most likely be combined with 2D and 3D  ultrasound  and a fusion of these modalities may become helpful. The reason is that the metal devices are optimally imaged without artifacts by fluoroscopy whereas the valve itself is better evaluated with  ultrasound . As an alternative to  transesophageal echocardiography , the use of intracardiac 2D and 3D echo may prove useful because it would allow avoiding  general anesthesia  in selected patients. [ 11 ]


For  aneurysms  of the  thoracic aorta ,  thoracic endovascular aortic repair  (TEVAR) has become a valid alternative to open repair. This method may even be applied to  pathologies  of the  aortic arch  and the  distal descending aorta . [ 12 ]  A common complication of  EVAR  are endoleaks. These may be missed by 2D angiographic evaluation. Rotational angiography, providing CT-like 3D imaging with the angiographic C-arm enables the surgeon to diagnose this complication intraoperatively and correct it right away.  An indication that a hybrid technique would be most beneficial and successful is that the patient has had a previous aortic repair. Patients with chronic dissecting aneurysms are not good candidates for the hybrid approach. In the hybrid one-stage procedure the graft can be check immediately after the placement of the stent.  [ 3 ]  In the hybrid two-stage procedure the total operation time is much shorter and decreases postoperative complications, however there is a risk that the aneurysm could rupture between the two stages. [ 3 ]  In cases where the hybrid technique was used to repair an aortic aneurysm complications that have been experiences are  permanent paraplegia , stroke,  spinal cord ischemia  and other neurological complications. [ 3 ] [ 13 ]


With regards to rhythm disturbances, in particular  atrial fibrillation  (AF), a hybrid procedure involves the combination of the surgical  epicardial  approach with the interventional  endocardial  approach. [ medical citation needed ]


In many cases for differing heart diseases and conditions the morbidity rates greatly decreased when a hybrid approach was used. The hybrid cardiac procedures have also shown to decrease post-operative complications. Patients have also had shorter hospital stays post-operative and have had quicker recovery times. [ 1 ] [ 3 ] [ 13 ]


A  hyperoxia test  is a test that is performed—usually on an infant—to determine whether the patient's  cyanosis  is due to lung disease or a problem with blood circulation. It is performed by measuring the  arterial blood gases  of the patient while they breathe room air, then re-measuring the blood gases after the patient has breathed 100% oxygen for 10 minutes. [ 1 ] :141 [ 2 ] :141 [ 3 ]


If the cause of the cyanosis is poor oxygen saturation by the lungs, allowing the patient to breathe 100% oxygen will augment the lungs' ability to saturate the blood with oxygen, and the  partial pressure  of oxygen in the arterial blood will rise (usually above 150  mmHg [ 3 ] ). However, if the lungs are healthy and already fully saturating the blood that is delivered to them, then supplemental oxygen will have no effect, and the partial pressure of oxygen will usually remain below 100 mmHg. [ 3 ]  In this case, the cyanosis is most likely due to blood that moves from the systemic veins to the systemic arteries via a  right-to-left shunt  without ever going through the lungs. [ 1 ] :141


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Impella  is a family of medical devices used for temporary  ventricular support  in patients with depressed heart function. Some versions of the device can provide left heart support during other forms of mechanical circulatory support including  ECMO  and Centrimag. [ 1 ]


The device is approved for use in high-risk  percutaneous coronary intervention  (PCI) and  cardiogenic shock  following  heart attack  or  open heart surgery  and is placed through a  peripheral artery . [ 2 ]  From the peripheral artery it pumps blood to the  left  or  right heart  via the  ascending aorta  or  pulmonary artery .


The Impella technology was acquired by  Abiomed  in 2005. [ 3 ]  As of March 2019, the Impella series includes: the Impella 2.5, Impella 5.0/LD, Impella CP and Impella RP. [ 4 ] [ 5 ] [ 6 ]


The Impella device is an alternative for  percutaneous  mechanical circulatory support that has been utilized as a bridge to recovery. Used alone or in tandem sets, it utilizes the concept of  magnetic levitation [ clarification needed ]  to reduce moving parts to an absolute minimum, thus reducing  anticoagulation  requirements.  Cardiogenic shock  has been addressed by many devices, most notably the  intraaortic balloon pump  (IABP). The technology deployed by the Impella device similarly alters the fundamental characteristics of the human circulatory system. As the propeller is accelerated to give respite to an acutely injured  myocardium , the circulatory system transitions from a pulsatile mechanism to continuous flow. Cellular response to cardiogenic shock is poorly described by either method ( counterpulsation  or  continuous flow ). Control of directional flow of the device (magnetic vectors) is under investigation for addressing  right - versus  left-sided heart failure . Transseptal intervention in addressing  physiologic mismatch in perfusion  between left- and right-sided heart failure is in experimental status. [ citation needed ]
However, recent studies point to significantly greater in-hospital risks of major bleeding, death, and other adverse events for patients supported by Impella devices, compared with those managed with an IABP. [ 7 ]
A  propensity-matched  comparison of patients receiving mechanical circulatory support (MCS) for  myocardial infarction –related shock saw a nearly one-third excess in mortality and almost a doubling in risk of major bleeding, both in-hospital endpoints, with use of Impella compared to IABP.
Impella may provide some of the results similar to venoarterial  extracorporeal life support  and TandemHeart. [ 8 ]


In patients with acute myocardial infarction complicated by cardiogenic shock,  haemodynamic  support with the Impella device had no significant effect on thirty-day mortality as compared with IABP. [ 9 ]
Overall outcomes in the population, regardless of MCS device, were significantly worse for patients after the 2008 approval of Impella. [ clarification needed ]  Among hospitals using Impella, those using it the most had significantly worse outcomes with Impella than those using it the least. [ citation needed ]


Potential complications related to the use of Impella are device related, [ clarification needed ]  peripheral vascular and distal  thrombus  formation with subsequent strokes. The most common complications reported were bleeding requiring  transfusion ,  vascular access  complications, infection,  haemolysis , vascular complications requiring  surgical repair , limb  ischaemia , and bleeding requiring surgical intervention (2.6%). Valvular complications included  aortic  and  mitral valve  injury or  mitral valve regurgitation . [ 10 ]


Impella heart pumps are percutaneous microaxial pumps that act as mechanical circulatory support devices in patients in need of  hemodynamic support . [ 11 ]  The pumps are mounted on support catheters and typically inserted through the  femoral artery , although  axillary  and  subclavian artery  approaches are not uncommon. [ 12 ]


The Impella Device is a generational extension of the Intra aortic balloon pump (IABP) in addressing cardiogenic shock. Tech has allowed a single moving piece floated by magnetically steered mechanisms to deploy an "Archimedes Pump" just north of the Aortic Valve that purports to reduce both preload and afterload. The same tech can apparently also be deployed just above the pulmonary (pulmonic) valve as a gate on right sided heart failure.


Designed to provide hemodynamic support when the patient's heart is unable to produce sufficient  cardiac output , Impella heart pumps can supply one to five liters per minute of blood flow. [ 13 ]  The physiological consequences of left-sided support are threefold. First, it unloads the left ventricle by reducing left ventricular  end-diastolic volume  and pressure, thereby decreasing ventricular  wall stress ,  work , and myocardial  oxygen demand . [ 14 ] [ 15 ] [ 16 ] [ 17 ]  Second, it increases  mean arterial pressure ,  diastolic pressure , and  cardiac output , improving cardiac  power  output and  cardiac index . [ 15 ]  The combined effects on wall stress and perfusion pressure (especially diastolic pressure) augment coronary perfusion. [ 14 ] [ 18 ]  Lastly, augmented cardiac output and forward flow from the left ventricle decreases  pulmonary capillary wedge pressure  and reduces right ventricular  afterload . [ 19 ] [ 20 ] [ 21 ]


Impella was approved for mechanical circulatory support in 2008, but large-scale, real-world data on its use are lacking.
In June 2008, the Impella 2.5 heart pump received  FDA   510(k)  clearance [ 22 ]  for partial circulatory support for periods of up to six hours during cardiac procedures not requiring  cardiopulmonary bypass . In March 2015, it received FDA  premarket approval  for elective and urgent high-risk percutaneous intervention procedures. [ 23 ]  In December 2016, the premarket approval was expanded to include the Impella CP heart pump. [ 24 ]


In April 2009, the Impella 5.0 and Impella LD heart pumps received 510(k) clearance for circulatory support for periods of up to six hours during cardiac procedures not requiring cardiopulmonary bypass. [ 25 ]  In July 2010, the automated Impella controller received FDA 510(k) clearance for use by trained healthcare professionals in healthcare facilities and  medical transport . [ 26 ]


In January 2015, the Impella RP was granted a  humanitarian device exemption  to provide circulatory assistance for patients with  right heart failure . [ 27 ]


In February 2018, the FDA approved the sale of the Impella ventricular support systems. [ 5 ]


Deaths and strokes in the data base overall increased after the Impella gained regulatory approval in 2008, compared to
earlier years; mortality went up 17% and strokes more than tripled. [ 28 ]


In July 2023, the FDA issued a  Class I recall  for all Impella left-sided blood pumps due to risk of motor damage after contact with a  transcatheter aortic valve replacement  stent. [ 29 ] [ 30 ]


In March 2024, the FDA issued a warning about Impella left-sided blood pumps being linked to 49 deaths due to left ventricular perforation or wall rupture. [ 31 ] [ 32 ]


Instruments used specially in  cardiology   are as follows:


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Intima–media thickness  ( IMT ), also called  intimal medial thickness , is a measurement of the thickness of  tunica intima  and  tunica media , the innermost two layers of the wall of an  artery . The measurement is usually made by external  ultrasound  and occasionally by  internal, invasive ultrasound catheters . Measurements of the total wall thickness of  blood vessels  can also be done using other imaging modalities.


