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Keywords: heart failure, heart failure with reduced ejection fraction, sacubitril/valsartan, ARNI, neprilysin inhibition Author: Domingo Pascual-Figal and Nicolás Manito Creator: LaTeX with hyperref package + hypdvips Producer: dvips + MiKTeX GPL Ghostscript 9.0 CreationDate: Fri Nov 5 10:26:47 2021 CET ModDate: Fri Nov 5 10:38:24 2021 CET Custom Metadata: no Metadata Stream: yes Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 21 Encrypted: no Page size: 595.26 x 779.52 pts Page rot: 0 File size: 2648394 bytes Optimized: no PDF version: 1.6 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- NHTPZF+HelveticaNeueLTStd-Bd Type 1C Custom yes yes no 53 0 DZBQSK+HelveticaNeueLTStd-Lt Type 1C Custom yes yes no 58 0 PUGCYQ+HelveticaNeueLTStd-BdIt Type 1C WinAnsi yes yes no 71 0 NIHHOA+HelveticaNeueLTStd-LtIt Type 1C Custom yes yes no 73 0 NJKOEF+HelveticaNeueLTStd-MdIt Type 1C WinAnsi yes yes no 79 0 OOXZRM+MTSY Type 1C Custom yes yes no 97 0 HHCDKO+MinionPro-It Type 1C Custom yes yes no 116 0 OBAZBH+RMTMI Type 1C WinAnsi yes yes no 118 0 IKFAEG+MinionPro-Regular Type 1C Custom yes yes no 87 0 NOVLOK+MinionPro-Bold Type 1C Custom yes yes no 140 0 QLRTYW+HelveticaNeueLTStd-Md Type 1C WinAnsi yes yes no 315 0 UADLTO+MTSYB Type 1C Custom yes yes no 426 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2025-11-23 05:26:05 CET RepresentationInformation: pmc_34859070.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2023-03-31 12:06:26 CEST Size: 2648394 Format: PDF Version: 1.6 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 651 FreeObjects: 26 IncrementalUpdates: 0 DocumentCatalog: ViewerPreferences: HideToolbar: false HideMenubar: false HideWindowUI: false FitWindow: true CenterWindow: false DisplayDocTitle: false NonFullScreenPageMode: UseNone Direction: L2R ViewArea: CropBox ViewClip: CropBox PrintArea: CropBox PageClip: CropBox PageLayout: SinglePage PageMode: UseOutlines Language: en Outlines: Item: Title: Sacubitril-Valsartan, Clinical Benefits and Related Mechanisms of Action in Heart Failure With Reduced Ejection Fraction. A Review Destination: ariclecounter.1 Children: Item: Title: Introduction Destination: section*.2 Item: Title: Mortality, Sudden Death, and Ventricular Arrhythmias Destination: section*.3 Children: Item: Title: Reduced Mortality in HF Patients Destination: section*.4 Item: Title: Reduction of CV Mortality Due to Sudden Death Destination: section*.5 Item: Title: Effect on Ventricular Arrhythmias Destination: section*.6 Item: Title: Mechanism of Action of ARNIs in Mortality Reduction Destination: section*.7 Item: Title: Clinical Progression: Hospitalization and Rehospitalization Destination: section*.8 Children: Item: Title: Prevention of Hospitalizations in Chronic HFrEF Destination: section*.9 Item: Title: Prevention of Hospitalization in Acutely Decompensated HF Destination: section*.10 Item: Title: Relationship Between HF Hospitalization and Disease Progression Destination: section*.11 Item: Title: Cardiac Remodeling and Neprilysin Inhibition Destination: section*.12 Children: Item: Title: Effects of Sacubitril/Valsartan on the Pathophysiology of Myocardial Remodeling Destination: section*.13 Item: Title: Effects of Sacubitril-Valsartan on Cardiac Geometry and Function Destination: section*.14 Item: Title: Hemodynamic Effects of Neprilysin Inhibition Destination: section*.15 Item: Title: Biomarkers: NPs, Troponins, and ST2 Destination: section*.16 Children: Item: Title: HF Biomarkers Destination: section*.17 Item: Title: NT-ProBNP Destination: section*.18 Item: Title: HsTnT Destination: section*.19 Item: Title: ST2 Destination: section*.20 Item: Title: Renal Impact of Neprilysin Inhibition Destination: section*.21 Children: Item: Title: Mechanistic Effects of the Renal Impact of Neprilysin Inhibition Destination: section*.22 Item: Title: Clinical Consequences of the Renal Impact of the Neprilysin Inhibition Destination: section*.23 Children: Item: Title: Heart Failure Destination: section*.24 Item: Title: Chronic Kidney Disease Destination: section*.25 Item: Title: Metabolic Effects: T2DM and Uric Acid Destination: section*.26 Children: Item: Title: HF and T2DM Destination: section*.27 Item: Title: HF and Uric Acid Destination: section*.28 Item: Title: Quality of Life and Functional Capacity Destination: section*.29 Children: Item: Title: Quality of Life Destination: section*.30 Item: Title: Functional Capacity Destination: section*.31 Item: Title: Safety: Renal Failure, Hyperkalemia, Hypotension, Angioedema, in Outpatients and Hospitalized Patients Destination: section*.32 Children: Item: Title: Renal Insufficiency Destination: section*.33 Item: Title: Hyperkalemia Destination: section*.34 Item: Title: Arterial Hypotension Destination: section*.35 Item: Title: Angioedema Destination: section*.36 Item: Title: Tolerance Destination: section*.37 Item: Title: Discussion Destination: section*.38 Item: Title: Author Contributions Destination: section*.39 Item: Title: Funding Destination: section*.40 Item: Title: References Destination: section*.41 Info: Title: Sacubitril-Valsartan, Clinical Benefits and Related Mechanisms of Action in Heart Failure With Reduced Ejection Fraction. A Review Author: Domingo Pascual-Figal and Nicolás Manito Subject: Heart failure (HF) is a clinical syndrome characterized by the presence of dyspnea or limited exertion due to impaired cardiac ventricular filling and/or blood ejection. Keywords: heart failure, heart failure with reduced ejection fraction, sacubitril/valsartan, ARNI, neprilysin inhibition Creator: LaTeX with hyperref package + hypdvips Producer: dvips + MiKTeX GPL Ghostscript 9.0 CreationDate: Fri Nov 05 10:56:47 CET 2021 ModDate: Fri Nov 05 11:08:24 CET 2021 ID: 0xa5eba8e0cd3890cc43f134ad3c390ad9, 0xf4882d96c9c1ed4780b8cbe1dbb35b54 Filters: FilterPipeline: FlateDecode FilterPipeline: DCTDecode Images: Image: NisoImageMetadata: FormatName: image/png ImageWidth: 279 ImageHeight: 279 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Filter: FlateDecode Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 1536 ImageHeight: 1128 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Interpolate: true Image: NisoImageMetadata: FormatName: image/jpg CompressionScheme: JPEG ImageWidth: 1776 ImageHeight: 936 ColorSpace: RGB BitsPerSample: 8 BitsPerSampleUnit: integer Interpolate: true Image: NisoImageMetadata: 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Domingo Pascual-Figal and Nicolás Manito Sacubitril-Valsartan, Clinical Benefits and Related Mechanisms of Action in Heart Failure With Reduced Ejection Fraction. 