Carotid IMT is used to detect the presence of  atherosclerosis  in humans and, more contentiously, to track the regression, arrest or progression of atherosclerosis. [ 1 ]   Ultrasound measurements of carotid IMT were first proposed and validated  in vitro  by Paolo Pignoli in 1984 [ 2 ]  and further details were subsequently published in a highly cited article. [ 3 ]  The use of IMT as a non-invasive tool to track changes in arterial walls has increased substantially  since the mid-1990s. [ 1 ]  Although carotid IMT is predictive of future  cardiovascular events , [ 4 ]  the usefulness of measuring  change  in carotid IMT over time is disputed, as meta-analyses have not found that change in carotid IMT is predictive of cardiovascular events. [ 5 ] [ 6 ]  As such, the use of change in carotid IMT as a  surrogate endpoint  measure of drug efficacy in  clinical trials , or in clinical management of cardiovascular disease, is debated. [ 5 ]


Carotid IMT is occasionally used in clinical practice, but its role is not clear. [ 7 ]  After systematically reviewing the evidence base, the  United States Preventive Services Task Force  found no support for its routine use in stratification of risk for people at intermediate cardiovascular risk. [ 8 ]  However, in 2003 the European Society of Hypertension– European Society of Cardiology  guidelines for the management of arterial hypertension [ 9 ]  recommended the use of carotid IMT measurements in high-risk patients to help identify target organ damage and in 2010 the  American Heart Association  and the  American College of Cardiology  advocated the use of carotid IMT on intermediate risk patients if usual risk classification was not satisfactory. [ 10 ]


IMT can be measured using external ultrasound in large arteries relatively close to the skin (e.g. the  carotid ,  brachial ,  radial , or  femoral  arteries). External ultrasound methods have the advantage of being non-invasive, comparatively low cost and convenient. Deeper internal arteries, such as the  coronary arteries  require special intravascular catheters employing  ultrasound  or  optical coherence tomography  to measure IMT. [ 11 ]


The carotid artery is the usual site of measurement of IMT and consensus statements for carotid IMT have been published for adults [ 12 ]  and children. [ 13 ]  Often, carotid IMT is measured in three locations: in the common carotid artery (typically at one cm proximal to the flow divider), at the bifurcation, and in the internal carotid artery. [ 14 ] [ 15 ]   IMT measurements of the far (deeper) wall, by ultrasound, are generally considered more reliable than measurements performed on the near (more superficial) wall; [ 14 ]  although measurement of both near and far wall IMT has also been advocated. [ 16 ]


Carotid IMT has been used in many epidemiological and clinical studies and these have shown associations with several risk factors, including  type 2 diabetes , [ 17 ]   familial hypercholesterolemia , [ 18 ]   high-density lipoprotein  cholesterol (HDL-C),  triglycerides , [ 19 ]   rheumatoid arthritis , [ 20 ]   non-alcoholic fatty liver disease , [ 21 ]  and  air pollution . [ 22 ]  Since the 1990s, some  clinical trials  of  lifestyle  and  pharmaceutical  interventions have also used carotid artery IMT as a  surrogate endpoint  for evaluating the regression and/or progression of atherosclerotic cardiovascular disease; [ 23 ]  however the appropriateness of carotid IMT in this context is uncertain. [ 24 ]  Although carotid intima–media thickness is strongly associated with  atherosclerosis , thickening of the intima–media may not always be due to atherosclerosis. Intima–medial thickening is a complex process, depending on a variety of factors, including  blood pressure , [ 25 ]  local  hemodynamics , [ 25 ]   shear stress [ 25 ]  and circumferential  tensile stress . [ 25 ]  Variations in IMT between different locations (e.g. the common carotid artery, the  carotid bulb  and the  internal carotid artery )  may reflect differences in local hemodynamic forces.


The  intra-aortic balloon pump  ( IABP ) is a mechanical device that increases  myocardial   oxygen  perfusion and indirectly increases  cardiac output  through  afterload  reduction. It consists of a cylindrical polyurethane balloon that sits in the  aorta , approximately 2 centimeters (0.79 in) from the left  subclavian artery . [ 1 ]  The balloon inflates and deflates via counter pulsation, meaning it actively deflates in  systole  and inflates in  diastole . Systolic deflation decreases afterload through a vacuum effect and indirectly increases forward flow from the heart. Diastolic inflation increases blood flow to the  coronary arteries  via retrograde flow. These actions combine to decrease myocardial oxygen demand and increase myocardial oxygen supply. [ 2 ] [ 3 ]


A computer-controlled mechanism inflates the balloon with  helium  from a cylinder during diastole, usually linked to either an  electrocardiogram  (ECG) or a pressure  transducer  at the  distal  tip of the  catheter ; some IABPs, such as the Datascope System 98XT, allow asynchronous counterpulsation at a set rate, though this setting is rarely used. Helium is used to inflate the balloon as its low density means there is little turbulent flow, so the balloon can inflate quickly and deflate slowly. It is also relatively benign and eliminated quickly if there is a leak or rupture in the balloon. [ 4 ]


The following situations may benefit from this device. [ 2 ] [ 3 ]


The following conditions will always exclude patients for treatment: [ 2 ] [ 3 ]


The following conditions make IABP therapy inadvisable except under pressing circumstances: [ 2 ]


IABP has a beneficiary effect to the struggling heart. It decreases myocardial demand for oxygen and increases coronary flow. [ 7 ]


Since the device is placed in the  femoral artery  and aorta it could provoke  ischemia , and  compartment syndrome . The leg is at highest risk of becoming ischemic if the femoral artery it is supplied by becomes obstructed. Placing the balloon too  distal  from the  aortic arch  may induce occlusion of the  renal artery  and subsequent  kidney failure . Other possible complications are  cerebral embolism  during insertion, infection,  dissection  of the aorta or  iliac artery , perforation of the artery and  bleeding  in the  mediastinum . Mechanical failure of the balloon itself is also a risk which entails vascular surgery to remove under that circumstance. After balloon removal there is also a risk of 'embolic shower' from micro clots that have formed on the surface of the balloon, and can lead to peripheral thrombosis,  myocardial ischemia , hemodynamic decompensation, and late  pseudoaneurysm . [ 2 ] [ 3 ]


The first publication of intra-aortic balloon counter-pulsation appeared in the American Heart Journal of May 1962; 63: 669-675 by S. Moulopoulos, S. Topaz and W. Kolff. [ citation needed ]


The device and the balloons were then developed for commercial use between 1967 and 1969  heart surgery  by William Rassman at Cornell Medical Center and were manufactured by Datascope Corporation in 1969.  The system was subsequently used clinically by David Bregman in 1976 at  NewYork-Presbyterian Hospital  in  New York City . [ 8 ]


The first clinical implant was performed at  Maimonides Medical Center , Brooklyn, N.Y. in June 1967 by  Dr. Adrian Kantrowitz  and Dr. Steven Phillips. [ 9 ]  The patient, a 48-year-old woman, was in cardiogenic shock and unresponsive to traditional therapy. An IABP was inserted by a cut down on the left  femoral artery . Pumping was performed for approximately 6 hours. Shock reversed and the patient was discharged. [ citation needed ]


The size of the original balloon was 15  French  but eventually 9 and 8  French  balloons were developed. [ 6 ]  A second operation removed the balloon. Since 1979 the placement of the balloon has been modified using the Seldinger technique. [ 6 ] [ 10 ]


An  isochrone map  in  geography  and  urban planning  is a map that depicts the area accessible from a point within a certain time threshold. [ 1 ]  An  isochrone  (iso = equal, chrone = time) is defined as "a line drawn on a map connecting points at which something occurs or arrives at the same time". [ 2 ]  In  hydrology  and  transportation planning  isochrone maps are commonly used to depict areas of equal travel time. The term is also used in  cardiology [ 3 ] [ 4 ] [ 5 ]  as a tool to visually detect abnormalities using body surface distribution. [ 6 ]


Early examples of Isochrone maps include the  Galton's   Isochronic Postal Charts  and  Isochronic Passage Charts  of 1881 and 1882, [ 8 ]   Bartholomew's   Isochronic Distance Map and Chart  first published 1889, [ 9 ]  and  Albrecht Penck's   Isochronenkarte  first published 1887. [ 10 ]  Where as Galton and the Bartholomews published maps depicting the days or weeks it took to travel long distances, Albrecht further developed the idea to not only depict long distances and world travel but also smaller areas. Penck also created a series of maps that only depict the travel times of a certain transportation mode, for example  rail transport . Isochrone maps are commonly used in the UK in connection with  development control . [ 11 ] [ 12 ] [ 13 ] [ 14 ]  Isochrones are currently typically computed by via generating  shortest-path trees  on network  graphs , and then generating a  convex hull  around the accessible nodes. Increases in computation, data storage, and improvements in algorithms have facilitated the rapid generation of isochrones. [ 1 ] [ 15 ]  Recent techniques in visualization include linking travel times to network edges to show the paths accessible from a point rather than show the area accessible from a point. [ 1 ]


Isochrone and related maps are used to show the time taken for  runoff  water within a  drainage basin  to reach a lake, reservoir or outlet, assuming constant and uniform effective rainfall. [ 16 ] [ 17 ] [ 18 ] [ 19 ]  An early example of this method was demonstrated by Clark in 1945. [ 20 ]


Isochrone maps have been used in transportation planning since at least 1887. [ 21 ] [ 22 ]  Isochrone maps in the context of transport planning are essentially maps of  accessibility  where travel time is used as the cost metric. Isochrone maps can be created for different  modes of transportation , [ 23 ]  e.g. foot, bicycle, motor vehicle. Put simply, the output of an isochrone map for transport will show how far (in distance) is reachable from a start point, including the parameter of time.


Such maps for private motor transport were widely used in a 1972 study into airport accessibility in  Hampshire ,  South East England . [ 24 ]  At that time, their use was disadvantaged by being time-consuming to create. [ 24 ]


The term isodapane map is used to refer to a map were the contour represent transportation  cost  instead of transportation  time . [ 25 ]


Journey time websites have been built using mapping technologies and  open data . [ 26 ] [ 27 ]  Isochrones can be used by house hunters wishing to evaluate  residential areas . [ 28 ]  An isochrone map of the  London Underground  network was made available in 2007. [ 29 ]


Several digital tools exist which can generate isochrone maps.


openstreetmap -based solutions: [ 30 ]


GTFS-based solutions:


Proprietary data solutions:


The  JUPITER trial  ( J ustification for the  U se of Statins in Primary  P revention: An  I ntervention  T rial  E valuating  R osuvastatin trial) was a  clinical trial  aimed at evaluating whether  statins  reduce  heart attacks  and strokes in people with normal  cholesterol  levels.


JUPITER was a  randomized   double-blind   placebo-controlled study  investigating the use of  rosuvastatin  in the  primary prevention  of  cardiovascular disease . The trial focused on patients with normal  low-density lipoprotein  (LDL)  cholesterol  levels but increased levels of  high-sensitivity C-reactive protein  (hs-CRP). JUPITER was the first  clinical trial  to indicate that statin therapy may provide benefit to patients with low-to-normal LDL levels and no known cardiovascular disease. [ 1 ] [ 2 ]  The trial, which began in 2003, was directed by  Paul Ridker  of  Brigham and Women’s Hospital . [ 3 ]


Because half of all vascular events occur in patients with normal or low levels of LDL cholesterol, JUPITER was designed to determine whether hs-CRP testing could identify these patients, and whether statin therapy could prevent cardiovascular events among them. [ 4 ]  Elevated hs-CRP levels are thought to be a  biomarker  of inflammation, and have been  associated  with an increased risk of  myocardial infarction ,  stroke ,  peripheral arterial disease , and  sudden cardiac death . [ 4 ]


The trial analyzed 17,802 patients without evidence of heart disease but with high CRP levels. In 2008, results presented at the  American Heart Association  meeting and published in the  New England Journal of Medicine   (NEJM)  found that patients with low-to-normal LDL cholesterol receiving rosuvastatin had a lower rate of major cardiovascular events. Compared to patients taking a  placebo , patients given rosuvastatin had reductions in LDL and CRP levels, and a reduction of 0.2% to 0.6% in their  absolute risk  of  heart attack ,  stroke , and death at one year. [ 5 ] [ 6 ] [ 7 ]  The study's authors estimated that the  number needed to treat  with rosuvastatin to prevent one cardiovascular event was 95 over two years, extrapolated to 25 over five years. The trial was stopped early, after just 1.9 years median duration, by the study's Independent Data Monitoring Board, because the interim results met the study's predefined stopping criteria (it had been predetermined that it would be unethical to continue the study once it became clear that the patients in one arm of the study had a significantly higher cardiovascular risk than the other arm's patients). [ 1 ] [ 8 ]


The trial was sponsored by  AstraZeneca , the marketer of Crestor (rosuvastatin). [ 3 ]  The company saw an increase in its share of the U.S. statin drug market following the November 2008  NEJM  publication. [ 9 ]


Reports of serious adverse events within JUPITER were equally distributed between the study's rosuvastatin and placebo arms. There were no significant differences between the treatment groups with respect to muscle pain, muscle weakness, hepatic function, or renal function; however, the researchers noted small but  statistically significant  increases in the rate of physician-reported  diabetes  and  glycated hemoglobin  values in the rosuvastatin group, an effect that has also been seen in studies with other statins. [ 5 ] [ 8 ]  Those latter findings, along with concerns over the safety of very low LDL levels, rosuvastatin's higher cost compared to  generic  statins, and the validity of biomarkers used in the diagnosis of cardiovascular disease, have been cited by those urging caution before expanding indications for statin treatment. [ 10 ] [ 11 ] [ 12 ] [ 13 ]


In 2010, Dr. Michel de Lorgeril, et al., published "a critical reappraisal" of the JUPITER Trial in the  Archives of Internal Medicine . The article's authors critiqued what they saw as flaws in the trial, pointing out that the cardiovascular mortality rate and the case-fatality rate for myocardial infarction were much lower than they expected. They also raised concerns about conflict of interest in the trial design and leadership: nine of 14 authors of the main report had financial ties to the sponsor,  AstraZeneca , and the lead investigator held the patent for the C-reactive protein test, whose use in screening would be promoted by the results as reported. [ 14 ]  They also argued that the trial's premature termination may have distorted the results, and raised concerns that AstraZeneca scientists had controlled and managed the raw data.  They concluded that, "The results of the trial do not support the use of statin treatment for primary prevention of cardiovascular diseases and raise troubling questions concerning the role of commercial sponsors." [ 14 ]


In addition, some prior and some subsequent studies have contrasted with the JUPITER trial results.  On the role of C-reactive protein, a 2009 study employing  Mendelian randomization , published in the  Journal of the American Medical Association  suggested that CRP does not play a causal role in cardiovascular disease; the results may argue against CRP's use as a marker of cardiovascular disease risk or for identifying subjects for statin therapy as in JUPITER, and more strongly argue against using CRP as a therapeutic target  per se . [ 15 ]  The discordant results of this subsequent study provoked debate over the role and value of CRP as a biomarker and possible therapeutic target in heart disease. [ 16 ]


Lancisi's sign  is a  clinical sign  in which a large venous wave, or  Giant V wave , is visible in the  jugular vein  in patients with  tricuspid regurgitation . It is caused by blood flowing backwards into the jugular vein through the incompetent  tricuspid valve  during  ventricular systole . [ 1 ]


The sign is named after  Giovanni Maria Lancisi . [ 2 ]


Left ventricular mass  or  LVM  refers to the  mass  of the  left ventricle of the heart .


Left ventricular mass index  or  LVMi  is LVM divided by  body surface area .


LVM is usually estimated using linear measurements obtained from  echocardiography , [ 1 ]  but can also be calculated using  CT  or  MRI  images. [ 2 ]  LVM increases withe  ageing , though ageing related  remodeling  of the left ventricle's geometry can lead to a discordancy between CT and echocardiographic based measurements of LVM. [ 3 ]


Published normal ranges for LVMi are 49–115 g/m 2  for men and 43–95 g/m 2  for women. [ 1 ] [ 4 ]   left ventricular hypertrophy  (LVH) is defined as an abnormal increase in LVM, an important independent  risk factor  for  cardiovascular morbidity  and mortality. [ 5 ] [ 6 ] [ 7 ]  LVM is also an independent risk factor for cardiovascular disease even within the normal limits. [ 8 ]   A reduction in LVM following  antihypertensive treatment  or  aortic vale replacement  is associated with a reduced rate of complications. [ 9 ] [ 10 ]


Intensive athletic training can cause physiologic changes in the heart (" athlete's heart ") which include an increase in LVM. [ 11 ]


A  Lewis Lead  (also called the  S5 lead ) is a modified  ECG  lead used to detect  atrial flutter  waves when atrial flutter is suspected clinically, based on signs and symptoms, but is not definitely demonstrated on the standard 12 lead ECG. In order to create the Lewis Lead, the right arm electrode is moved to the  manubrium  adjacent to the  sternum . Then the left arm electrode is moved to the right, fifth intercostal space adjacent to the sternum. The left leg electrode is placed on the right lower costal margin. The Lewis Lead is then read as Lead I on the ECG and, since in most patients it will be roughly perpendicular to the wave of ventricular  depolarization , atrial flutter waves may be more apparent.


This article related to  medical imaging  is a  stub . You can help Wikipedia by  expanding it .