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157, 29, 217, 37 Annotation: Subtype: Link Rect: 418, 29, 551, 38 Page: Label: 13 Sequence: 13 Annotations: Annotation: Subtype: Link Rect: 178, 182, 189, 194 Destination: External Annotation: Subtype: Link Rect: 264, 148, 275, 159 Destination: External Annotation: Subtype: Link Rect: 109, 68, 120, 79 Destination: External Annotation: Subtype: Link Rect: 504, 171, 515, 182 Destination: External Annotation: Subtype: Link Rect: 452, 90, 463, 101 Destination: External Annotation: Subtype: Link Rect: 43, 30, 154, 38 Annotation: Subtype: Link Rect: 157, 29, 217, 37 Annotation: Subtype: Link Rect: 418, 29, 551, 38 Page: Label: 14 Sequence: 14 Annotations: Annotation: Subtype: Link Rect: 327, 351, 337, 361 Destination: External Annotation: Subtype: Link Rect: 87, 205, 98, 217 Destination: External Annotation: Subtype: Link Rect: 224, 171, 236, 182 Destination: External Annotation: Subtype: Link Rect: 169, 91, 180, 102 Destination: External Annotation: Subtype: Link Rect: 81, 65, 116, 76 Destination: External Annotation: Subtype: Link Rect: 307, 274, 323, 285 Destination: External Annotation: Subtype: Link Rect: 539, 78, 546, 90 Destination: External Annotation: Subtype: Link Rect: 43, 30, 154, 38 Annotation: Subtype: Link Rect: 157, 29, 217, 37 Annotation: Subtype: Link Rect: 418, 29, 551, 38 Page: Label: 15 Sequence: 15 Annotations: Annotation: Subtype: Link Rect: 130, 434, 145, 446 Destination: External Annotation: Subtype: Link Rect: 47, 423, 62, 434 Destination: External Annotation: Subtype: Link Rect: 267, 274, 283, 285 Destination: External Annotation: Subtype: Link Rect: 47, 228, 62, 239 Destination: External Annotation: Subtype: Link Rect: 254, 217, 269, 228 Destination: External Annotation: Subtype: Link Rect: 244, 194, 260, 205 Destination: External Annotation: Subtype: Link Rect: 253, 146, 287, 156 Destination: External Annotation: Subtype: Link Rect: 47, 136, 62, 148 Destination: External Annotation: Subtype: Link Rect: 238, 136, 253, 148 Destination: External Annotation: Subtype: Link Rect: 493, 446, 509, 457 Destination: External Annotation: Subtype: Link Rect: 365, 388, 380, 400 Destination: External Annotation: Subtype: Link Rect: 507, 354, 523, 366 Destination: External Annotation: Subtype: Link Rect: 515, 125, 546, 133 Destination: External Annotation: Subtype: Link Rect: 389, 78, 396, 90 Destination: External Annotation: Subtype: Link Rect: 43, 30, 154, 38 Annotation: Subtype: Link Rect: 157, 29, 217, 37 Annotation: Subtype: Link Rect: 418, 29, 551, 38 Page: Label: 16 Sequence: 16 Annotations: Annotation: Subtype: Link Rect: 322, 691, 328, 700 Destination: External Annotation: Subtype: Link Rect: 481, 691, 486, 700 Destination: External Annotation: Subtype: Link Rect: 197, 491, 209, 502 Destination: External Annotation: Subtype: Link Rect: 274, 468, 285, 479 Destination: External Annotation: Subtype: Link Rect: 240, 433, 251, 445 Destination: External Annotation: Subtype: Link Rect: 255, 433, 266, 445 Destination: External Annotation: Subtype: Link Rect: 118, 388, 129, 399 Destination: External Annotation: Subtype: Link Rect: 151, 376, 158, 388 Destination: External Annotation: Subtype: Link Rect: 216, 307, 227, 319 Destination: External Annotation: Subtype: Link Rect: 191, 284, 206, 296 