Liebermeister's rule  concerns the increment ratio between an adult individual's cardiac frequency and temperature when in fever. Each Celsius grade of  body temperature  increment corresponds to an 8  beats per minute  increase in cardiac frequency, although the exact number of this rule varies significantly across different sources. [ 1 ] [ 2 ]  An exception to this rule by creating a  relative   bradycardia  is known as  Faget sign  (pulse-temperature dissociation) common in some diseases, especially  yellow fever , tularaemia and salmonella typhi. It is named for  Carl von Liebermeister . [ citation needed ]


A  lipoprotein  is a  biochemical  assembly whose primary function is to transport  hydrophobic   lipid  (also known as  fat ) molecules in water, as in  blood plasma  or other  extracellular fluids . They consist of a  triglyceride  and  cholesterol  center, surrounded by a  phospholipid  outer shell, with the  hydrophilic  portions oriented outward toward the surrounding water and  lipophilic  portions oriented inward toward the lipid center. A special kind of protein, called  apolipoprotein , is embedded in the outer shell, both stabilising the complex and giving it a functional identity that determines its role.


Plasma lipoprotein particles  are commonly divided into five main classes, based on size, lipid composition, and apolipoprotein content:  HDL ,  LDL ,  IDL ,  VLDL  and  chylomicrons . Subgroups of these plasma particles are primary drivers or modulators of  atherosclerosis . [ 1 ]


Many  enzymes ,  transporters , structural proteins,  antigens ,  adhesins , and  toxins  are sometimes also classified as lipoproteins, since they are formed by lipids and proteins.


Some transmembrane  proteolipids , especially those found in  bacteria , are referred to as lipoproteins; they are not related to the lipoprotein particles that this article is about. [ 2 ]  Such  transmembrane proteins  are difficult to isolate, as they bind tightly to the lipid membrane, often require lipids to display the proper structure, and can be water-insoluble.  Detergents  are usually required to isolate transmembrane lipoproteins from their associated biological membranes.


Because fats are insoluble in water, they cannot be transported on their own in extracellular water, including blood plasma. Instead, they are surrounded by a hydrophilic external shell that functions as a transport vehicle. The role of lipoprotein particles is to transport fat molecules, such as  triglycerides , phospholipids, and cholesterol within the extracellular water of the body to all the cells and tissues of the body. The proteins included in the external shell of these particles, called apolipoproteins, are synthesized and secreted into the extracellular water by both the  small intestine  and  liver  cells. The external shell also contains phospholipids and cholesterol.


All  cells  use and rely on fats and cholesterol as building blocks to create the multiple  membranes  that cells use both to control internal water content and internal water-soluble elements and to organize their internal structure and protein enzymatic systems. The outer shell of lipoprotein particles have the hydrophilic groups of phospholipids, cholesterol, and apolipoproteins directed outward. Such characteristics make them soluble in the salt-water-based blood pool.  Triglycerides  and  cholesteryl esters  are carried internally, shielded from the water by the outer shell. The kind of apolipoproteins contained in the outer shell determines the functional identity of the lipoprotein particles. The interaction of these apolipoproteins with enzymes in the blood, with each other, or with specific proteins on the surfaces of cells, determines whether triglycerides and cholesterol will be added to or removed from the lipoprotein transport particles.


Characterization in human plasma [ 3 ]


Lipoproteins are complex particles that have a central hydrophobic core of non-polar lipids, primarily cholesteryl esters and triglycerides. This hydrophobic core is surrounded by a hydrophilic membrane consisting of phospholipids, free cholesterol, and apolipoproteins. Plasma lipoproteins, found in  blood plasma , are typically divided into five main classes based on size, lipid composition, and apolipoprotein content:  HDL ,  LDL ,  IDL ,  VLDL  and  chylomicrons . [ 4 ]


The handling of lipoprotein particles in the body is referred to as  lipoprotein particle metabolism . It is divided into two pathways,  exogenous  and  endogenous , depending in large part on whether the lipoprotein particles in question are composed chiefly of dietary (exogenous) lipids or whether they originated in the liver (endogenous), through  de novo synthesis  of triglycerides.


The  hepatocytes  are the main platform for the handling of triglycerides and cholesterol; the liver can also store certain amounts of  glycogen  and triglycerides. While  adipocytes  are the main storage cells for triglycerides, they do not produce any lipoproteins.


Bile  emulsifies fats contained in the  chyme , then  pancreatic lipase  cleaves triglyceride molecules into two fatty acids and one 2-monoacylglycerol.  Enterocytes  readily absorb the small molecules from the chymus. Inside of the enterocytes, fatty acids and  monoacylglycerides  are transformed again into triglycerides. Then these lipids are assembled with  apolipoprotein B-48  into  nascent  chylomicrons . These particles are then secreted into the  lacteals  in a process that depends heavily on apolipoprotein B-48. As they circulate through the  lymphatic vessels , nascent chylomicrons bypass the liver circulation and are drained via the  thoracic duct  into the bloodstream.


In the blood stream,  nascent chylomicron particles  interact with HDL particles, resulting in HDL donation of  apolipoprotein C-II  and  apolipoprotein E  to the nascent chylomicron. The chylomicron at this stage is then considered mature. Via apolipoprotein C-II, mature chylomicrons activate  lipoprotein lipase  (LPL), an enzyme on  endothelial cells  lining the blood vessels. LPL catalyzes the  hydrolysis  of triglycerides that ultimately releases glycerol and  fatty acids  from the chylomicrons. Glycerol and fatty acids can then be absorbed in peripheral tissues, especially  adipose  and  muscle , for energy and storage.


The hydrolyzed chylomicrons are now called  chylomicron remnants . The chylomicron remnants continue circulating the bloodstream until they interact via apolipoprotein E with chylomicron remnant receptors, found chiefly in the liver. This interaction causes the  endocytosis  of the chylomicron remnants, which are subsequently hydrolyzed within  lysosomes . Lysosomal  hydrolysis  releases glycerol and fatty acids into the cell, which can be used for energy or stored for later use.


The liver is the central platform for the handling of lipids: it is able to store glycerols and fats in its cells, the  hepatocytes . Hepatocytes are also able to create triglycerides via de novo synthesis. They also produce the bile from cholesterol. The intestines are responsible for absorbing cholesterol. They transfer it over into the blood stream.


In the hepatocytes, triglycerides and cholesteryl esters are assembled with  apolipoprotein B-100  to form  nascent VLDL particles . Nascent VLDL particles are released into the bloodstream via a process that depends upon apolipoprotein B-100.


In the blood stream,  nascent VLDL particles  bump with HDL particles; as a result, HDL particles donate  apolipoprotein C-II  and apolipoprotein E to the nascent VLDL particle. Once loaded with apolipoproteins C-II and E, the nascent VLDL particle is considered mature. VLDL particles circulate and encounter LPL expressed on  endothelial cells . Apolipoprotein C-II activates LPL, causing hydrolysis of the VLDL particle and the release of glycerol and fatty acids. These products can be absorbed from the blood by peripheral tissues, principally adipose and muscle. The hydrolyzed VLDL particles are now called  VLDL remnants  or  intermediate-density lipoproteins  (IDLs). VLDL remnants can circulate and, via an interaction between apolipoprotein E and the remnant receptor, be absorbed by the liver, or they can be further hydrolyzed by  hepatic lipase .


Hydrolysis by hepatic lipase releases glycerol and fatty acids, leaving behind  IDL remnants , called  low-density lipoproteins  (LDL), which contain a relatively high cholesterol content [ 5 ]  ( see native LDL structure at 37°C  on  YouTube ). LDL circulates and is absorbed by the liver and peripheral cells. Binding of LDL to its target tissue occurs through an interaction between the  LDL receptor  and apolipoprotein B-100 on the LDL particle. Absorption occurs through  endocytosis , and the internalized LDL particles are hydrolyzed within lysosomes, releasing lipids, chiefly cholesterol.


Plasma lipoproteins may carry oxygen gas. [ 6 ]  This property is due to the crystalline hydrophobic structure of lipids, providing a suitable environment for O 2  solubility compared to an aqueous medium. [ 7 ]


Inflammation , a biological system response to stimuli such as the introduction of a  pathogen , has an underlying role in numerous systemic biological functions and pathologies. This is a useful response by the immune system when the body is exposed to pathogens, such as bacteria in locations that will prove harmful, but can also have detrimental effects if left unregulated. It has been demonstrated that lipoproteins, specifically HDL, have important roles in the inflammatory process. [ 8 ]


When the body is functioning under normal, stable physiological conditions, HDL has been shown to be beneficial in several ways. [ 8 ]  LDL contains apolipoprotein B (apoB), which allows LDL to bind to different tissues, such as the artery wall if the  glycocalyx  has been damaged by high  blood sugar levels . [ 8 ]  If oxidised, the LDL can become trapped in the proteoglycans, preventing its removal by HDL cholesterol efflux. [ 8 ]  Normal functioning HDL is able to prevent the process of oxidation of LDL and the subsequent inflammatory processes seen after oxidation. [ 8 ]


Lipopolysaccharide , or LPS, is the major pathogenic factor on the cell wall of  Gram-negative bacteria .  Gram-positive bacteria  has a similar component named  Lipoteichoic acid , or LTA. HDL has the ability to bind LPS and LTA, creating HDL-LPS complexes to neutralize the harmful effects in the body and clear the LPS from the body. [ 9 ]  HDL also has significant roles interacting with cells of the immune system to modulate the availability of cholesterol and modulate the immune response. [ 9 ]


Under certain abnormal physiological conditions such as system  infection  or  sepsis , the major components of HDL become altered, [ 9 ] [ 10 ]  The composition and quantity of lipids and apolipoproteins are altered as compared to normal physiological conditions, such as a decrease in HDL cholesterol (HDL-C), phospholipids, apoA-I (a major lipoprotein in HDL that has been shown to have beneficial anti-inflammatory properties), and an increase in  Serum amyloid A . [ 9 ] [ 10 ]  This altered composition of HDL is commonly referred to as acute-phase HDL in an acute-phase inflammatory response, during which time HDL can lose its ability to inhibit the oxidation of LDL. [ 8 ]  In fact, this altered composition of HDL is associated with increased mortality and worse clinical outcomes in patients with sepsis. [ 9 ]


Lipoproteins may be classified as five major groups, listed from larger and lower density to smaller and higher density. Lipoproteins are larger and less dense when the fat to protein ratio is increased. They are classified on the basis of  electrophoresis ,  ultracentrifugation  and  nuclear magnetic resonance spectroscopy  via the  Vantera Analyzer . [ 11 ]


For young healthy research subjects, ~70 kg (154 lb), these data represent averages across individuals studied, percentages represent % dry weight:


[ 12 ] [ 13 ]  However, these data are not necessarily reliable for any one individual or for the general clinical population.


It is also possible to classify lipoproteins as "alpha" and "beta", according to the classification of proteins in  serum protein electrophoresis . This terminology is sometimes used in describing lipid disorders such as  abetalipoproteinemia .


Lipoproteins, such as LDL and HDL, can be further subdivided into subspecies isolated through a variety of methods. [ 14 ] [ 15 ]  These are subdivided by density or by the protein contents/ proteins they carry. [ 14 ]  While the research is currently ongoing, researchers are learning that different subspecies contain different apolipoproteins, proteins, and lipid contents between species which have different physiological roles. [ 14 ]  For example, within the HDL lipoprotein subspecies, a large number of proteins are involved in general lipid metabolism. [ 14 ]  However, it is being elucidated that HDL subspecies also contain proteins involved in the following functions:  homeostasis ,  fibrinogen ,  clotting cascade , inflammatory and immune responses, including the  complement system ,  proteolysis  inhibitors,  acute-phase response  proteins, and the  LPS-binding protein ,  heme  and iron metabolism,  platelet  regulation, vitamin binding and general transport. [ 14 ]


High levels of lipoprotein(a) are a significant  risk factor  for  atherosclerotic   cardiovascular diseases  via mechanisms associated with  inflammation  and  thrombosis . [ 16 ]  The links of mechanisms between different lipoprotein isoforms and risk for cardiovascular diseases, lipoprotein synthesis, regulation, and metabolism, and related risks for  genetic diseases  are under active research, as of 2022. [ 16 ]


1I71 ,  1JFN ,  1KIV ,  2FEB ,  4BV5 ,  4BV7 ,  4BVC ,  4BVD ,  4BVV ,  4BVW ,  3KIV ,  4KIV


Lipoprotein(a)  is a  low-density lipoprotein  variant containing a protein called  apolipoprotein(a) . Genetic and  epidemiological studies  have identified lipoprotein(a) as a risk factor for  atherosclerosis  and related diseases, such as  coronary heart disease  and  stroke . [ 3 ] [ 4 ] [ 5 ] [ 6 ]


Lipoprotein(a) was discovered in 1963 by  Kåre Berg . [ 7 ]  The human  gene  encoding apolipoprotein(a) was successfully cloned in 1987. [ 8 ]


Lipoprotein(a) [Lp(a)] consists of an  LDL -like particle and the specific apolipoprotein(a), which is bound covalently to the  apoB  contained in the outer shell of the particle. Lp(a) plasma concentrations are highly heritable [ 9 ] [ 10 ]  and mainly controlled by the  LPA  gene [ 11 ]  located on  chromosome 6q 25.3–q26. [ 12 ]   Apo(a) proteins vary in size due to a size polymorphism [KIV-2  VNTR ], which is caused by a variable number of  kringle  IV repeats in the  LPA  gene. [ 13 ]  This size variation at the gene level is expressed on the protein level as well, resulting in apo(a) proteins with 10 to more than 50 kringle IV repeats (each of the variable kringle IV consists of 114  amino acids ). [ 8 ] [ 14 ]  These variable apo(a) sizes are known as "apo(a)  isoforms ".


There is a general inverse correlation between the size of the apo(a) isoform and the Lp(a) plasma concentration. [ 15 ]  One theory explaining this correlation involves different rates of protein synthesis. Specifically, the larger the isoform, the more apo(a) precursor protein accumulates  intracellularly  in the  endoplasmic reticulum . Lp(a) is not fully synthesised until the precursor protein is released from the cell, so the slower rate of production for the larger isoforms limits the plasma concentration. [ 16 ] [ 17 ]


Lp(a) concentrations can vary by more than one thousand between individuals, from <0.2 to >200 mg/dL. This range of concentrations is observed in all populations studied by scientists so far. The mean and median concentrations differ among world populations. Most prominently, there is a two- to threefold higher mean Lp(a) plasma concentration in populations of African descent compared to Asian, Oceanic, or European populations. [ 18 ] [ 19 ]  The general inverse correlation between apo(a) isoform size and Lp(a) plasma concentration is observed in all populations. [ 15 ]  However, it was also discovered that mean Lp(a) associated with certain apo(a) isoforms varies between populations. [ citation needed ]


In addition to size effects, mutations in the LPA promoter may lead to a decreased apo(a) production. [ 20 ]


The  Atherosclerosis Risk in Communities  (ARIC) Study is a community-based cohort from 4 geographically diverse US communities. The ARIC Study found that the proportion of Atherosclerotic Cardiovascular Disease cases potentially attributable to elevated Lp(a) was 10.2% among Black adults compared with 4.7% among white adults. The population-attributable fraction ratio for Black adults compared with white adults was 2.30.
Because the hazard ratios for ASCVD associated with higher Lp(a) did not significantly differ between races, the ARIC study concluded that these differences appeared to be driven largely by racial differences in the distribution of Lp(a) levels. [ 21 ]


Lp(a) is assembled at the  hepatocyte  cell membrane surface, which is similar to typical LDL particles. However, there are other possible locations of assembly. The particles mainly exist in plasma. [ 22 ] [ 23 ] [ 24 ] [ 25 ]


Lp(a) contributes to the process of  atherogenesis . The structure of apolipoprotein(a) is similar to  plasminogen  and tPA ( tissue plasminogen activator ) and it competes with plasminogen for its binding site, leading to reduced  fibrinolysis . [ 26 ] [ 27 ]  Also, because Lp(a) stimulates secretion of  PAI-1 , it leads to  thrombogenesis . [ 28 ] [ 3 ] [ 29 ]  It also may enhance coagulation by inhibiting the function of tissue factor pathway inhibitor. [ 30 ]


Moreover, Lp(a) carries  atherosclerosis -causing cholesterol and binds atherogenic pro-inflammatory oxidised phospholipids as a preferential carrier of oxidised phospholipids in human plasma, [ 31 ]  which attracts inflammatory cells to vessel walls and leads to smooth muscle cell proliferation. [ 32 ] [ 33 ] [ 34 ]  Moreover, Lp(a) also is hypothesised to be involved in wound healing and tissue repair by interacting with components of the vascular wall and  extracellular matrix . [ 35 ] [ 36 ]  Apo(a), a distinct feature of the Lp(a) particle, binds to immobilized fibronectin and endows Lp(a) with the serine-proteinase-type proteolytic activity. [ 37 ]


Nonetheless, individuals without Lp(a) or with very low Lp(a) levels seem to be healthy. [ citation needed ]  Thus, plasma Lp(a) is not vital, at least under normal environmental conditions. [ citation needed ]  Since apo(a)/Lp(a) appeared rather recently in mammalian evolution — only  old world monkeys  and humans have been shown to harbour Lp(a) — its function might not be vital, but just evolutionarily advantageous under certain environmental conditions, e.g. in case of exposure to certain infectious diseases. [ 20 ]


Another possibility, suggested by  Linus Pauling , is that Lp(a) is a primate adaptation to  L-gulonolactone oxidase  (GULO) deficiency, found only in certain lines of mammals. GULO is required for converting  glucose  to  ascorbic acid  (vitamin C), which is needed to repair arteries; following the loss of GULO, those primates who adopted diets less abundant in vitamin C may have used Lp(a) as an ascorbic-acid surrogate to repair arterial walls. [ 38 ]


The half-life of Lp(a) in circulation is approximately three to four days. [ 23 ]  The mechanism and sites of Lp(a) catabolism are largely unknown. The LDL receptor has been reported as a receptor for Lp(a) clearance, but is not a major pathway of Lp(a) metabolism under normal or hypercholesterolemic conditions. [ 29 ] [ 39 ] [ 40 ]  The kidney has been identified as playing a role in Lp(a) clearance from plasma. [ 41 ]