Destination: External Annotation: Subtype: Link Rect: 156, 227, 162, 239 Destination: External Annotation: Subtype: Link Rect: 126, 181, 133, 193 Destination: External Annotation: Subtype: Link Rect: 150, 124, 165, 135 Destination: External Annotation: Subtype: Link Rect: 440, 502, 456, 514 Destination: External Annotation: Subtype: Link Rect: 338, 468, 353, 479 Destination: External Annotation: Subtype: Link Rect: 499, 416, 506, 428 Destination: External Annotation: Subtype: Link Rect: 508, 416, 515, 428 Destination: External Annotation: Subtype: Link Rect: 322, 405, 338, 416 Destination: External Annotation: Subtype: Link Rect: 463, 405, 469, 416 Destination: External Annotation: Subtype: Link Rect: 353, 324, 364, 336 Destination: External Annotation: Subtype: Link Rect: 433, 267, 444, 279 Destination: External Annotation: Subtype: Link Rect: 430, 256, 441, 267 Destination: External Annotation: Subtype: Link Rect: 359, 198, 370, 210 Destination: External Annotation: Subtype: Link Rect: 392, 176, 408, 187 Destination: External Annotation: Subtype: Link Rect: 422, 135, 429, 147 Destination: External Annotation: Subtype: Link Rect: 506, 124, 517, 135 Destination: External Annotation: Subtype: Link Rect: 43, 30, 154, 38 Annotation: Subtype: Link Rect: 157, 29, 217, 37 Annotation: Subtype: Link Rect: 418, 29, 551, 38 Page: Label: 17 Sequence: 17 Annotations: Annotation: Subtype: Link Rect: 131, 662, 138, 674 Destination: External Annotation: Subtype: Link Rect: 199, 628, 215, 639 Destination: External Annotation: Subtype: Link Rect: 182, 594, 189, 605 Destination: External Annotation: Subtype: Link Rect: 176, 571, 183, 582 Destination: External Annotation: Subtype: Link Rect: 174, 420, 185, 431 Destination: External Annotation: Subtype: Link Rect: 239, 385, 245, 397 Destination: External Annotation: Subtype: Link Rect: 358, 685, 364, 697 Destination: External Annotation: Subtype: Link Rect: 367, 685, 374, 697 Destination: External Annotation: Subtype: Link Rect: 368, 651, 379, 662 Destination: External Annotation: Subtype: Link Rect: 382, 651, 397, 662 Destination: External Annotation: Subtype: Link Rect: 493, 582, 504, 594 Destination: External Annotation: Subtype: Link Rect: 508, 582, 519, 594 Destination: External Annotation: Subtype: Link Rect: 522, 582, 533, 594 Destination: External Annotation: Subtype: Link Rect: 466, 571, 472, 582 Destination: External Annotation: Subtype: Link Rect: 522, 571, 533, 582 Destination: External Annotation: Subtype: Link Rect: 537, 571, 548, 582 Destination: External Annotation: Subtype: Link Rect: 375, 559, 386, 571 Destination: External Annotation: Subtype: Link Rect: 390, 559, 401, 571 Destination: External Annotation: Subtype: Link Rect: 430, 525, 436, 536 Destination: External Annotation: Subtype: Link Rect: 438, 525, 445, 536 Destination: External Annotation: Subtype: Link Rect: 447, 525, 463, 536 Destination: External Annotation: Subtype: Link Rect: 218, 255, 273, 265 Annotation: Subtype: Link Rect: 292, 209, 60, 228 Annotation: Subtype: Link Rect: 108, 181, 168, 189 Annotation: Subtype: Link Rect: 81, 142, 132, 151 Annotation: Subtype: Link Rect: 157, 114, 236, 122 Annotation: Subtype: Link Rect: 168, 96, 250, 104 Annotation: Subtype: Link Rect: 176, 67, 254, 75 Annotation: Subtype: Link Rect: 397, 303, 452, 312 Annotation: Subtype: Link Rect: 372, 246, 452, 255 Annotation: Subtype: Link Rect: 415, 208, 496, 217 Annotation: Subtype: Link Rect: 480, 161, 535, 170 Annotation: Subtype: Link Rect: 552, 103, 320, 124 Annotation: Subtype: Link Rect: 489, 66, 546, 75 Annotation: Subtype: Link Rect: 43, 29, 154, 37 Annotation: Subtype: Link Rect: 157, 28, 217, 36 Annotation: Subtype: Link Rect: 418, 28, 551, 37 Page: Label: 18 Sequence: 18 Annotations: Annotation: Subtype: Link Rect: 85, 669, 184, 678 Annotation: Subtype: Link Rect: 112, 621, 192, 631 Annotation: Subtype: Link Rect: 85, 583, 163, 593 Annotation: Subtype: Link Rect: 85, 527, 184, 536 Annotation: Subtype: Link Rect: 108, 489, 187, 498 Annotation: Subtype: Link Rect: 108, 461, 187, 469 Annotation: Subtype: Link Rect: 88, 404, 176, 413 Annotation: Subtype: Link Rect: 111, 358, 200, 365 Annotation: Subtype: Link Rect: 81, 329, 209, 337 Annotation: Subtype: Link Rect: 292, 281, 60, 300 Annotation: Subtype: Link Rect: 104, 233, 182, 242 Annotation: Subtype: Link Rect: 102, 195, 156, 205 Annotation: Subtype: Link Rect: 81, 148, 159, 157 Annotation: Subtype: Link Rect: 85, 112, 218, 119 Annotation: Subtype: Link Rect: 144, 93, 278, 100 Annotation: Subtype: Link Rect: 365, 697, 445, 706 Annotation: Subtype: Link Rect: 334, 651, 463, 659 Annotation: Subtype: Link Rect: 341, 612, 421, 621 Annotation: Subtype: Link Rect: 341, 564, 396, 574 Annotation: Subtype: Link Rect: 345, 509, 473, 517 Annotation: Subtype: Link Rect: 345, 470, 425, 479 Annotation: Subtype: Link Rect: 423, 422, 478, 432 Annotation: Subtype: Link Rect: 456, 394, 551, 403 Annotation: Subtype: Link Rect: 321, 385, 475, 394 Annotation: Subtype: Link Rect: 429, 347, 528, 356 Annotation: Subtype: Link Rect: 345, 311, 473, 318 Annotation: Subtype: Link Rect: 345, 262, 433, 271 Annotation: Subtype: Link Rect: 433, 214, 513, 223 Annotation: Subtype: Link Rect: 368, 186, 446, 195 Annotation: Subtype: Link Rect: 446, 148, 526, 157 Annotation: Subtype: Link Rect: 345, 93, 479, 100 Annotation: Subtype: Link Rect: 43, 30, 154, 38 Annotation: Subtype: Link Rect: 157, 29, 217, 37 Annotation: Subtype: Link Rect: 418, 29, 551, 38 Page: Label: 19 Sequence: 19 Annotations: Annotation: Subtype: Link Rect: 85, 680, 203, 687 Annotation: Subtype: Link Rect: 115, 632, 244, 640 Annotation: Subtype: Link Rect: 138, 593, 219, 602 Annotation: Subtype: Link Rect: 90, 557, 175, 564 Annotation: Subtype: Link Rect: 88, 517, 168, 526 Annotation: Subtype: Link Rect: 85, 479, 165, 489 Annotation: Subtype: Link Rect: 136, 441, 214, 450 Annotation: Subtype: Link Rect: 107, 405, 186, 413 Annotation: Subtype: Link Rect: 136, 377, 265, 384 Annotation: Subtype: Link Rect: 81, 328, 159, 337 Annotation: Subtype: Link Rect: 111, 292, 245, 299 Annotation: Subtype: Link Rect: 81, 254, 170, 261 Annotation: Subtype: Link Rect: 108, 205, 193, 214 Annotation: Subtype: Link Rect: 207, 176, 291, 186 Annotation: Subtype: Link Rect: 61, 169, 125, 176 Annotation: Subtype: Link Rect: 108, 92, 209, 101 Annotation: Subtype: Link Rect: 430, 699, 509, 706 Annotation: Subtype: Link Rect: 430, 670, 513, 678 Annotation: Subtype: Link Rect: 393, 631, 492, 640 Annotation: Subtype: Link Rect: 372, 593, 458, 602 Annotation: Subtype: Link Rect: 444, 565, 526, 573 Annotation: Subtype: Link Rect: 345, 518, 444, 526 Annotation: Subtype: Link