High Lp(a) in blood correlates with  coronary heart disease  (CHD),  cardiovascular disease  (CVD),  atherosclerosis ,  thrombosis , and stroke. [ 42 ]  However, the association between Lp(a) levels and stroke is not as strong as that between Lp(a) and cardiovascular disease. [ 3 ]  Lp(a) concentrations may be affected by disease states (for example kidney failure), but are only slightly affected by diet, exercise, and other environmental factors. [ citation needed ]


Most commonly prescribed lipid-reducing drugs have little or no effect on Lp(a) concentration. Results using  statin  medications have been mixed in most trials, although a meta-analysis published in 2012 suggests that  atorvastatin  may be of benefit. [ 43 ]


Niacin  (Vitamin B 3 ) has been shown to reduce the levels of Lp(a) significantly in individuals with high levels of low-molecular weight Lp(a). [ 44 ] [ 45 ]


High Lp(a) correlates with early atherosclerosis independently of other cardiac risk factors, including LDL. In patients with advanced cardiovascular disease, Lp(a) indicates a coagulant risk of plaque thrombosis. Apo(a) contains domains that are very similar to plasminogen (PLG). Lp(a) accumulates in the vessel wall and inhibits the binding of PLG to the cell surface, reducing plasmin generation, which increases clotting. This inhibition of PLG by Lp(a) also promotes the proliferation of  smooth muscle  cells. These unique features of Lp(a) suggest that Lp(a) causes generation of clots and atherosclerosis. [ 46 ]


In one homogeneous tribal population of Tanzania, vegetarians have higher levels of Lp(a) than fish eaters, raising the possibility that pharmacologic amounts of fish oil supplements may help lower the levels of Lp(a). [ 47 ]  Researchers in studies in 1995 and 1998 concluded that regular consumption of moderate amounts of alcohol led to a significant decline in plasma levels of Lp(a). [ 48 ]  Other studies did not report this.


Numerous studies confirming a strong correlation between elevated Lp(a) and heart disease have led to the consensus that Lp(a) is an important independent predictor of  cardiovascular disease . [ 3 ]  Animal studies have shown that Lp(a) may directly contribute to atherosclerotic damage by increasing plaque size, inflammation, instability, and smooth muscle cell growth. [ 49 ]  Genetic data also support the theory that Lp(a) causes cardiovascular disease. [ 4 ]


The European Atherosclerosis Society currently recommends that patients with a moderate or high risk of cardiovascular disease should have their Lp(a) levels checked. Any patient with one of the following risk factors should be screened:


If the level is elevated, treatment should be initiated to bring the level below 50 mg/dL. In addition, the patient's other cardiovascular risk factors (including LDL levels) should be managed optimally. [ 3 ]  Apart from the total Lp(a) plasma concentration, the apo(a) isoform might be an important risk parameter as well. [ 50 ] [ 51 ]


Prior studies of the relationship between Lp(a) and ethnicity have shown inconsistent results. Lp(a) levels seem to differ in different populations. For example, in some African populations, Lp(a) levels are higher on average than in other groups, so that using a risk threshold of 30 mg/dl could classify over 50% of the individuals as higher risk. [ 52 ] [ 53 ] [ 54 ] [ 55 ]  Some part of this complexity may be related to the different genetic factors involved in determining Lp(a) levels.  One recent study showed that in different ethnic groups, different genetic alterations were associated with increased Lp(a) levels. [ 56 ]


More recent data suggest that prior studies were underpowered. The  Atherosclerosis Risk in Communities (ARIC)  Study followed 3467 African Americans and 9851 whites for 20 years. The researchers found that an elevated Lp(a) conferred the same risk in each group. African Americans had roughly three times the level of Lp(a), however, and Lp(a) also predicted an increased risk of stroke. [ 57 ]


Approximate levels of risk are indicated by the results below, although at present there are a variety of different methods by which to measure Lp(a). A standardized international reference material has been developed and is accepted by the  WHO Expert Committee on Biological Standardization  and the  International Federation of Clinical Chemistry and Laboratory Medicine . Although further standardization is still needed, development of a reference material is an importance step toward standardizing results. [ 58 ] [ 59 ]


Lipoprotein(a) — Lp(a) [ 60 ]


Lp(a) appears with different isoforms (per kringle repeats) of apolipoprotein; 40% of the variation in Lp(a) levels when measured in mg/dl can be attributed to different isoforms. Lighter Lp(a) are also associated with disease. Thus, a test with simple quantitative results may not provide a complete assessment of risk. [ 61 ]


The  US FDA  has  given the Tina-quant® lipoprotein Lp(a) RxDx assay from Roche, a Breakthrough Device Designation. The assay is designed to identify patients who may benefit from therapies aimed at decreasing Lp(a) levels. [ 62 ]


The current simplest treatment for elevated Lp(a) is to take 1–3 grams of  niacin  daily, typically in an extended-release form. Niacin therapy may reduce Lp(a) levels by 20–30%. [ 63 ]


A meta-analysis suggested that atorvastatin may lower Lp(a) levels. [ 43 ]  In severe cases, such as familial hypercholesterolemia or treatment-resistant hypercholesterolemia,  LDL apheresis  may dramatically reduce Lp(a). The goal of the treatment is to reduce levels to below 50 mg/dL. Cost is prohibitively high. [ 3 ]


A meta-analysis of six clinical trials confirmed that  flaxseed  supplementation modestly lowers Lp(a) levels. [ 64 ]


Testosterone is known to reduce Lp(a) levels. [ 65 ]  Testosterone replacement therapy also appears to be associated with lower Lp(a) levels. [ 65 ] [ 66 ]  Estrogen replacement therapy in post-menopausal women will reduce Lp(a). [ 67 ]   Raloxifene  has not been shown to reduce Lp(a), while  tamoxifen  has. [ 68 ]


L-carnitine may also reduce Lp(a) levels. A systematic review and meta-analysis found a significant reduction with oral but not intravenous carnitine. [ 69 ]  Other medications that are in various stages of development include thyromimetics, cholesterol-ester-transfer protein (CETP inhibitors), anti-sense oligonucleopeptides (such as  Pelacarsen  and  Olpasiran ), and proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) inhibitors. [ 66 ] [ 70 ]


The  American Academy of Pediatrics  now recommends that all children between the ages of nine and eleven years old be screened for hyperlipidemia. Lp(a) levels should be considered in particular in children with a family history of early heart disease or high blood cholesterol levels. However, there have not been enough studies to determine which therapies might be beneficial. [ 71 ]


Lp(a) has been shown to  interact  with  calnexin , [ 72 ] [ 73 ]   fibronectin , [ 37 ]  and  fibrinogen beta chain . [ 74 ]


The following are  medications  commonly prescribed  cardiac pharmaceutical agents .
The specificity of the following medications is highly variable, and often are not particularly specific to a given class.
As such, they are listed as are commonly accepted.


Group of  pharmaceuticals  that are used to suppress abnormally fast rhythms ( tachycardias ), such as  atrial fibrillation ,  supraventricular tachycardia  and  ventricular tachycardia .


Class of  antihypertensives  that work by causing relaxation of blood vessels as well as a decrease in  blood volume , which leads to lower  blood pressure  and decreased  oxygen  demand from the  heart . [ 1 ]


Class of  antihypertensives  that bind to and inhibit the  angiotensin II receptor type 1  and thereby block the  arteriolar contraction  and  sodium retention  effects of  renin–angiotensin system .


Class of medications that are competitive antagonists that block the receptor sites for the endogenous catecholamines epinephrine (adrenaline) and norepinephrine (noradrenaline) on adrenergic beta receptors, of the sympathetic nervous system.


Litten's sign  is a  clinical sign  in which  cotton wool spots  are seen on  fundoscopic  examination of the  retina  in patients with  infective endocarditis . [ 1 ]


The sign is named after  Moritz Litten .


The Louis and Artur Lucian Award in Cardiovascular Diseases  is a prize for cardiovascular medicine conferred by  McGill University . Described as Canada's "top cardiovascular research prize", [ 1 ]  it has been awarded annually since 1978, except in 2007. [ 2 ] [ 3 ]


Source:  McGill University


This  award -related article is a  stub . You can help Wikipedia by  expanding it .


Low-density lipoprotein  ( LDL ) is one of the five major groups of  lipoprotein  that transport all  fat  molecules around the body in extracellular water. [ 1 ]  These groups, from least dense to most dense, are  chylomicrons  (aka  ULDL  by the overall density naming convention),  very low-density lipoprotein  (VLDL),  intermediate-density lipoprotein  (IDL), low-density lipoprotein (LDL) and  high-density lipoprotein  (HDL). LDL delivers fat molecules to  cells . LDL has been associated with the progression of  atherosclerosis .


Lipoproteins transfer  lipids  ( fats ) around the body in the  extracellular fluid , making fats available to body cells for  receptor-mediated endocytosis . [ 2 ] [ 3 ]  Lipoproteins are complex particles composed of multiple  proteins , typically 80–100 proteins per particle (organized by a single  apolipoprotein B  for LDL and the larger particles). A single LDL particle is about 220–275  angstroms  in diameter, typically transporting 3,000 to 6,000 fat molecules per particle, and varying in size according to the number and mix of fat molecules contained within. [ 4 ]  The lipids carried include all fat molecules with  cholesterol ,  phospholipids , and  triglycerides  dominant; amounts of each vary considerably. [ 5 ]


A good clinical interpretation of blood lipid levels is that high LDL, in combination with a high amount of triglycerides, which indicates a high likelihood of the LDL being oxidised, is associated with increased risk of  cardiovascular diseases . [ 6 ]


Each native LDL particle enables emulsification, i.e. surrounding the fatty acids being carried, enabling these fats to move around the body within the water outside cells. Each particle contains a single  apolipoprotein  B-100 molecule ( Apo B-100 , a protein that has 4536  amino acid  residues and a mass of 514  kDa ), along with 80 to 100 additional ancillary proteins. Each LDL has a highly hydrophobic core consisting of  polyunsaturated fatty acid  known as  linoleate  and hundreds to thousands (about 1500 commonly cited as an average) of  esterified  and unesterified cholesterol molecules. This core also carries varying numbers of triglycerides and other fats and is surrounded by a shell of phospholipids and unesterified cholesterol, as well as the single copy of Apo B-100. LDL particles are approximately 22 nm (0.00000087 in.) to 27.5 nm in diameter and have a mass of about 3 million daltons. [ 7 ]  Since LDL particles contain a variable and changing number of fatty acid molecules, there is a distribution of LDL particle mass and size. [ 4 ]  Determining the structure of LDL has been difficult for biochemists because of its heterogeneous structure. However, the structure of LDL at human body temperature in native condition, with a resolution of about 16  Angstroms  using  cryogenic electron microscopy , has been described in 2011. [ 8 ]


LDL particles are formed when triglycerides are removed from VLDL by the  lipoprotein lipase  enzyme (LPL) and they become smaller and denser (i.e. fewer fat molecules with same protein transport shell), containing a higher proportion of cholesterol esters. [ 9 ] [ 10 ]


When a cell requires additional cholesterol (beyond its current internal  HMGCoA  production pathway), it synthesizes the necessary  LDL receptors  as well as  PCSK9 , a  proprotein convertase  that marks the LDL receptor for degradation. [ 11 ]  LDL receptors are inserted into the plasma membrane and diffuse freely until they associate with  clathrin -coated pits. When LDL receptors bind LDL particles in the bloodstream, the clathrin-coated pits are endocytosed into the cell. [ citation needed ]


Vesicles containing LDL receptors bound to LDL are delivered to the  endosome . In the presence of low  pH , such as that found in the endosome, LDL receptors undergo a conformation change, releasing LDL. LDL is then shipped to the  lysosome , where  cholesterol esters  in the LDL are  hydrolysed . LDL receptors are typically returned to the plasma membrane, where they repeat this cycle. If LDL receptors bind to PCSK9, however, transport of LDL receptors is redirected to the lysosome, where they are degraded. [ 12 ]


LDL interferes with the  quorum sensing  system that upregulates genes required for invasive  Staphylococcus aureus  infection. The mechanism of antagonism entails binding apolipoprotein B to a  S. aureus   autoinducer  pheromone, preventing signaling through its receptor. Mice deficient in apolipoprotein B are more susceptible to invasive bacterial infection. [ 13 ]


LDL can be grouped based on its size: large low density LDL particles are described as  pattern A , and small high density LDL particles are  pattern B . [ 14 ]   Pattern B  has been associated by some with a higher risk for  coronary heart disease . [ 15 ] : 1–10   This is thought to be because the smaller particles are more easily able to penetrate the  endothelium  of  arterial walls .  Pattern I , for  intermediate , indicates that most LDL particles are very close in size to the normal gaps in the endothelium (26 nm). According to one study, sizes 19.0–20.5 nm were designated as pattern B and LDL sizes 20.6–22 nm were designated as pattern A. [ 16 ]  Other studies have shown no such correlation at all. [ 17 ]


Some evidence suggests the correlation between Pattern B and coronary heart disease is stronger than the correspondence between the LDL number measured in the standard lipid profile test. Tests to measure these LDL subtype patterns have been more expensive and not widely available, so the common lipid profile test is used more often. [ 15 ]


There has also been noted a correspondence between higher triglyceride levels and higher levels of smaller, denser LDL particles and alternately lower triglyceride levels and higher levels of the larger, less dense ("buoyant") LDL. [ 18 ] [ 19 ]


With continued research, decreasing cost, greater availability and wider acceptance of other  lipoprotein subclass analysis  assay methods, including  NMR spectroscopy , research studies have continued to show a stronger correlation between human clinically obvious cardiovascular events and quantitatively measured particle concentrations. [ 20 ]


Oxidized LDL is a general term for LDL particles with oxidatively modified structural components. As a result, from  free radical  attack, both lipid and protein parts of LDL can be oxidized in the vascular wall. Besides the oxidative reactions taking place in vascular wall, oxidized lipids in LDL can also be derived from oxidized dietary lipids. [ 21 ] [ 22 ]   Oxidized LDL is known to associate with the development of  atherosclerosis , and it is therefore widely studied as a potential risk factor of  cardiovascular diseases . [ 23 ]  Atherogenicity of oxidized LDL has been explained by lack of recognition of oxidation-modified LDL structures by the LDL receptors, preventing the normal metabolism of LDL particles and leading eventually to development of atherosclerotic plaques. [ 23 ]  Of the lipid material contained in LDL, various lipid oxidation products are known as the ultimate atherogenic species. [ 24 ]  Acting as a transporter of these injurious molecules is another mechanism by which LDL can increase the risk of atherosclerosis. [ 22 ] [ 25 ]


Blood tests  commonly report LDL-C: the amount of cholesterol which is estimated to be contained with LDL particles, on average, using a formula, the  Friedewald equation . In clinical context, mathematically calculated estimates of LDL-C are commonly used as an estimate of how much low density lipoproteins are driving progression of atherosclerosis. The problem with this approach is that LDL-C values are commonly discordant with both direct measurements of LDL particles and actual rates of atherosclerosis progression. [ citation needed ]


Direct LDL measurements are also available and better reveal individual issues but are less often promoted or done due to slightly higher costs and being available from only a couple of laboratories in the  United States . In 2008, the  ADA  and  ACC  recognized direct LDL particle measurement by NMR as superior for assessing individual risk of cardiovascular events. [ 26 ]


Chemical measures of lipid concentration have long been the most-used clinical measurement, not because they have the best correlation with individual outcome, but because these lab methods are less expensive and more widely available.


The lipid profile does not measure LDL particles. It only estimates them using the Friedewald equation [ 19 ] [ 27 ]
by subtracting the amount of cholesterol associated with other particles, such as  HDL  and VLDL, assuming a prolonged fasting state, etc.:


There are limitations to this method, most notably that samples must be obtained after a 12 to 14 h fast and that LDL-C cannot be calculated if plasma triglyceride is >4.52 mmol/L (400 mg/dL). Even at triglyceride levels 2.5 to 4.5 mmol/L, this formula is considered inaccurate. [ 28 ]   If both total cholesterol and triglyceride levels are elevated then a modified formula, with quantities in mg/dL, may be used


This formula provides an approximation with fair accuracy for most people, assuming the blood was drawn after fasting for about 14 hours or longer, but does not reveal the actual LDL particle concentration because the percentage of fat molecules within the LDL particles which are cholesterol varies, as much as 8:1 variation. There  are several formulas published addressing the inaccuracy in LDL-C estimation. [ 29 ] [ 30 ] [ 31 ]  The inaccuracy is based on the assumption that VLDL-C (Very low density lipoprotein cholesterol) is always one-fifth of the triglyceride concentration. Another formulae addresses this issue by using an adjustable factor  [ 32 ]  or by using a regression equation. [ 33 ]  There are few studies which have compared the LDL-C values derived from this formula and values obtained by direct enzymatic method. [ 34 ]  Direct enzymatic method are found to be accurate and it has to be the test of choice in clinical situations. In the resource poor settings, the option of using the formula has to be considered. [ 34 ]


However, the concentration of LDL particles, and to a lesser extent their size, has a stronger and consistent correlation with individual clinical outcome than the amount of cholesterol within LDL particles, even if the LDL-C estimation is approximately correct. There is increasing evidence and recognition of the value of more targeted and accurate measurements of LDL particles. Specifically, LDL particle number (concentration), and to a lesser extent size, have shown slightly stronger correlations with atherosclerotic progression and cardiovascular events than obtained using chemical measures of the amount of cholesterol carried by the LDL particles. [ 35 ]  It is possible that the LDL cholesterol concentration can be low, yet LDL particle number high and cardiovascular events rates are high. Correspondingly, it is possible that LDL cholesterol concentration can be relatively high, yet LDL particle number low and cardiovascular events are also low. [ citation needed ]


In the US, the  American Heart Association ,  NIH , and  NCEP  provide a set of guidelines for fasting LDL-Cholesterol levels, estimated or measured, and risk for heart disease. As of about 2005, these guidelines were: [ 36 ] [ 37 ] [ 38 ]


Over time, with more clinical research, these recommended levels keep being reduced because LDL reduction, including to abnormally low levels, was the most effective strategy for reducing cardiovascular death rates in one large  double blind , randomized clinical trial of men with  hypercholesterolemia ; [ 39 ]  far more effective than coronary angioplasty/stenting or bypass surgery. [ 40 ]


For instance, for people with known atherosclerosis diseases, the 2004 updated American Heart Association, NIH and NCEP recommendations are for LDL levels to be lowered to less than 70 mg/dL. This low level of less than 70 mg/dL was recommended for primary prevention of 'very-high risk patients' and in secondary prevention as a 'reasonable further reduction'. This position was disputed. [ 41 ]  Statin drugs involved in such clinical trials have  numerous physiological effects  beyond simply the reduction of LDL levels.