Rect: 441, 489, 521, 498 Annotation: Subtype: Link Rect: 345, 470, 425, 479 Annotation: Subtype: Link Rect: 375, 422, 455, 431 Annotation: Subtype: Link Rect: 401, 385, 481, 394 Annotation: Subtype: Link Rect: 435, 347, 535, 356 Annotation: Subtype: Link Rect: 345, 318, 425, 327 Annotation: Subtype: Link Rect: 392, 301, 526, 308 Annotation: Subtype: Link Rect: 371, 235, 505, 242 Annotation: Subtype: Link Rect: 488, 195, 539, 205 Annotation: Subtype: Link Rect: 368, 169, 450, 176 Annotation: Subtype: Link Rect: 345, 139, 406, 148 Annotation: Subtype: Link Rect: 368, 110, 420, 119 Annotation: Subtype: Link Rect: 393, 72, 445, 82 Annotation: Subtype: Link Rect: 43, 30, 154, 38 Annotation: Subtype: Link Rect: 157, 29, 217, 37 Annotation: Subtype: Link Rect: 418, 29, 551, 38 Page: Label: 20 Sequence: 20 Annotations: Annotation: Subtype: Link Rect: 85, 678, 165, 687 Annotation: Subtype: Link Rect: 108, 650, 159, 659 Annotation: Subtype: Link Rect: 115, 613, 244, 621 Annotation: Subtype: Link Rect: 166, 576, 227, 583 Annotation: Subtype: Link Rect: 112, 527, 190, 536 Annotation: Subtype: Link Rect: 144, 489, 199, 498 Annotation: Subtype: Link Rect: 129, 460, 215, 469 Annotation: Subtype: Link Rect: 115, 424, 200, 431 Annotation: Subtype: Link Rect: 221, 394, 272, 403 Annotation: Subtype: Link Rect: 104, 347, 204, 356 Annotation: Subtype: Link Rect: 147, 309, 202, 318 Annotation: Subtype: Link Rect: 203, 290, 288, 299 Annotation: Subtype: Link Rect: 212, 262, 291, 271 Annotation: Subtype: Link Rect: 292, 223, 60, 243 Annotation: Subtype: Link Rect: 85, 186, 154, 195 Annotation: Subtype: Link Rect: 112, 157, 190, 166 Annotation: Subtype: Link Rect: 108, 120, 163, 129 Annotation: Subtype: Link Rect: 161, 82, 238, 91 Annotation: Subtype: Link Rect: 397, 689, 531, 696 Annotation: Subtype: Link Rect: 415, 650, 509, 659 Annotation: Subtype: Link Rect: 431, 612, 530, 621 Annotation: Subtype: Link Rect: 449, 585, 505, 593 Annotation: Subtype: Link Rect: 368, 546, 454, 555 Annotation: Subtype: Link Rect: 552, 489, 320, 508 Annotation: Subtype: Link Rect: 450, 460, 535, 470 Annotation: Subtype: Link Rect: 365, 422, 443, 431 Annotation: Subtype: Link Rect: 354, 385, 418, 394 Annotation: Subtype: Link Rect: 368, 347, 446, 356 Annotation: Subtype: Link Rect: 345, 309, 425, 318 Annotation: Subtype: Link Rect: 365, 262, 463, 271 Annotation: Subtype: Link Rect: 428, 214, 522, 224 Annotation: Subtype: Link Rect: 478, 176, 529, 186 Annotation: Subtype: Link Rect: 357, 129, 450, 138 Annotation: Subtype: Link Rect: 43, 30, 154, 38 Annotation: Subtype: Link Rect: 157, 29, 217, 37 Annotation: Subtype: Link Rect: 418, 29, 551, 38 Page: Label: 21 Sequence: 21 Annotations: Annotation: Subtype: Link Rect: 524, 649, 551, 656 Annotation: Subtype: Link Rect: 304, 640, 336, 647 Annotation: Subtype: Link Rect: 337, 640, 373, 648 Annotation: Subtype: Link Rect: 375, 640, 398, 647 Annotation: Subtype: Link Rect: 400, 639, 429, 648 Annotation: Subtype: Link Rect: 43, 30, 154, 38 Annotation: Subtype: Link Rect: 157, 29, 217, 37 Annotation: Subtype: Link Rect: 418, 29, 551, 38 Checksum: a5abc599 Type: CRC32 Checksum: 557e8b595e1684296e51e194770ab649 Type: MD5 Checksum: e71233efaa2812d803571830bb20c4f7714d1526 Type: SHA-1 Checksum: d3c5e8951063c5be53cb7c07b24f4e1ecdf404112fbe1fdb0ae24a2b5b3f03a1 Type: SHA-256