From longitudinal population studies following progression of atherosclerosis-related behaviors from early childhood into adulthood, [ 42 ]  the usual LDL in childhood, before the development of  fatty streaks , is about 35 mg/dL. However, all the above values refer to chemical measures of lipid/cholesterol concentration within LDL, not measured low-density lipoprotein concentrations, the accurate approach. [ 35 ]


A study was conducted measuring the effects of guideline changes on LDL cholesterol reporting and control for diabetes visits in the US from 1995 to 2004. It was found that although LDL cholesterol reporting and control for diabetes and coronary heart disease visits improved continuously between 1995 and 2004, [ 43 ] [ 44 ]  neither the 1998 ADA guidelines nor the 2001 ATP III guidelines increased LDL cholesterol control for diabetes relative to coronary heart disease. [ 45 ]


There are several competing methods for measurement of lipoprotein particle concentrations and size. The evidence is that the NMR methodology (developed, automated & greatly reduced in costs while improving accuracy as pioneered by  Jim Otvos  and associates) results in a 22-25% reduction in cardiovascular events within one year, [ 46 ]  contrary to the longstanding claims by many in the medical industry that the superiority over existing methods was weak, even by statements of some proponents. [ 47 ]


Since the later 1990s, because of the development of NMR measurements, it has been possible to clinically measure lipoprotein particles at lower cost [under $80 US (including shipping) & is decreasing; versus the previous costs of >$400 to >$5,000] and higher accuracy. There are two other assays for LDL particles, however, like LDL-C, most only estimate LDL particle concentrations. [ citation needed ]


Direct LDL particle measurement by NMR was mentioned by the ADA and ACC, in a 28 March 2008 joint consensus statement, [ 48 ]  as having advantages for predicting individual risk of atherosclerosis disease events, but the statement noted that the test is less widely available, is more expensive [about $13.00 US (2015 without insurance coverage) from some labs which use the Vantera Analyzer [ 49 ] ]. Debate continues that it is "...unclear whether LDL particle size measurements add value to measurement of LDL-particle concentration", though outcomes have always tracked LDL particle, not LDL-C, concentrations.


Using NMR, the total LDL particle concentrations, in nmol/L plasma, are typically subdivided by percentiles referenced to the 5,382 men and women, not on any lipid medications, who are participating in the MESA trial. [ 50 ]


LDL particle concentration can also be measured by measuring the concentration of the protein ApoB, based on the generally accepted principle that each LDL or VLDL particle carries one ApoB molecule. [ 51 ]


The LDL particle concentrations are typically categorized by percentiles, <20%, 20–50%, 50th–80th%, 80th–95% and >95% groups of the people participating and being tracked in the  MESA trial , a medical research study sponsored by the United States National Heart, Lung, and Blood Institute.


The lowest incidence of atherosclerotic events over time occurs within the <20% group, with increased rates for the higher groups.  [ citation needed ]  Multiple other measures, including particle sizes, small LDL particle concentrations, large total and HDL particle concentrations, along with estimations of  insulin resistance  pattern and standard cholesterol lipid measurements (for comparison of the plasma data with the estimation methods discussed above) are also routinely provided.


(Per 2004 United States Government Minimum Guidelines [ 52 ] [ 53 ] )


The  mevalonate pathway  serves as the basis for the biosynthesis of many molecules, including cholesterol. The enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase ( HMG CoA reductase ) is an essential component and performs the first of 37 steps within the cholesterol production pathway, and is present in every animal cell. [ citation needed ]


LDL-C is not a measurement of actual LDL particles. LDL-C is only an estimate (not measured from the individual's blood sample) of how much cholesterol is being transported by all LDL particles, which is either a smaller concentration of large particles or a high concentration of small particles. LDL particles carry many fat molecules (typically 3,000 to 6,000 fat molecules per LDL particle); this includes cholesterol, triglycerides, phospholipids and others. Thus even if the hundreds to thousands of cholesterol molecules within an average LDL particle were measured, this does not reflect the other fat molecules or even the number of LDL particles.


LDL cholesterol can be lowered through dietary intervention by limiting foods with  saturated fat  and avoiding foods with  trans fat . [ 65 ]  Saturated fats are found in meat products (including poultry), full-fat dairy, eggs, and refined tropical oils like coconut and palm. [ 66 ]  Added trans fat (in the form of partially hydrogenated oils) has been banned in the US since 2021. [ 67 ]  However, trans fat can still be found in red meat and dairy products as it is produced in small amounts by ruminants such as sheep and cows. [ 68 ]  LDL cholesterol can also be lowered by increasing consumption of soluble fiber and plant-based foods. [ 69 ]


Another lifestyle approach to reduce LDL cholesterol has been minimizing total body fat, in particular fat stored inside the  abdominal cavity  ( visceral body fat ). Visceral fat, which is more metabolically active than subcutaneous fat, has been found to produce many enzymatic signals, e.g.  resistin , which increase  insulin resistance  and circulating VLDL particle concentrations, thus both increasing LDL particle concentrations and accelerating the development of diabetes mellitus.


In 2021, scientists demonstrated that  CRISPR gene editing  can decrease blood levels of LDL cholesterol in  Macaca fascicularis  monkeys for months by 60% via  knockout  of  PCSK9  in the  liver . [ 70 ] [ 71 ]


Marden–Walker syndrome  ( MWS ) is a rare  autosomal   recessive   congenital disorder . [ 1 ] [ 2 ]  It is characterized by  blepharophimosis ,  microcephaly ,  micrognathia , multiple  joint   contractures ,  arachnodactyly ,  camptodactyly ,  kyphoscoliosis  and delayed  motor development  and is often associated with  cystic   dysplastic   kidneys ,  dextrocardia ,  Dandy–Walker malformation  and  agenesis of corpus callosum . [ 3 ]


Most of the signs of MWS are present during the neonatal period. The most common signs at this state are multiple congenital joint contractures, dysmorphic features with mask-like face,  blepharophimosis ,  ptosis ,  micrognathia , cleft or high arched palate, low-set ears,  arachnodactyly , chest deformation as pectus,  kyphoscoliosis  and absent deep tendon reflexes are frequent minor malformations have also been described and consist of renal anomalies, cardiovascular abnormalities,  hypospadias ,  omphalomesenteric  duct, hypertrophic pyloric stenosis and duodenal bands, hypoplastic right lower lobe of the lung, displacement of the  larynx  to the right and vertebral abnormalities, cerebral malformations. [ 4 ]


The natural history of MWS is not well known: many patients died in infancy and clinical follow-up has been reported in few surviving adults. However, diagnosis may be more difficult to establish in adults patients, such as:  blepharophimosis ,  contractures ,  growth retardation , and  developmental delay , whereas minor face anomalies are less noticeable as the patient grows older. [ 5 ]


MWS is a  heterogeneous , initially described as a syndrome. But this condition is more on the lines of a  phenotypic  expression of various heterogeneous diseases and belongs to the second group in the classification of  arthrogryposis . Unknown congenital  myopathy  has been suspected to underlie MWS due to muscular involvement, but extension of the  neuromuscular  systems failed to identify a primary myopathy in patients with MWS. Secondary muscle involvement from a CNS lesion may occur. This could lead to congenital weakness with hypoatonia deep tendon reflex. [ 6 ]


MWS is inherited in an autosomal recessive manner. [ 2 ]  This means the defective gene responsible for the disorder is located on an  autosome , and two copies of the defective gene (one inherited from each parent) are required in order to be born with the disorder. The parents of an individual with an autosomal recessive disorder both  carry  one copy of the defective gene, but usually do not experience any signs or symptoms of the disorder. [ citation needed ]


Though the pathomechanism of Marden–Walker syndrome is unknown, it may be caused by a genetic defect which manifests as a  dysfunctional molecular mechanism  in the primary  cilia  structures of the  cell .  These  organelles  are present in many cellular types throughout the  human  body.  The cilia defects adversely affect "numerous critical developmental signaling pathways" essential to cellular development. [ 3 ]


The only treatment for MWS is only symptomatic, with multidisciplinary management [ 7 ]


There have been 30 cases of Marden-Walker Syndrome reported since 1966. The first case of this was in 1966 a female infant was diagnosed with  blepharophimosis ,  joint contractures , arachnodactyly and growth development delay. She ended up dying at 3 months due to pneumonia. [ citation needed ]


Multicenter Automatic Defibrillator Implantation Trial [ 1 ]  and MADIT II [ 2 ]   are  implantable cardioverter defibrillator  (or ICD) trials which investigate whether prophylactic ICD therapy in moderately high-risk  coronary  patients (in addition to conventional therapy) would significantly reduce death compared with patients treated with conventional therapy alone.